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Hypothesis and Theory ARTICLE

Front. Med., 04 January 2018 | https://doi.org/10.3389/fmed.2017.00239

Immunological Tolerance, Pregnancy, and Preeclampsia: The Roles of Semen Microbes and the Father

  • 1The Irish Centre for Fetal and Neonatal Translational Research (INFANT), University College Cork, Cork, Ireland
  • 2Department of Obstetrics and Gynecology, University College Cork, Cork, Ireland
  • 3Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
  • 4School of Chemistry, The University of Manchester, Manchester, United Kingdom
  • 5The Manchester Institute of Biotechnology, The University of Manchester, Manchester, United Kingdom

Although it is widely considered, in many cases, to involve two separable stages (poor placentation followed by oxidative stress/inflammation), the precise originating causes of preeclampsia (PE) remain elusive. We have previously brought together some of the considerable evidence that a (dormant) microbial component is commonly a significant part of its etiology. However, apart from recognizing, consistent with this view, that the many inflammatory markers of PE are also increased in infection, we had little to say about immunity, whether innate or adaptive. In addition, we focused on the gut, oral and female urinary tract microbiomes as the main sources of the infection. We here marshall further evidence for an infectious component in PE, focusing on the immunological tolerance characteristic of pregnancy, and the well-established fact that increased exposure to the father’s semen assists this immunological tolerance. As well as these benefits, however, semen is not sterile, microbial tolerance mechanisms may exist, and we also review the evidence that semen may be responsible for inoculating the developing conceptus (and maybe the placenta) with microbes, not all of which are benign. It is suggested that when they are not, this may be a significant cause of PE. A variety of epidemiological and other evidence is entirely consistent with this, not least correlations between semen infection, infertility and PE. Our view also leads to a series of other, testable predictions. Overall, we argue for a significant paternal role in the development of PE through microbial infection of the mother via insemination.

“In one of the last articles which he wrote, the late Professor F.J. Browne (1958) expressed the opinion that all the essential facts about pregnancy toxemia are now available and that all that is required to solve the problem is to fit them together in the right order, like the pieces of a jigsaw puzzle. (1)”

“It appears astonishing how little attention has been given in reproductive medicine to the maternal immune system over the last few decades. (2)”

Introduction

Preeclampsia (PE) is a multifactorial disease of pregnancy, in which the chief manifestations are hypertension and proteinuria (311). It is commonest in primigravidae, where it affects some 3–5% of such pregnancies worldwide (10, 12, 13), and is associated (if untreated) with high morbidity and mortality (1418). The incidence can be even greater in some geographical locations (19, 20). There is much literature on accompanying features, and, notwithstanding possible disease subdivisions (21, 22), the development of PE is typically seen as a “two-stage” process [e.g., Ref. (2329)], in which in a first stage incomplete remodeling of spiral arteries leads to poor placentation. In a second stage, the resulting stress, especially hypoxia-induced oxidative stress (3036) (and possibly hypoxia-reperfusion injury), then leads to the symptoms typical of later-pregnancy PE. However, the various actual originating causes of either of these two stages remain obscure. Many theories have been proposed [albeit a unitary explanation is unlikely (21)], and indeed, PE has been referred to as a “disease of theories” (1, 3739). The only effective “cure” is delivery (40, 41), which often occurs significantly preterm, with its attendant complications for both the neonate and in later life (42, 43). Consequently, it would be highly desirable to improve our understanding of the ultimate causes of PE, so that better prevention or treatments might be possible.

The “two-stage” theory is well established, and nothing we have to say changes it. However, none of this serves to explain what “initiating” or “external” factors are typically responsible for the poor placentation, inflammation, and other observable features of PE (44).

Microbes are ubiquitous in the environment, and one potential external or initiating factor is low-level microbial infection. In a recent review (44), we developed the idea (and summarized extensive evidence for it) that a significant contributor to PE might be a [largely dormant (4548) and non-replicating] microbiome within the placenta and related tissues, also detectable in blood and urine. Others [e.g., Ref. (4956)] have drawn similar conclusions. Interestingly, recent analyses (21, 57) of placental gene expression in PE implicate changes in the expression of triggering receptor on myeloid cells-1 and the metalloprotease INHA, and in one case (21) also lactotransferrin, that also occur during infection (5861). Although we highlighted the role of antibiotics as potentially preventative of PE (44), and summarized the significant evidence for that, we had relatively little to say about immunology, and ignored another well-known antidote to infectious organisms in the form of vaccines. There is certainly also an immune component to PE [e.g., Ref. (26, 6270) and below]. One of the main theories of (at least part of the explanation of) PE is that of “immune maladaptation” (62, 64, 66, 71). Thus, the main focus of the present analysis is to assess the extent to which there is any immunological evidence for a role of infectious agents (and the utility of immunotolerance to or immunosuppression of them) in PE. Figure 1 summarizes our review in the form of a “mind map” (72). We begin with the broad question of immunotolerance, before turning to an epidemiological analysis. A preprint has been lodged in bioRxiv (73).

FIGURE 1
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Figure 1. A “mind map” (72) of the review. Start at “midnight” and read clockwise.

Immune Tolerance in Pregnancy

Much of the original thinking on this dates back to Sir Peter Medawar (7479), who recognized that the paternal origin of potentially half the antigens of the fetus (80) created an immunological conundrum: it should normally be expected that the fetus’s alloantigens would cause it to be attacked by the maternal immune system as “foreign.” There would therefore have to be an “immune tolerance” (79, 8183). Historically it was believed that the fetus is largely “walled off” from the mother (84); however, we now appreciate (8588) that significant trafficking of fetal material across the placenta into the maternal circulation and vice versa occurs throughout pregnancy. Indeed, this is the basis for the development of non-invasive prenatal testing. In line with this, grams of trophoblast alloantigens are secreted daily into the maternal circulation during the third trimester (Figure 2), and this is related to the prevalence of PE (8995). Consequently, both the concept and the issue of immune tolerance are certainly both real and important. At all events, the immunobiology of the fetus has been treated in theory largely in the way that a transplanted graft is treated, and uteroplacental dysfunction [leading to PET and intrauterine growth restriction (IUGR)] has in some cases been regarded as a graft rejection [e.g., Ref. (70, 96102)]. Clearly there are relationships between the immunogenicity of the foreign agent and the responsiveness of the host; to this end, Zelante et al. (103) recognize the interesting similarities between tolerance to paternal alloantigens (as in pregnancy) and the tolerance observed in chronic fungal infections. This said, the host–graft analogy is increasingly seen as somewhat naive (104106).

FIGURE 2
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Figure 2. Effective lowering of the normal immunological response to fetal cell trafficking [sometimes referred to as “suppressed” but in fact a highly dynamic state (104, 106)] leads to a normal pregnancy, while its failure can lead to preeclampsia. We note too that other Thelper populations may play roles in the physiologic and pathologic immune interactions between mother and offspring.

The Clinical Course of Automimmune Disease during Pregnancy: An Inconsistent Effect

The seminal observation by Philip Hench that the symptoms of the rheumatoid arthritis (RA) were frequently and dramatically ameliorated by several conditions, including pregnancy (107), led to the discovery of cortisone (108) and gave unique insights into the complex interaction between the maternal immune system and the developing fetal/placental unit. Contemporary data suggests that the improvement in RA is not ubiquitous as first thought. Amongst all pregnant women about 25% of women have no improvement in their symptoms at any stage in pregnancy and in a small number of cases the disease may actually worsen (109). The process by which pregnancy affects disease activity in RA is not completely understood and several putative mechanisms have been proposed. Of interest, although plasma cortisol rises during pregnancy and was initially thought to be key in the amelioration of symptoms, there is actually no correlation between cortisol concentrations and disease state (110). It has also been reported that the degree of maternal and paternal MHC mismatch has been shown to correlate with the effect of the RA remission during pregnancy (111), leading to the hypothesis that the early immunological events in pregnancy that establish tolerance to the fetal allograft contribute to RA remission. Clearly, this may also account for the disparity in response to pregnancy. RA is not unique in being the only autoimmune disease to be profoundly altered by pregnancy. Although less well studied, non-infectious uveitis tends to improve during pregnancy from the second trimester onward, with the third trimester being associated with the lowest disease activity (112). Again, the mechanism underlying this phenomenon is not completely elucidated.

It is now generally accepted (113) that, notwithstanding the sweeping generalization, autoimmune diseases with a strong cellular (innate) pathophysiology (RA, multiple sclerosis) improve, whereas diseases characterized by autoantibody production such as systemic lupus erythematous and Grave’s disease tend toward increased severity in pregnancy.

We have previously reported an association between pregnancy and the risk of subsequent maternal autoimmune disease which was also related to the mode and gestation of delivery. There was an increased risk of autoimmune disease after cesarean section may be explained by amplified fetal cell traffic at delivery, while decreased risks after abortion may be due to the transfer of more primitive fetal stem cells (114).

Mechanisms of Immune Tolerance during Pregnancy

Following the recognition of maternal immunotolerance, a chief discovery was the choice of HLA-G, a gene with few alleles, for the antigens used at the placental interface. Thus, the idea that placental HLA-G proteins facilitate semiallogeneic pregnancy by inhibiting maternal immune responses to foreign (paternal) antigens via these actions on immune cells is now well established (115120).

It is also well established that regulatory T cells (Tregs) play an indispensable role in maintaining immunological unresponsiveness to self-antigens and in suppressing excessive immune responses deleterious to the host (121). Consequently, much of present thinking seems to involve a crucial role for Tregs in maintaining immunological tolerance during pregnancy (70, 77, 122132), with the result that effector T cells cannot accumulate within the decidua (the specialized stromal tissue encapsulating the fetus and placenta) (133).

In an excellent review, Williams et al. (134) remark “Regulatory T cells (Tregs) are a subset of inhibitory CD4+ helper T cells that function to curb the immune response to infection, inflammation, and autoimmunity.” “There are two developmental pathways of Tregs: thymic (tTreg) and extrathymic or peripheral (pTreg). tTregs appear to suppress autoimmunity, whereas pTregs may restrain immune responses to foreign antigens, such as those from diet, commensal bacteria, and allergens.” Their differential production is controlled by a transcription factor called Foxp3.

Further, “a Foxp3 enhancer, conserved noncoding sequence 1 (CNS1), essential for pTreg but dispensable for tTreg cell generation, is present only in placental mammals. It is suggested that during evolution, a CNS1-dependent mechanism of extrathymic differentiation of Treg cells emerged in placental animals to enforce maternal–fetal tolerance” (135).

Williams et al. conclude that “These findings indicate that maternal–fetal tolerance to paternal alloantigens is an active process in which pTregs specifically respond to paternal antigens to induce tolerance. Thus, therapies should aim not to suppress the maternal immune system but rather to enhance tolerance. These findings are consistent with an increase in the percentage of Tregs during pregnancy and with no such increase in women with recurrent pregnancy loss (136)” (134). Thus maternal tolerance is based on exposure to the paternal alloantigens, although mechanisms such as the haem oxygenase detoxification of haem from degrading erythrocytes (137) are also important. Note too that pregnancy loss is often caused by automimmune activity (138) (and see later).

Additionally, Treg cells have several important roles in the control of infection [e.g., Ref. (139144)]. These include moderating the otherwise potentially dangerous response to infection and being exploited by certain parasites to induce immunotolerance.

Finally, here, it is also recognized that the placenta does allow maternal IgG antibodies to pass to the fetus to protect it against infections. Also, foreign fetal cells persist in the maternal circulation (145) [as does fetal DNA (146, 147), nowadays used in prenatal diagnosis]. One cause of PE is clearly an abnormal immune response toward the placenta. There is substantial evidence for exposure to partner’s semen as prevention for PE, largely due to the absorption of several immune modulating factors present in seminal fluid (148). We discuss this in detail below.

Innate and Adaptive Immunity

Although they are not entirely independent (149, 150), and both respond to infection, it is usual to discriminate (the faster) innate and (the more leisurely) adaptive immune responses [e.g., Ref. (151155)]. As is well known [reviewed recently (156)], the innate immune system is responsible for the recognition of foreign organisms such as microbes. It would be particularly convenient if something in the immune response did actually indicate an infection rather than simply any alloantigen, but unfortunately—especially because of the lengthy timescale over which PE develops—innate responses tend to morph into adaptive ones. This means (i) that there may be specific signals from early innate events that may be more or less specific to innate responses and (ii) that it also does not exclude the use of particular patterns of immune responsive elements (157159) to characterize disease states.

An alteration of the immune system is widely recognized as an accompaniment to normal pregnancy (77, 104106, 127, 160162), and especially in PE (6365, 67, 6971, 163170), and it is worth looking at it a little more closely.

The innate immune system responds to microbial components such as lipopolysaccharide (LPS) via cell membrane receptors. Innate immune cells express a series of evolutionarily conserved receptors known as pattern-recognition receptors (PRRs). PRRs recognize and bind conserved sequences known as pathogen-associated molecular patterns (PAMPs). Bacterial LPS and peptidoglycan, and double stranded viral RNA are unique to microbes and act as canonical PAMPs, while the main family of PRRs is represented by the Toll-like receptors (TLRs) (171, 172). Downstream events, as with many others (173, 174) converge on the NF-κB system and/or interferon, leading to the release of a series of inflammatory cytokines such as IL-2, IL-6, IL-8, TNF-α, and especially IL-1β.

Matzinger’s “danger model” (175180) [and see Ref. (79) and Figure 3] suggested that activation of the immune system could be evoked by danger signals from endogenous molecules expelled from injured/damaged tissues, rather than simply from the recognition of non-self (although of course in the case of pregnancy some of these antigens are paternal alloantigens). Such endogenous molecules are referred to as damage-associated molecular patterns (DAMPs), but are not our focus here, albeit they likely have a role in at least some elements of PE (181). We shall see later, however, that Matzinger’s theory is entirely consistent with the kinds of microbial (and disease) tolerance that do seem to be an important part of pregnancy and PE [and see Ref. (182)].

FIGURE 3
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Figure 3. Matzinger’s “danger model” vs. the classical theory of self vs. self-nonself. Based on and redrawn from Ref. (178).

The maternal innate immune system plays an important role both in normal pregnancy and in particular in hypertensive disorders of pregnancy including preeclampsia (PE) (167, 183189). One persuasive and widely accepted view is that normal pregnancy is characterized by a low-grade systemic inflammatory response and specific metabolic changes, and that virtually all of the features of normal pregnancy are simply exaggerated in PE (44, 183, 190, 191). Certainly it is long established that “Normal pregnancy and PE both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis” (183), and there are innate immune defenses in the uterus during pregnancy (160). Normal pregnancy has been considered to be a Th2 type immunological state that favors immune tolerance in order to prevent fetal rejection (137). However, normal pregnancy actually fluctuates between pro- (implantation and placentation; parturition) and anti-inflammatory (fetal growth) phases (105, 106). By contrast, PE has been classically described as a Th1/Th2 imbalance (125, 164, 192194), but as mentioned above [and before (44)], recent studies have highlighted the role of Tregs as part of a Th1/Th2/Th17 paradigm (167, 168). This leads to the question of whether there is some kind of trade-off between the responses to paternal alloantigens and those of microbes.

A Trade-Off for Mating and Immune Defense against Infection

Certainly there is some evidence for a trade-off between mating and immune defense against infection (195197). Consistent with this (albeit with much else) is the fact (198200) that pregnancy is associated with an increased severity of at least some infectious diseases. There is evidence (201, 202) that “adaptive immune responses are weakened, potentially explaining reduced viral clearance. Evidence also suggests a boosted innate response, which may represent a compensatory immune mechanism to protect the pregnant mother and the fetus and which may imply decreased susceptibility to initial infection” (199).

The Role(S) of Complement in PE

Complement, or more accurately the complement cascade, is an important part of the innate immune system that responds to infection. Later (downstream) elements also respond to the adaptive immune system. Our previous review (44) listed many proteins whose concentrations are changed in both infection and PE. Since we regard low-level infection as a major cause of the inflammation observed in PE, one would predict that the complement system is activated in PE, and this observation is amply borne out (203217). Some of the details are mentioned in Table 1.

TABLE 1
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Table 1. Changes in the complement system during PE and related pregnancy disorders.

The complement cascade may be activated in three main ways (Figure 4), known as classical, alternative or lectin pathways (150, 206, 208, 228, 229). Complement activation by the classical, alternative or lectin pathway results in the generation of split products C3a, C4a, and C5a with proinflammatory properties.

FIGURE 4
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Figure 4. The complement system [based on figures in Ref. (155, 208)].

Because both innate and adaptive immunity can activate elements of the downstream complement system, it is hard to be definitive, but there is some evidence that elements such as Ba and Bb [the latter of known structure (230)] are selectively released during infection, very much upstream and in the alternative pathway (208, 228, 229, 231233). Most importantly (Table 1), while probably not a specific serum marker, there is considerable evidence that Bb levels are increased in PE, arguably providing further evidence for a role of infectious agents in the etiology of PE.

We might also note that C1q−/− mice shows features of PE (234), consistent with the view that lowering levels of anti-infection response elements of the complement system leads to PE, consistent again with an infectious component to PE.

Induction of Tolerance by Exposure to Antigens and Our Main Hypothesis: Roles of Semen and Seminal Plasma

A number of groups [e.g., Ref. (118, 148, 235240)] have argued for a crucial role of semen in inducing maternal immunological protection, and this is an important part of our own hypothesis here. The second component, however, is a corollary of it. If it is accepted that semen can have beneficial effects, it may also be that in certain cases it can also have harmful effects. Specifically, we rehearse the fact that semen is not sterile, and that it can be a crucial source of the microbes that may, over time, be responsible for the development of PE (and indeed other disorders of pregnancy, some of which we rehearse).

Semen consists essentially of the sperm cells suspended in a fluid known as seminal plasma (241). Seminal plasma contains many components (242, 243), such as transforming growth factor β (TGF-β) (236, 244248), and there is much evidence that a number of them are both protective and responsible for inducing the immune tolerance observed in pregnancy. Thus, in a key article on the issue, Robertson et al. state, “TGF-β has potent immune-deviating effects and is likely to be the key agent in skewing the immune response against a Type-1 bias. Prior exposure to semen in the context of TGF-β can be shown to be associated with enhanced fetal/placental development late in gestation. In this article, we review the experimental basis for these claims and propose the hypothesis that, in women, the partner-specific protective effect of insemination in PE might be explained by induction of immunological hyporesponsiveness conferring tolerance to histocompatibility antigens present in the ejaculate and shared by the conceptus” (148).

Transforming growth factor-β and prostaglandin E [also prevalent in seminal fluid (249)] are potent Treg cell-inducing agents, and coitus is one key factor involved in expanding the pool of inducible Treg cells that react with paternal alloantigens shared by conceptus tissues (250253).

Both in humans and in agricultural practice, semen may be stored with or without the seminal fluid (in the latter cases, the sperm have been removed from it and they alone are used in the insemination). However, a number of articles have shown very clearly that it is the seminal fluid itself that contains many protective factors, not least in improving the likelihood of avoiding adverse pregnancy outcomes (148, 197, 254, 255). Thus semen is the preferred substrate for inducing immunotolerance and hence protection against PE.

Evidence from Epidemiology—Semen Can be Protective Against PE

As well as those [such as preexisting diseases such as hypertension and diabetes (256, 257), that we covered previously (44)], there are several large-scale risk (or antirisk) factors that correlate with the incidence of PE. They are consistent with the idea that a woman’s immune system adapts slowly to (semen) proteins from a specific male partner (148, 235, 236), and that the content of semen thus has major phenotypic effects well beyond its donation of (epi)genetic material. We believe that our hypothesis about the importance of semen in PE has the merit of being able to explain each of them in a simple and natural way:

1. The first pregnancy with any given partner means an increased susceptibility to PE (5, 258, 259).

2. Conception early in a new relationship means an increased susceptibility to PE (260262).

3. Conception after using barrier contraceptives means an increased susceptibility to PE (261, 263, 264).

4. Conception after using non-barrier methods or after a long period of cohabitation means a decreased susceptibility to PE (235, 261).

5. Donor egg pregnancies have a hugely inflated chance of PE (259, 265267).

6. PE in a first pregnancy increases its likelihood in subsequent pregnancies (268).

7. Oral sex with the father is protective against PE in a subsequent pregnancy (269, 270).

8. Age is a risk factor for PE (271275).

9. Donor sperm pregnancies (artificial insemination) are much more likely to lead to PE (270, 276279).

We consider each in turn (Figure 5).

FIGURE 5
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Figure 5. Some epidemiological risk factors for preeclampsia.

The First Pregnancy with Any Given Partner Means an Increased Susceptibility to PE

This is extremely well established [e.g., Ref. (5, 67, 163, 256, 258, 259, 280288)]. Thus, Duckitt and Harrington (256) showed nulliparity to have a risk ratio (over pregnant women with previous pregnancies) of 2.91 (95% CI 1.28–6.61). Luo et al. (283) find an odds ratio (OR) of 2.42 (95% CI 2.16–2.71) for PE in primiparous vs. multiparous women, while Deis et al. found the OR to be 2.06 (CI 1.63–2.60), P = 0.0021. Dildy et al. (289) summarize several studies, including a very large one by Conde-Agudelo and Belizán (290) (RR 2.38; 95% CI 2.28–2.49), while the meta-analysis of English et al. (287) gives a risk ratio for nulliparity of 2.91 (CI 1.28–6.61). The consistency of each of these studies allows one to state with considerable confidence that there is a two- to threefold greater chance of PE with a first baby.

However, an additional and key clue here is not simply (and maybe even not mainly) that it is just being nulliparous (i.e., one’s first pregnancy) but that it is primipaternity—one’s first pregnancy with a given father—that leads to an increased susceptibility to PE (19, 204, 291303) [cf. (304)]. Changing partners effectively “resets the clock” such that the risk with a new father is essentially as for first pregnancies. Thus, Lie et al. (305) noted that if a woman becomes pregnant by a man who has already fathered a pre-eclamptic pregnancy in a different woman her increased risk of developing pre-eclampsia is 1.8-fold (CI 1.2–2.6). This is far greater than the typical incidence of PE, even for nulliparous women. The equivalent figure in the study of Lynch et al. (204) was RR = 5.1, 95% CI 1.6–15. The strong implication of all of this is that the father can have bad effects but that some kind of “familiarity” with the partner is protective (301), the obvious version—and that more or less universally accepted—being an immunological familiarity (i.e., tolerance). Note, however, that this is when the pregnancy goes to term: a prior birth confers a strong protective effect against PE, whereas a prior abortion confers only a weaker protective effect (259).

Conception Early in a New Relationship Means an Increased Susceptibility to PE

The idea that conception early in a new relationship means an increased susceptibility to PE follows immediately from the above. The landmark studies here are those of Robillard et al. (19, 260, 296), of Einarsson et al. (261), and of Saftlas et al. (262).

Robillard et al. (260) studied 1,011 consecutive mothers in an obstetrics unit. The incidence of pregnancy-induced hypertension (PIH) was 11.9% among primigravidae, 4.7% among same-paternity multigravidae, and 24.0% among new-paternity multigravidae. For both primigravidae and multigravidae, the length of (sexual) cohabitation before conception was inversely related to the incidence of PIH (P < 0.0001).

Einarsson et al. (261) studied both the use of barrier methods and the extent of cohabitation prior to pregnancy. For those (allegedly, etc.) using barrier methods before insemination, the OR for PE when prior cohabitation was only 0–4 months versus the OR for PE: normotensive was 17.1 (CI 2.9–150.6) versus 1.2 (CI 0.1–11.5) when the period of cohabitation was 8–12 months, and 1.0 for periods of cohabitation exceeding 1 year.

Saftlas et al. (262) recognized that parous women who change partners before a subsequent pregnancy appear to lose the protective effect of a prior birth. In a large study (mainly based around calcium supplementation), they noted that women with a history of abortion who conceived again with the same partner had nearly half the risk of PE [adjusted odds ratio (aOR) = 0.54, 95% confidence interval: 0.31–0.97]. In contrast, women with an abortion history who conceived with a new partner had the same risk of PE as women without a history of abortion (aOR = 1.03, 95% confidence interval: 0.72–1.47). Thus, the protective effect of a prior abortion operated only among women who conceived again with the same partner.

Conception after Using Barrier Contraceptives Means an Increased Susceptibility to PE

A prediction that follows immediately from the idea that paternal antigens in semen (or seminal fluid) are protective is that the regular use of barrier methods will lower maternal exposure to them, and hence increase the likelihood of PE. This too is borne out (261, 263, 264). Thus Klonoff-Cohen et al. found a 2.37-fold (CI 1.01–5.58) increased risk of PE for users of contraceptives that prevent exposure to sperm. A dose-response gradient was observed, with increasing risk of PE for those with fewer episodes of sperm exposure. Similarly, Hernández-Valencia et al. (264) found that the OR for PE indicated a 2.52-fold (CI 1.17–5.44, P < 0.05), increased risk of PE for users of barrier contraceptives compared with women using nonbarrier contraceptive methods.

Conception after Using Non-Barrier Methods or after a Long Period of Cohabitation Means a Decreased Susceptibility to PE

This is the flip side of the studies given above [e.g., Ref. (260262)]. It is clear that maternal–fetal HLA sharing is associated with the risk of PE, and the benefits of long-term exposure to the father’s semen, while complex (306), seem to be cumulative (307). Thus, short duration of sexual relationship was more common in women with PE compared with uncomplicated pregnancies [≤6 months 14.5 versus 6.9%, aOR 1.88, 95% CI 1.05–3.36; ≤ 3 months 6.9% versus 2.5%, aOR 2.32, 95% CI 1.03–5.25 (308)]. Oral contraceptives are somewhat confounding here, in that they may either be protective or a risk factor depending on the duration of their use and the mother’s physiological reaction to them (309).

Donor Egg Pregnancies Have a Hugely Inflated Chance of PE

If an immunological component is important to PE (as it evidently is), it is to be predicted that donor egg pregnancies are likely to be at much great risk of PE, and they are [e.g., Ref. (259, 265267, 310314)] [and also of preterm birth (PTB) (315)]. Thus, Letur et al. (265, 266) found that PE was some fourfold more prevalent using donated eggs (11.2 vs. 2.8%, P < 0.001), while Tandberg et al. (259) found that various “assisted reproductive technologies” had risk ratios of 1.3 (1.1–1.6) and 1.8 (1.2–2.8) in second and third pregnancies, respectively. Pecks et al. studied PIH (not just PE) and found that the calculated OR for PIH after oocyte donation, compared to conventional reproductive therapy, was 2.57 (CI 1.91–3.47), while the calculated OR for PIH after oocyte donation, compared to other women in the control group, was 6.60 (CI 4.55–9.57). Stoop et al. (316) found a Risk Ratio of 1.502 (CI 1.024–2.204) for PIH. In a study by Levron et al. (317), adjustment for maternal age, gravidity, parity, and chronic hypertension revealed that oocyte donation was independently associated with a higher rate of hypertensive diseases of pregnancy (P < 0.01). In a twins study, Fox et al. (318) found, on adjusted analysis, that the egg donation independently associated with PE (aOR 2.409, CI 1.051–5.524). The meta-anaysis of Thomopoulos et al. (319) gave a risk ratio for egg donation of 3.60 (CI 2.56–5.05) over controls, a value similar to that of Blázquez et al. (320). Finally, a recent meta-analysis by Masoudian et al. (313) found that that the risk of PE is considerably higher in oocyte-donation pregnancies compared to other methods of assisted reproductive technology (OR, 2.54; CI 1.98–3.24; P < 0.0001) or to natural conception (OR, 4.34; CI 3.10–6.06; P < 0.0001). The incidence of gestational hypertension and PE was significantly higher in ovum donor recipients compared with women undergoing autologous IVF [24.7% compared with 7.4%, P < 0.01, and 16.9% compared with 4.9%, P < 0.02 (321)]. All of these are entirely consistent with an immune component being a significant contributor to PE. Given our suggestion that many of these disorders of pregnancy have a microbial component, one obvious question pertains to whether the use of antibiotics assists the successful progression of IVF. Unfortunately this question has been little researched in humans (322).

PE in a First Pregnancy Increases Its Likelihood in Subsequent Pregnancies

This too is well established: a woman who has had PE has an increased risk of PE in subsequent pregnancies (288, 323), especially if suffering from hypertension (324). This may be seen as relatively unsurprising, and of course bears many explanations, and the increased risks can be very substantial (268). In the overall analysis of English et al. (287), the risk ratio was 7.19 (CI 5.85–8.83). Other examples give the recurrence risk, overall, as some 15–18% (288). The risk of recurrent PE is inversely related to gestational age at the first delivery, and in the study of Mostello et al. (325) was 38.6% for 28 weeks’ gestation or earlier, 29.1% for 29–32 weeks, 21.9% for 33–36 weeks, and 12.9% for 37 weeks or more. Low birthweight in the first pregnancy is an independent predictor of PE in the second: birth weight below the tenth percentile in the first delivery accounted for 10% of the total cases of PE in the second pregnancy and 30% of recurrent cases (326). From the perspective developed here, the suggestion is that whatever is responsible for PE in one pregnancy can “live on” in the mother and afflict subsequent ones. One thing that can “live on” is a dormant microbial community. We discussed at length in the previous review (44), and develop in more detail later (in the section “host tolerance to microbial pathogens”) the evidence that dormant microbes (such as Helicobacter pylori and Mycobacterium tuberculosis) can live within their host for decades.

Oral Sex with the Father Is Protective against PE in a Subsequent Pregnancy

Oral sex (with the father of one’s baby) protects against PE (269, 270) (P = 0.0003), arguably because exposure to the paternal antigens in the seminal fluid have a greater exposure to the blood stream via the buccal mucosa than they would via the vagina. This is a particularly interesting (and probably unexpected) finding, that is relatively easily understood from an immunological point of view, and it is hard to conceive of alternative explanations. [Note, however, that in the index study (269), the correlation or otherwise of oral and vaginal sex was not reported, so it is not entirely excluded that more oral sex also meant more vaginal sex.]

Age Is a Risk Factor for PE

Age is a well known risk factor for PE (271275), and of course age is a risk factor for many other diseases, so we do not regard this as particularly strong evidence for our ideas. However, we have included it in order to note that age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction (327).

Donor Sperm Pregnancies (Artificial Insemination) Are Much More Likely to Lead to PE

Finally, here, turning again to the father, it has been recognized that certain fathers can simply be “dangerous” in terms of their ability to induce PE in those who they inseminate (302, 328). By contrast, if immunotolerance to a father builds up slowly as a result of cohabitation and unprotected sex, a crucial prediction is that donor sperm pregnancies will not have this property, and should lead to a much greater incidence of PE. This is precisely what is observed (270, 276279, 310).

In an early study (276), Need et al. observed that the overall incidence of PE was high (9.3%) in pregnancies involving artificial insemination by donor (AID) compared with the expected incidence of 0.5–5.0%. The expected protective effect of a previous pregnancy was not seen, with a 47-fold increase in PE (observed versus expected) in AID pregnancies after a previous full-term pregnancy. That is a truly massive risk ratio.

Smith et al. (277) compared the frequency of PE when AI was via washed sperm from a partner or a donor, finding a relative risk for PE of 1.85 (95% CI 1.20–2.85) for the latter, and implying that the relevant factor was attached to (in or on) the sperm themselves.

In a similar kind of study, Hoy et al. found (278), after adjusting for maternal age, multiple birth, parity and presentation, that “donor sperm” pregnancies were more likely to develop PE (OR 1.4, 95% CI 1.2–1.8).

Salha et al. (310) found that the incidence of PE in pregnancies resulting from donated spermatozoa was 18.2% (6/33) compared with 0% in the age- and parity-matched partner insemination group (P < 0.05).

Wang et al. (329) found that the risk of PE tripled in those never exposed to their partner’s sperm, i.e., those treated with intracytoplasmatic sperm injection done with surgically obtained sperm.

In a study of older women, Le Ray et al. (330) noted that the PE rate differed significantly between various groups using assisted reproductive technology (3.8% after no IVF, 10.0% after IVF only, and 19.2% after IVF with oocyte donation, P < 0.001).

Davis and Gallup reviewed what was known in 2006 (279), particularly from an evolutionary point of view, concluding that one interpretation of PE was that it was the mother’s way of removing “unsuitable” fetuses. This does not sit easily with the considerable mortality and morbidity associated with PE predelivery, especially in the absence of treatment. However, Davis and Gallup (279) did recognize that “pregnancies and children that result from unfamiliar semen have a lower probability of receiving sufficient paternal investment than do pregnancies and children that result from familiar semen,” and that is fully consistent with our general thinking here. Bonney draws a similar view (182), based on the “danger” model (176, 178), that takes a different view from that of the “allograft” or “self-nonself discrimination” model. In the “danger model,” the decision to initiate an immune response is based not on discrimination between self and non-self, but instead is based on the recognition of “danger” (abnormal cell death, injury, or stress). One such recognition is the well-established recognition of microbes as something likely to be causative of undesirable outcomes.

In the study of González-Comadran et al. (331), conception using donor sperm was again associated with an increased risk of PE (OR 1.63, 95% CI 1.36–1.95).

Thomopoulos et al. carried out two detailed and systematic reviews (319, 332); the latter (319) covered 7,038,029 pregnancies (203,375 following any invasive ART) and determined that the risk of PE was increased by 75% (95% CI 50–103%).

Overall, these studies highlight very strongly indeed that the use of unfamiliar male sperm is highly conducive to PE relative to that of partner’s sperm, especially when exposure is over a long period. We next turn to the question of why, in spite of this, we also see PE even in partner-inseminated semen, as well as more generally.

Evidence from Epidemiology—Semen Can be Harmful and Can Contribute Strongly to PE

In our previous review (44), we rehearsed the evidence for a considerable placental and vaginal microbiome [see also (333335)], but did not discuss the semen microbiome at all. To repeat, therefore, the particular, and essentially novel, part of our hypothesis here is that if it is accepted that semen (and seminal plasma) can have beneficial effects, it should also be recognized that in certain cases it can also have harmful effects. In particular, we shall be focusing on its microbial content [we ignore any epigenetic effects (336)]. We note that this idea would fit easily with the recognition that as well as inducing tolerance to paternal antigens, exposures to the father’s semen can build tolerance (immunity) to its microbes, thereby decreasing the risk of PE. However, microbes and their associated PAMPs are well known to be highly inflammatory, whether or not they are reproducing, and we consider that it is this that is likely the particular driver of the sequelae observable in PE.

Microbes Associated with PE

The female’s urogenital microbiome is important in a number of pregnancy disorders (56, 337339). Specifically, we previously found many examples in which microbes are associated with PE, and we here update the CC-BY-licensed Table 2 thereof (44).

TABLE 2
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Table 2. Many studies have identified a much greater prevalence of infectious agents in the blood or urine or gums of those exhibiting PE than in matched controls.

In addition, we recognize the considerable evidence for a role of viruses in various disorders of pregnancy (106, 382, 383).

Microbiology of Semen

Semen itself is very far from being sterile, even in normal individuals, with infection usually being defined as 103 organisms/mL semen (384). Of course the mere existence of sexually transmitted diseases implies strongly that there is a seminal fluid (or semen) microbiome that can vary substantially between individuals, and that can contribute to infection [e.g., Ref. (385387)], fertility (385) (and see below), and any other aspect of pregnancy (388), or even health in later life (389).

It is logical to start here with the observation that semen is a source of microbes from the fact that there are a great many sexually transmitted infectious diseases for which it is the vehicle. Table 3 summarizes some of these.

TABLE 3
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Table 3. Organisms of well-known sexually transmitted diseases that have been associated with semen.

Notwithstanding the difficulties of measurement (405), there is, in particular, a considerable literature on fertility (406), since infertile males tend to donate sperm for assay in fertility clinics, and infection is a common cause of infertility [e.g., Ref. (384) and Table 4]. Note that “infertility” is not always an absolute term: pregnancies result in 27% of cases of treated “infertile” couples followed up after trying to conceive for 2 years, and with oligozoospermia as the primary cause of infertility (407). Most studies involve bacteria (bacteriospermia). Articles on this and other microbial properties of semen beyond STDs include those in Table 4.

TABLE 4
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Table 4. Some examples of the semen microbiome and reproductive biology.

We deliberately avoid discussing mechanisms in any real detail here, since our purpose is merely to show that semen is commonly infected with microbes, whose presence might well lead to PE. However, we were very struck by the ability of Escherichia coli and other organisms (440, 448, 471) actually to immobilize sperm [e.g., Ref. (472475)]. As with amyloidogenic blood clotting (476, 477), bacterial LPS (156) may be a chief culprit (459). The Gram-positive equivalent, lipoteichoic acid (LTA), is just as potent in the fibrinogen-clotting amyloidogen assay (478), but while Gram-positives can also immobilize sperm (479, 480), the influence of purified LTA on sperm seems not to have been tested.

Another prediction from this analysis is that since infection is a significant cause of both infertility and PE [and it may account for 15% of infertile cases (384, 473)], we might expect to see some correlations between them. Although one might argue that anything seen as imperfect “background” health or subfecundity might impinge on the incidence of PE [such as endocrine disruption (481) or DNA damage of whatever cause (482)], the risk ratio for PE in couples whose infertility had an unknown basis was 5.61 (CI 3.3–9.3) in one study in Aberdeen (483) and 1.29 (CI 1.05–1.60) in another in Norway (484). Time to pregnancy in couples may be used (in part) as a surrogate for (in)fertility and is associated with a variety of poor pregnancy outcomes (485); in this case, the risk ratio for PE for TTP exceeding 6 months was 2.47 (CI 1.3–4.69) (486). Given the prevalence of infection in infertile sperm (Table 4), and the frequency of infertility [10% in the Danish study (485), which defined it as couples taking a year or more to conceive], it seems reasonable to suggest that microbiological testing of semen should be done on a more routine basis. It would also help to light up any relationships between the microbiological properties of sperm and the potentially causal consequence of increased PE risk.

We also note, as thoughtfully and importantly suggested by referee 1, that the microbes in the semen may already induce inflammation in the endometrium a few days before the conceptus implants. This may itself constitute a hostile “environment” that can contribute to the process of defective implantation, rather than working via the fetus itself.

More quantitatively, and importantly intellectually, if infection is seen as a major cause of PE, as we argue here, and it is known that infection is a cause of infertility, then one should suppose that infertility, and infertility caused by infection, should be at least as common, and probably more common than is PE, and this is the case, adding some considerable weight to the argument. Indeed, if PE was much more common than infertility or even infection, it would be much harder to argue that the latter was a major cause of the former. In European countries ~10–15% of couples are afflicted by infertility (384, 485), and in some 60% of cases infection or a male factor is implicated (384). In some countries, the frequency of male infertility is 13–15% http://bionumbers.hms.harvard.edu/bionumber.aspx?id=113483&ver=0 or higher (487), and the percentage of females with impaired fecundity has been given as 12.3% https://www.cdc.gov/nchs/fastats/infertility.htm. These kinds of numbers would imply that 6–9% of couples experience infection- or male-based infertility, and this exceeds the 3–5% incidence of PE.

In a similar vein, antibiotics, provided they can get through the relevant membranes (488490), should also have benefits on sperm parameters or fertility if a lack of it is caused by infection, and this has indeed been observed [e.g., Ref. (436, 452, 491)].

Roles of the Prostate and Testes

In the previous review, we focused on the gut, periodontitis, and the urinary tract of the mother as the main source of organisms that might lead to PE. Here we focus on the male, specifically the prostate and the testes, given the evidence for how common infection is in semen. The main function of the prostate gland is to secrete prostate fluid, one of the components of semen. Thus, although it is unlikely that measurements have regularly been done to assess any relationship between this and any adverse effects of pregnancy, it was of interest to establish whether it too is likely to harbor microbes. Indeed, such “male accessory gland infection” is common (492496). In some cases, the origin is probably periodontal (497). Recent studies have implicated microbial PRRs, especially TLRs, as well as inflammatory cytokines and their signaling pathways, in testicular function, implying an important link between infection/inflammation and testicular dysfunction (498). The testes are a common and important site of infection in the male (499, 500), and even bacterial LPS can cause testitis (501). Similarly, infection (especially urinary tract infection) is a common cause of prostatitis (502512). Finally, prostatitis is also a major cause of infertility (492, 493, 495). Such data contribute strongly to the recognition that semen is not normally going to be sterile, consistent with the view that it is likely to be a major originating cause of the infections characteristic of PE.

Microbial Infections in Spontaneous Abortions, Miscarriages, and PTB

Our logic would also imply a role for (potentially male-derived) microbes in miscarriages and spontaneous abortions. A microbial component to these seems well established for both miscarriages (513515) and spontaneous abortions (516521). Of course the ability of Brucella abortus to induce abortions in domesticated livestock, especially cattle (and occasionally in humans), is well known (522524); indeed, bacteriospermia is inimical to fertilization success (525), and nowadays it is well controlled in livestock by the use of vaccines (526) or antimicrobials (525). Indeed, stored semen is so widely used for the artificial insemination of livestock in modern agriculture that the recognition that semen is not sterile has led to the routine use of antibiotics in semen “extenders” [e.g., Ref. (527530)].

The same general logic is true for infection as a common precursor to PTB in the absence of PE, where it is much better established [e.g., Ref. (531565)]. It arguably has the same basic origins in semen.

Although recurrent pregnancy loss is usually treated separately from infertility (where the role of infection is reasonably well established) it is possible that in many cases it is, like PE, partly just a worsened form of an immune reaction, with both sharing similar causes (including the microbial infection of semen). There is in fact considerable evidence for this [e.g., Ref. (138, 443, 566580)]. Of course it is not unreasonable that poor sperm quality, that may be just sufficient to initiate a pregnancy, may ultimately contribute to its premature termination or other disorders of pregnancy, so this association might really be expected. It does, however, add considerable weight to the view that a more common screening of the male than presently done might be of value (581) in assessing a range of pregnancy disorders besides PE. In particular, it seems that infection affects motility (see above), and that this in turn is well correlated (573) with sperm DNA fragmentation and ultimate loss of reproductive quality.

Amyloids in semen are known to enhance human immunodeficiency virus infectivity (582). According to our own recent experimental analyzes, they may be caused by bacterial LPS (476, 477) or LTA (478). We note too that the sperm metabolome also influences offspring, e.g., from obese parents (583), and that many other variables are related to sperm quality, including oxidative stress (584591). Thus it is entirely reasonable to see semen as a cause of problems as well as benefits to an ensuing pregnancy.

Microbial Effects on Immunotolerance

If our thesis is sound, one may expect to find evidence for the effects of microbes on the loss of immunotolerance in other settings. One such is tolerance to dietary antigens, of which gluten, a cause of celiac disease, is preeminent. Recently, evidence has come forward that shows a substantial effect of a reovirus in lowering the immunotolerance to gluten in a mouse model of celiac disease, and thereby causing inflammation (592, 593). Interestingly, pregnancies in women with celiac disease were considerably more susceptible to PTB and other complications than were controls (594601), especially when mothers were not on a gluten-free diet. Similarly, preeclamptic pregnancies led to a much (4-fold) higher likelihood of allergic sensitization in the offspring (602) The roles of hygiene, the microbiome and disease are a matter of considerable current interest [e.g., Ref. (603)].

It was consequently logical to see if intolerance to peanut antigen was also predictive of PE, but we could find no evidence for this. Again, however, in a study (604) in which PE had roughly its normal prevalence, mothers experiencing it were significantly more likely to give birth to children with increased risk of asthma, eczema, and aeroallergen and food allergy.

Effects of Vaccination on Pregnancy Outcomes, Including PE

We noted above (and again below) that the evidence for a role of microbes in PTB is overwhelming [also reviewed in Ref. (44)]. From an immunological point of view, there seems to be a hugely beneficial outcome of vaccination against influenza in terms of lowering PTB (605610) [cf. (611)] or stillbirth (612). PE was not studied, save in Ref. (613) where the risk ratio of vaccination (0.484, CI 0.18–1.34) implied a marginal benefit. There do not seem to be any safety issues, either for influenza vaccine (612633) or for other vaccines (625) such as those against pertussis (634636) or human papillomavirus (637).

As well as miscarriage and PTB, other adverse pregnancy outcomes studied in relation to vaccine exposure (638) include IUGR. IUGR frequently presents as the fetal phenotype of PE, sharing a common etiology in terms of poor placentation in early pregnancy (639). These other adverse events have been scored more frequently than has been PE, and Table 5 summarizes the evidence for a protective effect of vaccines, though it is recognized that there is the potential for considerable confounding effects [e.g., Ref. (632, 640)]. While Table 5 does not have examples from PE this is because the tests have seemingly not been done; because the effects on related disorders of pregnancy are clear, we think these should be sufficient to encourage people to look at the effects on PE (indeed readers may already have unpublished data).

TABLE 5
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Table 5. Protective events of vaccines against various adverse pregnancy outcomes.

There are no apparent benefits of vaccine-based immunization vs. recurrent miscarriage (642, 643).

Unrelated to the present question, but very interesting, is the fact that the risk of RA for men was higher among men who fathered their first child at a young age (P for trend <0.001) (644). This is consistent with the fact that its prevalence in females is 3.5 times higher, and that it has a microbial origin (645648).

General or Specific?

The fact that vaccination against organisms not usually associated with adverse pregnancy outcomes is protective can be interpreted in one (or both) of two ways, i.e., that the vaccine is unselective in terms of inhibiting the effects of its target organism, or the generally raised level of <some kind of> immune response is itself protective. Data to discriminate these are not yet to hand.

In a similar vein, the survival of the host in any “battle” between host and parasite (e.g., microbe) can be effected in one or both of two main ways: (i) the host invokes antimicrobial processes such as the immune systems described above, or produces antimicrobial compounds or (ii) the host modifies itself in ways that allow it to become tolerant to the presence of a certain standing crop of microbes. We consider each in turn.

Antimicrobial Components of Human Semen, a Part of Resistance in the Semen Microbiome

Antimicrobial peptides (AMPs) [http://aps.unmc.edu/AP/main.php (649)] are a well-known part of the defense systems of many animals [e.g., Ref. (650659)] [and indeed plants (650, 660)], and are widely touted as potential anti-infectives [e.g., Ref. (661663)]. Their presence in the cells and tissues of the uterus, fetus and the neonate indicates an important role in immunity during pregnancy and in early life (657, 664668). Unsurprisingly, they have been proposed as agents for use in preventing the transmission of STDs (669, 670), and as antimicrobials for addition to stored semen for use in agriculture (671675). Our interest here, however, is around whether there are natural AMPs in human (or animal) semen, and the answer is in the affirmative. They include secretory leukocyte protease inhibitor (659), semen-derived enhancer of viral infection (676), and in particular the semenogelins (677, 678). HE2 is another AMP that resides in the epididymis (679, 680), while the human cathelicidin hCAP-18 [cathelicidin AMP, 18 kDa)] is inactive in seminal plasma but is processed to the AMP LL-37 by the prostate-derived protease gastricsin (668, 681). Thus it is clear that at least some of the reason that the semen microbiome is not completely unchecked is down to AMPs. Stimulating their production, provided they are not also spermicidal, would seem like an excellent therapeutic option.

Host Tolerance to Microbial Pathogens

It is a commonplace that—for any number of systems biology reasons based on biochemical individuality (682)—even highly virulent diseases do not kill everyone who is exposed to them at the same level. As indicated above, this could be because the host is resistant and simply clears the infections; this is certainly the more traditional view. However, an additional or alternative contribution is because while hosts do not clear all of them they can develop “tolerance” to them. This latter view is gaining considerable ground, not least since the work of Schneider, Ayres et al. (683) showing that a variety of Drosophila mutants with known genetic defects could differentially tolerate infection by Listeria monocytogenes. This concept of tolerance (684691) is very important to our considerations here, since it means that we do indeed have well-established methods of putting up with microbes more generally, without killing them. It is consistent with clearly established evolutionary theory (692694), and the relative importance of resistance and tolerance within a population affects host–microbe coevolution (695). The concept of tolerance sits easily with the Matzinger model of danger/damage [e.g., Ref. (175, 177, 178, 180)], as well as the concept of a resident population of dormant microbes (45, 47, 48), and may indeed be seen in terms of a coevolution or mutualistic association (696, 697). Some specific mechanisms are becoming established, e.g., the variation by microbes of their danger signal to promote host defense (698). Others, such as the difference in the host metabolomes [that we reviewed (44)] as induced by resistance vs. tolerance responses (690) may allow one to infer the relative importance of each. At all events, it is clear from the concept of dormancy that we do not kill all the intracellular microbes that our bodies harbor, and that almost by definition we must then tolerate them. As well as the established maternal immunotolerance of pregnancy, tolerance of microbes seems to be another hallmark of pregnancy.

Sequelae of a Role of Infection in PE: Microbes, Molecules and Processes

The chief line taken in our previous review (44) and herein is that this should be detectable by various means. Those three chief means involve detecting the microbes themselves, detecting molecules whose concentration changes as a result of the microbes (and their inflammatory components) being present, and detecting host processes whose activities have been changed by the presence of the microbes.

Previously (44), updated here (Table 2), we provided considerable evidence for the presence of microbes within the mother as part of PE. Here we have adduced the equally considerable evidence that in many cases semen is very far from being sterile, and that the source of the originating infection may actually be the father. Equally, we showed (44) that a long list of proteins that were raised (or less commonly lowered) in PE were equally changed by known infections, consistent with the view that PE also involved such infections, albeit at a lower level at which their overt presence could be kept in check. One protein we did not discuss was Placental Protein 13 (PP13) or galectin 1, so we now discuss this briefly.

PP13 (Galectin 13)

Galectins are glycan-binding proteins that regulate innate and adaptive immune responses. Three of the five human cluster galectins are solely expressed in the placenta (699). One of these, encoded by the LGALS13 gene (700, 701), is known as galectin-13 or PP13 (702). Its β-sheet-rich “jelly-roll” structure places it strongly as a galectin homolog (701). It has a MW of ~16 kDa [32 kDa dimer (703)] and is expressed solely in the placenta (700, 704) (and see http://www.proteinatlas.org/ENSG00000105198-LGALS13/tissue). A decreased placental expression of PP13 and its low concentrations in first trimester maternal sera are associated with elevated risk of PE (699, 705707), plausibly reflecting poor placentation. By contrast, and consistent with the usual oxidative stress, there is increased trophoblastic shedding of PP13-immunopositive microvesicles in PE, starting in the second trimester, which leads to high maternal blood PP13 concentrations (699, 708). Certain alleles such as promoter variant 98A-C predispose strongly to PE (709).

Galectin-1 is also highly overexpressed in PE (710). However, as with all the other proteomic biomarkers surveyed previously (44), galectins (including galectin-13 #http://amp.pharm.mssm.edu/Harmonizome/gene/LGALS13) are clear biomarkers of infection (711).

Toll-Like Receptors

Toll-like receptors are among the best known receptors for “DAMPs” such as LPS from Gram-negatives [TLR4 (156, 712714)], LTAs from Gram-positives [TLR2 (715726)] and viral DNA and its mimics (TLR3) (727). Note, however, that TLRs are not expressed solely at the cell surface, and that pathogens (and their DNA) may also be recognized intracellularly (728733), often via a pathway involving an AIM2 (“absent in melanoma 2”) inflammasome and or STING (“stimulator of interferon genes”).

As expected, they are intimately involved in disorders of pregnancy such as PE (185, 727, 734745). Indeed the animal model for PE developed by Faas et al. (746) actually involves injecting an ultralow dose of LPS into pregnant rat on day 14 of gestation. Overall, such data are fully consistent with the view that infection is a significant part of PE. In view of our suggestions surrounding the role of semen infection in PE it would be of interest to know if these markers were also raised in the semen of partners of women who later manifest PE. Sperm cells are well endowed with TLRs (498, 747749). However, we can find only one study showing that increased semen expression of TLRs is indeed observed during inflammation and oxidative stress such as occurs during infection and infertility (750). A more wide-ranging assessment of TLR expression in sperm cells as a function of fertility seems warranted.

LPS Mimics

An interesting and striking feature of PE is the common appearance (2–7 weeks before the onset of clinical disease) of inositolphosphoglycan-P type (IPG-P) in the urine of patients destined to manifest PE (20, 751762). These molecules are second messegers of insulin, and hence related to gestational diabetes. Robillard et al. (20) comment “These carbohydrate–lipid long-chain molecules mimic exactly endotoxins (such as E. coli or Plasmodium falciparum membranes). In theory, these compounds could circulate as endotoxins floating around in the bloodstream for weeks (before and during the appearance of clinical signs of PE). Would these greatly augment the systemic and more specific endothelial inflammation in the mother? This area needs urgent further research as anti-IPG-Pdrugs (or others, monoclonal antibodies, etc.) are intellectually conceivable.” In view of the arguments raised here about the role of other endotoxins such as LPS, we consider these observations as providing potentially significant clues. Surprisingly, little is known of changes in their levels that might accompany genuine infection.

Coagulopathies

Although we discussed this in the previous review (44), some further brief rehearsal is warranted, since coagulopathies are such a common feature of PE (44). Specifically, our finding that very low concentrations of cell wall products can induce amyloid formation during blood clotting (476, 478) has been further extended to recognize the ubiquity of the phenomenon in chronic, inflammatory diseases (477, 478, 648, 763766). Often, an extreme example gives strong pointers, and the syndrome with the highest likelihood of developing PE is antiphospholipid syndrome (APS) (767771), which is also caused by infection (772777) and where the coagulopathies are also especially noteworthy (778782). Consequently, the recognition of PE as an amyloidogenic coagulopathy (44, 783785) is significant.

APS and Cardiolipin

Antiphospholipid syndrome is an autoimmune disorder defined in particular by the presence high circulating titers of what are referred to as antiphospholipid antibodies (aPL) [e.g., Ref. (786)]. Given that every human cell’s plasma membrane contains phospholipids, one might wonder how “antiphospholipid antibodies” do not simply attack every cell. The answer, most interestingly, is that, despite the name, anticardiolipin antibodies, anti-β2-glycoprotein-I, and lupus anticoagulant are the main autoantibodies found in APS (787).

In contrast to common phospholipids such as phosphatidylcholine, phosphatidylserine, and phosphatidylethanolamine, cardiolipins [1,3-bis(sn-3′-phosphatidyl)-sn-glycerol derivatives] (see Figure 6 for some structures) are synthesized in (Ref. (788790)) and essentially confined to mitochondria, and in particular the inner mitochondrial membrane. While heart failure is a separate clinical condition, we note that such phospholipids can serve important functions in oxidative phosphorylation, apoptosis, and heart failure development (790797).

FIGURE 6
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Figure 6. Some cardiolipin structures.

Overall, there seems to be little doubt that APS and aPL are the result of infection (773777, 798800), and that, as with RA (645648, 801), the autoimmune responses are essentially due to molecular mimicry.

Now, of course, from an evolutionary point of view, mitochondria are considered to have evolved from (α-proteo)bacteria (802808) that were engulfed by a protoeukaryote (809), and bacteria might consequently be expected to possess cardiolipin. This is very much the case for both Gram-negative and Gram-positive strains (810814), with Gram-positive organisms typically having the greater content. Particularly significant, from our point of view, is that the relative content of cardiolipin among phospholipids increases enormously as (at least Gram-positive) bacterial cells become dormant (815).

Thus, the cardiolipin can come from two main sources: (i) host cell death that liberates mitochondrial products or (ii) invading bacteria (especially those that lay dormant and awaken). Serum ferritin is a cell death marker (816), and some evidence for the former source (817) [and see Ref. (818)] is that hyperferritinemia was present in 9% vs. 0% of APS patients and controls, respectively (P < 0.001), and that hyperferritinemia was present in 71% of catastrophic APS (cAPS) patients, and ferritin levels among this subgroup were significantly higher compared with APS-non-cAPS patients (816–847 vs. 120–230 ng/ml, P < 0.001). One easy hypothesis is that both are due to invading bacteria, but cAPS patients also exhibit comparatively large amounts of host cell death (Figure 7).

FIGURE 7
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Figure 7. Possible relationships between cardiolipin exposure and disease sequelae.

Treatment Options Based on (Or Consistent with) the Ideas Presented Here

Although often unwritten or implicit, the purposes of much of fundamental biomedical science are to find better diagnostics and treatments for diseases (a combination sometimes referred to as theranostics). Consequently, our purposes here are to rehearse some of those areas where appropriate tests (in the form, ultimately, of randomized clinical trials) may be performed. Clearly, as before (44), and recognizing the issues of antimicrobial resistance, one avenue would exploit antibiotics much more commonly than now. We note that pharmaceutical drugs are prescribed or taken during 50% or more of pregnancies (819828). Anti-infectives are the most common such drugs, and some 20–25% of women or more are prescribed one or more antibiotics during their pregnancies (820, 821, 824, 826, 828832).

Given the role of male semen infection, we suggest that more common testing of semen for infection is warranted, especially using molecular tests. Our analyses suggest that antibiotics might also be of benefit to those males presenting with high microbial semen loads or poor fertility (833). Another strategy might involve stimulating the production of AMPs in semen.

Of the list of bacteria given in Table 2 as being associated with PE, H. pylori stands out as the most frequent. One may wonder why a vaccine against it has not been developed, but it seems to be less straightforward than for other infections (834, 835), probably because—consistent with its ability to persist within its hosts—it elicits only a poor immune response (836, 837). Our own experience (838) is that many small molecules can improve the ability of other agents to increase the primary mechanisms that are the target assay, while having no direct effects on them themselves. Although “combinatorial” strategies often lead to quite unexpected beneficial effects [e.g., Ref. (839, 840)], this “binary weapon” strategy is both novel and untried.

As also rehearsed in more detail previously [e.g., Ref. (841, 842)] many polyphenolic antioxidants act through their ability to chelate unliganded iron, and thereby keep it from doing damage or acting as a source of iron for microbial proliferation. Such molecules may also be expected to be beneficial. Other strategies may be useful for inhibiting the downstream sequelae of latent infections, such as targeting inflammation or coagulopathies.

Conclusion, Summary, and Open Questions

We consider that our previous review (44) made a very convincing case for the role of (mostly dormant) microbes in the etiology of PE. However, we there paid relatively scant attention to two elements, viz (i) the importance of the immune system (164), especially in maternal immunotolerance and (ii) the idea that possibly the commonest cause of the microbes providing the initial infection was actually infected semen from the father. We also recognize that epigenetic information (389, 843845) can be provided by the father and this can be hard to discriminate from infection (if not measured), at least in the F1 generation. This said, microbiological testing of semen seems to be a key discriminator if applied. The “danger model” (175, 177180), in which it is recognized that immune activation owes more to the detection of specific damage signals than to “non-self,” thus seems to be highly relevant to PE (182).

Overall, we think the most important ideas and facts that we have rehearsed here include the following:

• Following Medawar’s recognition of the potential conundrum of paternal alloantigens in pregnancy, most thinking has focused on the role of maternal immunotolerance, and the role of Tregs therein.

• Many examples show that sexual familiarity with the father helps protect against PE; however, this does not explain why in many cases exposure to paternal antigens is actually protective (and not even merely neutral).

• Semen contains many protective and immune-tolerance-inducing substances such as TGF-β.

• However, semen is rarely sterile, and contains many microbes, some of which are not at all benign, and can be transferred to the mother during copulation.

• If one accepts that there is often a microbial component to the development of PE, and we and others have rehearsed the considerable evidence that it is so, then semen seems to a substantial, and previous largely unconsidered source of microbes.

• Some determinands, such as complement factor Bb, seem to reflect microbial infection and not just general inflammation that can have many other causes, and may therefore be of value in untangling the mechanisms involved.

• An improved understanding of the microbiology of semen, and the role of antibiotics and vaccination in the father, seems particularly worthwhile; novel antioxidants may also hold promise (846848).

• Coagulopathies are a somewhat underappreciated accompaniment to PE and may contribute to its etiology.

• The “danger model” of immune response seems much better suited to describing events in pregnancy and PE than is the classical self/non-self analysis.

• The features of PE are not at all well recapitulated in animal models (26), and certainly not in rodents. However, it seems likely that they still have much to contribute (849851).

Open questions and further research agenda items include the following:

• There is a need for improved molecular and culture-based methods of detecting microbes in blood and tissues in which they are normally considered to be absent, both in the mother and the father.

• Notwithstanding the promise of metabolomics [see e.g., Ref. (852, 853)], there remains a need for better diagnostics, especially early in pregnancy.

• Issues of antimicrobial resistance are well known [e.g., Ref. (854856)], and most antibiotics work only on growing cells, so there is a significant role for those that work on persisters and other non-replicating forms (857859).

• As increasing numbers of infectious diseases are seen to be associated with diseases previously considered noncommunicable [e.g., tuberculosis and Parkinson’s disease (860862)], we may anticipate more careful study of such an association between overt infection and PE.

• In these discussions, we have largely avoided discriminating between early-onset (<34 weeks) and late-onset (>34 weeks) PE, but recognize both the distinctions and their varying prevalences (20, 863867).

• The increasing online availability of patient information will permit greater exploitation to assess these ideas from an epidemiological point of view; in this sense, an improved understanding of the basis for the widely varying geographical incidence of PE (20) is also likely to offer important clues.

Author Contributions

In discussion, DK and LK jointly came up with the original idea for the role of semen in preeclampsia, and the many sequelae it entails, and during many subsequent discussions wrote the review.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

DK thanks the Biotechnology and Biological Sciences Research Council (grant BB/L025752/1) for financial support. LK is a Science Foundation Ireland Principal Investigator (grant number 08/IN.1/B2083). LK is also the Director of the Science Foundation Ireland-funded INFANT Research Centre (grant no. 12/RC/2272). The funders had no other role in the conception or submission of the manuscript, and have no conflicts of interest to declare.

References

1. Jeffcoate TNA. Pre-eclampsia and eclampsia: the disease of theories. Proc R Soc Med (1966) 59:397–404.

Google Scholar

2. Barad DH, Kushnir VA, Gleicher N. Focus on recurrent miscarriage phenotypes. Fertil Steril (2017) 107:64–5. doi:10.1016/j.fertnstert.2016.10.034

CrossRef Full Text | Google Scholar

3. Grill S, Rusterholz C, Zanetti-Dällenbach R, Tercanli S, Holzgreve W, Hahn S, et al. Potential markers of preeclampsia – a review. Reprod Biol Endocrinol (2009) 7:70. doi:10.1186/1477-7827-7-70

CrossRef Full Text | Google Scholar

4. Steegers EAP, Von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet (2010) 376:631–44. doi:10.1016/S0140-6736(10)60279-6

PubMed Abstract | CrossRef Full Text | Google Scholar

5. North RA, Mccowan LM, Dekker GA, Poston L, Chan EH, Stewart AW, et al. Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort. BMJ (2011) 342:d1875. doi:10.1136/bmj.d1875

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Uzan J, Carbonnel M, Piconne O, Asmar R, Ayoubi JM. Pre-eclampsia: pathophysiology, diagnosis, and management. Vasc Health Risk Manag (2011) 7:467–74. doi:10.2147/VHRM.S20181

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Kenny L. Improving diagnosis and clinical management of pre-eclampsia. MLO Med Lab Obs (2012) 44(12):14.

Google Scholar

8. Desai P. Obstetric Vasculopathies. New Delhi: Jaypee (2013).

Google Scholar

9. Chaiworapongsa T, Chaemsaithong P, Yeo L, Romero R. Pre-eclampsia part 1: current understanding of its pathophysiology. Nat Rev Nephrol (2014) 10:466–80. doi:10.1038/nrneph.2014.102

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Kenny LC, Black MA, Poston L, Taylor R, Myers JE, Baker PN, et al. Early pregnancy prediction of preeclampsia in nulliparous women, combining clinical risk and biomarkers: the Screening for Pregnancy Endpoints (SCOPE) international cohort study. Hypertension (2014) 64:644–52. doi:10.1161/HYPERTENSIONAHA.114.03578

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Sircar M, Thadhani R, Karumanchi SA. Pathogenesis of preeclampsia. Curr Opin Nephrol Hypertens (2015) 24:131–8. doi:10.1097/MNH.0000000000000105

CrossRef Full Text | Google Scholar

12. Abalos E, Cuesta C, Grosso AL, Chou D, Say L. Global and regional estimates of preeclampsia and eclampsia: a systematic review. Eur J Obstet Gynecol Reprod Biol (2013) 170:1–7. doi:10.1016/j.ejogrb.2013.05.005

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Vest AR, Cho LS. Hypertension in pregnancy. Curr Atheroscler Rep (2014) 16:395. doi:10.1007/s11883-013-0395-8

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF. WHO analysis of causes of maternal death: a systematic review. Lancet (2006) 367:1066–74. doi:10.1016/S0140-6736(06)68397-9

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol (2009) 33:130–7. doi:10.1053/j.semperi.2009.02.010

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Cantwell R, Clutton-Brock T, Cooper G, Dawson A, Drife J, Garrod D, et al. Saving mothers’ lives: reviewing maternal deaths to make motherhood safer: 2006–2008. The eighth report of the confidential enquiries into maternal deaths in the United Kingdom. BJOG (2011) 118(Suppl 1):1–203. doi:10.1111/j.1471-0528.2010.02847.x

CrossRef Full Text | Google Scholar

17. Ghulmiyyah L, Sibai B. Maternal mortality from preeclampsia/eclampsia. Semin Perinatol (2012) 36:56–9. doi:10.1053/j.semperi.2011.09.011

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Abalos E, Cuesta C, Carroli G, Qureshi Z, Widmer M, Vogel JP, et al. Pre-eclampsia, eclampsia and adverse maternal and perinatal outcomes: a secondary analysis of the World Health Organization multicountry survey on maternal and newborn health. BJOG (2014) 121(Suppl 1):14–24. doi:10.1111/1471-0528.12629

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Robillard PY, Dekker G, Chaouat G, Hulsey TC, Saftlas A. Epidemiological studies on primipaternity and immunology in preeclampsia – a statement after twelve years of workshops. J Reprod Immunol (2011) 89:104–17. doi:10.1016/j.jri.2011.02.003

CrossRef Full Text | Google Scholar

20. Robillard PY, Dekker G, Iacobelli S, Chaouat G. An essay of reflection: why does preeclampsia exist in humans, and why are there such huge geographical differences in epidemiology? J Reprod Immunol (2016) 114:44–7. doi:10.1016/j.jri.2015.07.001

CrossRef Full Text | Google Scholar

21. Brew O, Sullivan MH, Woodman A. Comparison of normal and pre-eclamptic placental gene expression: a systematic review with meta-analysis. PLoS One (2016) 11:e0161504. doi:10.1371/journal.pone.0161504

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Leavey K, Benton SJ, Grynspan D, Kingdom JC, Bainbridge SA, Cox BJ. Unsupervised placental gene expression profiling identifies clinically relevant subclasses of human preeclampsia. Hypertension (2016) 68:137–47. doi:10.1161/HYPERTENSIONAHA.116.07293

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Redman CWG. Current topic: pre-eclampsia and the placenta. Placenta (1991) 12:301–8. doi:10.1016/0143-4004(91)90339-H

CrossRef Full Text | Google Scholar

24. Roberts JM, Hubel CA. The two stage model of preeclampsia: variations on the theme. Placenta (2009) 30(Suppl A):S32–7. doi:10.1016/j.placenta.2008.11.009

CrossRef Full Text | Google Scholar

25. Baker PN, Kenny LC. Obstetrics by Ten Teachers. Boca Raton, FL: CRC Press (2011).

Google Scholar

26. Pennington KA, Schlitt JM, Jackson DL, Schulz LC, Schust DJ. Preeclampsia: multiple approaches for a multifactorial disease. Dis Model Mech (2012) 5:9–18. doi:10.1242/dmm.008516

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Redman CW, Sargent IL, Staff AC. IFPA senior award lecture: making sense of pre-eclampsia – two placental causes of preeclampsia? Placenta (2014) 35(Suppl):S20–5. doi:10.1016/j.placenta.2013.12.008

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Redman CWG. The six stages of pre-eclampsia. Pregnancy Hypertens (2014) 4:246. doi:10.1016/j.preghy.2014.04.020

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Perucci LO, Corrêa MD, Dusse LM, Gomes KB, Sousa LP. Resolution of inflammation pathways in preeclampsia-a narrative review. Immunol Res (2017) 65:774–89. doi:10.1007/s12026-017-8921-3

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Hung TH, Skepper JN, Burton GJ. In vitro ischemia-reperfusion injury in term human placenta as a model for oxidative stress in pathological pregnancies. Am J Pathol (2001) 159:1031–43. doi:10.1016/S0002-9440(10)61778-6

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Burton GJ, Jauniaux E. Placental oxidative stress: from miscarriage to preeclampsia. J Soc Gynecol Investig (2004) 11:342–52. doi:10.1016/j.jsgi.2004.03.003

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Burdon C, Mann C, Cindrova-Davies T, Ferguson-Smith AC, Burton GJ. Oxidative stress and the induction of cyclooxygenase enzymes and apoptosis in the murine placenta. Placenta (2007) 28:724–33. doi:10.1016/j.placenta.2006.12.001

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Cindrova-Davies T, Spasic-Boskovic O, Jauniaux E, Charnock-Jones DS, Burton GJ. Nuclear factor-kappa B, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress: effects of antioxidant vitamins. Am J Pathol (2007) 170:1511–20. doi:10.2353/ajpath.2007.061035

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Burton GJ, Yung HW, Cindrova-Davies T, Charnock-Jones DS. Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia. Placenta (2009) 30(Suppl A):S43–8. doi:10.1016/j.placenta.2008.11.003

CrossRef Full Text | Google Scholar

35. Burton GJ, Jauniaux E. Oxidative stress. Best Pract Res Clin Endocrinol Metab (2011) 25:287–99. doi:10.1016/j.bpobgyn.2010.10.016

CrossRef Full Text | Google Scholar

36. Sánchez-Aranguren LC, Prada CE, Riaño-Medina CE, Lopez M. Endothelial dysfunction and preeclampsia: role of oxidative stress. Front Physiol (2014) 5:1. doi:10.3389/fphys.2014.00372

CrossRef Full Text | Google Scholar

37. Broughton Pipkin F, Rubin PC. Pre-eclampsia – the ‘disease of theories’. Br Med Bull (1994) 50:381–96. doi:10.1093/oxfordjournals.bmb.a072898

CrossRef Full Text | Google Scholar

38. Schlembach D. Pre-eclampsia – still a disease of theories. Fukushima J Med Sci (2003) 49:69–115. doi:10.5387/fms.49.69

CrossRef Full Text | Google Scholar

39. George EM. The disease of theories: unravelling the mechanisms of pre-eclampsia. Biochemist (2017) 39:22–5.

Google Scholar

40. Hubel CA. Oxidative stress in the pathogenesis of preeclampsia. Proc Soc Exp Biol Med (1999) 222:222–35. doi:10.1046/j.1525-1373.1999.d01-139.x

PubMed Abstract | CrossRef Full Text | Google Scholar

41. George EM. New approaches for managing preeclampsia: clues from clinical and basic research. Clin Ther (2014) 36:1873–81. doi:10.1016/j.clinthera.2014.09.023

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Wu P, Kwok CS, Haththotuwa R, Kotronias RA, Babu A, Fryer AA, et al. Pre-eclampsia is associated with a twofold increase in diabetes: a systematic review and meta-analysis. Diabetologia (2016) 59:2518–26. doi:10.1007/s00125-016-4098-x

CrossRef Full Text | Google Scholar

43. Wu P, Haththotuwa R, Kwok CS, Babu A, Kotronias RA, Rushton C, et al. Preeclampsia and future cardiovascular health: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes (2017) 10:e003497. doi:10.1161/CIRCOUTCOMES.116.003497

CrossRef Full Text | Google Scholar

44. Kell DB, Kenny LC. A dormant microbial component in the development of pre-eclampsia. Front Med Obs Gynecol (2016) 3:60. doi:10.3389/fmed.2016.00060

CrossRef Full Text | Google Scholar

45. Kaprelyants AS, Gottschal JC, Kell DB. Dormancy in non-sporulating bacteria. FEMS Microbiol Rev (1993) 10:271–86. doi:10.1111/j.1574-6968.1993.tb05871.x

CrossRef Full Text | Google Scholar

46. Kell DB, Kaprelyants AS, Weichart DH, Harwood CL, Barer MR. Viability and activity in readily culturable bacteria: a review and discussion of the practical issues. Antonie Van Leeuwenhoek (1998) 73:169–87. doi:10.1023/A:1000664013047

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Kell DB, Potgieter M, Pretorius E. Individuality, phenotypic differentiation, dormancy and ‘persistence’ in culturable bacterial systems: commonalities shared by environmental, laboratory, and clinical microbiology. F1000Research (2015) 4:179. doi:10.12688/f1000research.6709.1

CrossRef Full Text | Google Scholar

48. Potgieter M, Bester J, Kell DB, Pretorius E. The dormant blood microbiome in chronic, inflammatory diseases. FEMS Microbiol Rev (2015) 39:567–91. doi:10.1093/femsre/fuv013

PubMed Abstract | CrossRef Full Text | Google Scholar

49. Herrera JA, Chaudhuri G, López-Jaramillo P. Is infection a major risk factor for preeclampsia? Med Hypotheses (2001) 57:393–7. doi:10.1054/mehy.2001.1378

CrossRef Full Text | Google Scholar

50. Trogstad LIS, Eskild A, Bruu AL, Jeansson S, Jenum PA. Is preeclampsia an infectious disease? Acta Obstet Gynecol Scand (2001) 80:1036–8. doi:10.1034/j.1600-0412.2001.801112.x

CrossRef Full Text | Google Scholar

51. Todros T, Vasario E, Cardaropoli S. Preeclampsia as an infectious disease. Exp Rev Obs Gynecol (2007) 2:735–41. doi:10.1586/17474108.2.6.735

CrossRef Full Text | Google Scholar

52. Conde-Agudelo A, Villar J, Lindheimer M. Maternal infection and risk of preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol (2008) 198:7–22. doi:10.1016/j.ajog.2007.07.040

PubMed Abstract | CrossRef Full Text | Google Scholar

53. López-Jaramillo P, Herrera JA, Arenas-Mantilla M, Jauregui IE, Mendoza MA. Subclinical infection as a cause of inflammation in preeclampsia. Am J Ther (2008) 15:373–6. doi:10.1097/MJT.0b013e318164c149

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Rustveld LO, Kelsey SF, Sharma R. Association between maternal infections and preeclampsia: a systematic review of epidemiologic studies. Matern Child Health J (2008) 12:223–42. doi:10.1007/s10995-007-0224-1

PubMed Abstract | CrossRef Full Text | Google Scholar

55. Di Simone N, Tersigni C, Cardaropoli S, Franceschi F, Di Nicuolo F, Castellani R, et al. Helicobacter pylori infection contributes to placental impairment in preeclampsia: basic and clinical evidences. Helicobacter (2017) 22:e12347. doi:10.1111/hel.12347

CrossRef Full Text | Google Scholar

56. Nourollahpour Shiadeh M, Behboodi Moghadam Z, Adam I, Saber V, Bagheri M, Rostami A. Human infectious diseases and risk of preeclampsia: an updated review of the literature. Infection (2017) 45:589–600. doi:10.1007/s15010-017-1031-2

CrossRef Full Text | Google Scholar

57. Kleinrouweler CE, Van Uitert M, Moerland PD, Ris-Stalpers C, Van Der Post JA, Afink GB. Differentially expressed genes in the pre-eclamptic placenta: a systematic review and meta-analysis. PLoS One (2013) 8:e68991. doi:10.1371/journal.pone.0068991

PubMed Abstract | CrossRef Full Text | Google Scholar

58. Chung MC, Jorgensen SC, Popova TG, Tonry JH, Bailey CL, Popov SG. Activation of plasminogen activator inhibitor implicates protease InhA in the acute-phase response to Bacillus anthracis infection. J Med Microbiol (2009) 58:737–44. doi:10.1099/jmm.0.007427-0

PubMed Abstract | CrossRef Full Text | Google Scholar

59. Ubagai T, Tansho S, Ieki R, Ono Y. Evaluation of TREM1 gene expression in circulating polymorphonuclear leukocytes and its inverse correlation with the severity of pathophysiological conditions in patients with acute bacterial infections. Jpn J Infect Dis (2012) 65:376–82. doi:10.7883/yoken.65.376

PubMed Abstract | CrossRef Full Text | Google Scholar

60. Ubagai T, Nakano R, Kikuchi H, Ono Y. Gene expression analysis of TREM1 and GRK2 in polymorphonuclear leukocytes as the surrogate biomarkers of acute bacterial infections. Int J Med Sci (2014) 11:215–21. doi:10.7150/ijms.7231

PubMed Abstract | CrossRef Full Text | Google Scholar

61. Fillerova R, Gallo J, Radvansky M, Kraiczova V, Kudelka M, Kriegova E. Excellent diagnostic characteristics for ultrafast gene profiling of DEFA1-IL1B-LTF in detection of prosthetic joint infections. J Clin Microbiol (2017) 55:2686–97. doi:10.1128/JCM.00558-17

PubMed Abstract | CrossRef Full Text | Google Scholar

62. Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia: current concepts. Am J Obstet Gynecol (1998) 179:1359–75. doi:10.1016/S0002-9378(98)70160-7

PubMed Abstract | CrossRef Full Text | Google Scholar

63. Sargent IL, Borzychowski AM, Redman CW. Immunoregulation in normal pregnancy and pre-eclampsia: an overview. Reprod Biomed Online (2006) 13:680–6. doi:10.1016/S1472-6483(10)60659-1

CrossRef Full Text | Google Scholar

64. Dekker G, Robillard PY. Pre-eclampsia: is the immune maladaptation hypothesis still standing? An epidemiological update. J Reprod Immunol (2007) 76:8–16. doi:10.1016/j.jri.2007.03.015

CrossRef Full Text | Google Scholar

65. Moffett A, Hiby SE. How does the maternal immune system contribute to the development of pre-eclampsia? Placenta (2007) 28(Suppl A):S51–6. doi:10.1016/j.placenta.2006.11.008

CrossRef Full Text | Google Scholar

66. Cudihy D, Lee RV. The pathophysiology of pre-eclampsia: current clinical concepts. J Obstet Gynaecol (2009) 29:576–82. doi:10.1080/01443610903061751

PubMed Abstract | CrossRef Full Text | Google Scholar

67. James JL, Whitley GS, Cartwright JE. Pre-eclampsia: fitting together the placental, immune and cardiovascular pieces. J Pathol (2010) 221:363–78. doi:10.1002/path.2719

CrossRef Full Text | Google Scholar

68. Jianjun Z, Yali H, Zhiqun W, Mingming Z, Xia Z. Imbalance of T-cell transcription factors contributes to the Th1 type immunity predominant in pre-eclampsia. Am J Reprod Immunol (2010) 63:38–45. doi:10.1111/j.1600-0897.2009.00763.x

PubMed Abstract | CrossRef Full Text | Google Scholar

69. Redman CWG, Sargent IL. Immunology of pre-eclampsia. Am J Reprod Immunol (2010) 63:534–43. doi:10.1111/j.1600-0897.2010.00831.x

PubMed Abstract | CrossRef Full Text | Google Scholar

70. Hsu P, Nanan RK. Innate and adaptive immune interactions at the fetal-maternal interface in healthy human pregnancy and pre-eclampsia. Front Immunol (2014) 5:125. doi:10.3389/fimmu.2014.00125

PubMed Abstract | CrossRef Full Text | Google Scholar

71. Dekker GA, Robillard PY, Hulsey TC. Immune maladaptation in the etiology of preeclampsia: a review of corroborative epidemiologic studies. Obstet Gynecol Surv (1998) 53:377–82. doi:10.1097/00006254-199806000-00023

PubMed Abstract | CrossRef Full Text | Google Scholar

72. Buzan T. How to Mind Map. London: Thorsons (2002).

Google Scholar

73. Kenny LC, Kell DB. Immunological Tolerance, Pregnancy and Pre-Eclampsia: The Roles of Semen Microbes and the Father. bioRxiv Preprint. bioRxiv, 198796 (2017). doi:10.1101/198796

CrossRef Full Text | Google Scholar

74. Medawar PB. Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates. Symp Soc Exp Biol (1953) 7:320–38.

Google Scholar

75. Billington WD. The immunological problem of pregnancy: 50 years with the hope of progress. A tribute to Peter Medawar. J Reprod Immunol (2003) 60:1–11. doi:10.1016/S0165-0378(03)00083-4

PubMed Abstract | CrossRef Full Text | Google Scholar

76. Trowsdale J, Betz AG. Mother’s little helpers: mechanisms of maternal-fetal tolerance. Nat Immunol (2006) 7:241–6. doi:10.1038/ni1317

PubMed Abstract | CrossRef Full Text | Google Scholar

77. Munoz-Suano A, Hamilton AB, Betz AG. Gimme shelter: the immune system during pregnancy. Immunol Rev (2011) 241:20–38. doi:10.1111/j.1600-065X.2011.01002.x

PubMed Abstract | CrossRef Full Text | Google Scholar

78. Colucci F, Moffett A, Trowsdale J. Medawar and the immunological paradox of pregnancy: 60 years on. Eur J Immunol (2014) 44:1883–5. doi:10.1002/eji.201470065

CrossRef Full Text | Google Scholar

79. Bonney EA. Immune regulation in pregnancy: a matter of perspective? Obstet Gynecol Clin North Am (2016) 43:679–98. doi:10.1016/j.ogc.2016.07.004

PubMed Abstract | CrossRef Full Text | Google Scholar

80. Haig D. Genetic conflicts in human pregnancy. Q Rev Biol (1993) 68:495–532. doi:10.1086/418300

PubMed Abstract | CrossRef Full Text | Google Scholar

81. Robertson SA, Sharkey DJ. The role of semen in induction of maternal immune tolerance to pregnancy. Semin Immunol (2001) 13:243–54. doi:10.1006/smim.2000.0320

PubMed Abstract | CrossRef Full Text | Google Scholar

82. Clark GF, Schust DJ. Manifestations of immune tolerance in the human female reproductive tract. Front Immunol (2013) 4:26. doi:10.3389/fimmu.2013.00026

PubMed Abstract | CrossRef Full Text | Google Scholar

83. Gleicher N, Kushnir VA, Barad DH. Redirecting reproductive immunology research toward pregnancy as a period of temporary immune tolerance. J Assist Reprod Genet (2017) 34:425–30. doi:10.1007/s10815-017-0874-x

PubMed Abstract | CrossRef Full Text | Google Scholar

84. Moffett A, Loke C. Immunology of placentation in eutherian mammals. Nat Rev Immunol (2006) 6:584–94. doi:10.1038/nri1897

PubMed Abstract | CrossRef Full Text | Google Scholar

85. Rusterholz C, Hahn S, Holzgreve W. Role of placentally produced inflammatory and regulatory cytokines in pregnancy and the etiology of preeclampsia. Semin Immunopathol (2007) 29:151–62. doi:10.1007/s00281-007-0071-6

PubMed Abstract | CrossRef Full Text | Google Scholar

86. Dutta P, Burlingham WJ. Microchimerism: tolerance vs. sensitization. Curr Opin Organ Transplant (2011) 16:359–65. doi:10.1097/MOT.0b013e3283484b57

CrossRef Full Text | Google Scholar

87. Rusterholz C, Messerli M, Hoesli I, Hahn S. Placental microparticles, DNA, and RNA in preeclampsia. Hypertens Pregnancy (2011) 30:364–75. doi:10.3109/10641951003599571

PubMed Abstract | CrossRef Full Text | Google Scholar

88. Kinder JM, Stelzer IA, Arck PC, Way SS. Immunological implications of pregnancy-induced microchimerism. Nat Rev Immunol (2017) 17:483–94. doi:10.1038/nri.2017.38

PubMed Abstract | CrossRef Full Text | Google Scholar

89. Knight M, Redman CWG, Linton EA, Sargent IL. Shedding of syncytiotrophoblast microvilli into the maternal circulation in pre-eclamptic pregnancies. Br J Obstet Gynaecol (1998) 105:632–40. doi:10.1111/j.1471-0528.1998.tb10178.x

PubMed Abstract | CrossRef Full Text | Google Scholar

90. Huppertz B, Kingdom J, Caniggia I, Desoye G, Black S, Korr H, et al. Hypoxia favours necrotic versus apoptotic shedding of placental syncytiotrophoblast into the maternal circulation. Placenta (2003) 24:181–90. doi:10.1053/plac.2002.0903

PubMed Abstract | CrossRef Full Text | Google Scholar

91. Sargent IL, Germain SJ, Sacks GP, Kumar S, Redman CWG. Trophoblast deportation and the maternal inflammatory response in pre-eclampsia. J Reprod Immunol (2003) 59:153–60. doi:10.1016/S0165-0378(03)00044-5

PubMed Abstract | CrossRef Full Text | Google Scholar

92. Gupta AK, Hasler P, Holzgreve W, Gebhardt S, Hahn S. Induction of neutrophil extracellular DNA lattices by placental microparticles and IL-8 and their presence in preeclampsia. Hum Immunol (2005) 66:1146–54. doi:10.1016/j.humimm.2005.11.003

PubMed Abstract | CrossRef Full Text | Google Scholar

93. Goswami D, Tannetta DS, Magee LA, Fuchisawa A, Redman CWG, Sargent IL, et al. Excess syncytiotrophoblast microparticle shedding is a feature of early-onset pre-eclampsia, but not normotensive intrauterine growth restriction. Placenta (2006) 27:56–61. doi:10.1016/j.placenta.2004.11.007

PubMed Abstract | CrossRef Full Text | Google Scholar

94. Reddy A, Zhong XY, Rusterholz C, Hahn S, Holzgreve W, Redman CWG, et al. The effect of labour and placental separation on the shedding of syncytiotrophoblast microparticles, cell-free DNA and mRNA in normal pregnancy and pre-eclampsia. Placenta (2008) 29:942–9. doi:10.1016/j.placenta.2008.08.018

PubMed Abstract | CrossRef Full Text | Google Scholar

95. Hartley JDR, Ferguson BJ, Moffett A. The role of shed placental DNA in the systemic inflammatory syndrome of preeclampsia. Am J Obstet Gynecol (2015) 213:268–77. doi:10.1016/j.ajog.2015.03.026

PubMed Abstract | CrossRef Full Text | Google Scholar

96. Clark DA, Chaput A, Tutton D. Active suppression of host-vs-graft reaction in pregnant mice. VII. Spontaneous abortion of allogeneic CBA/J x DBA/2 fetuses in the uterus of CBA/J mice correlates with deficient non-T suppressor cell activity. J Immunol (1986) 136:1668–75.

PubMed Abstract | Google Scholar

97. Mellor AL, Sivakumar J, Chandler P, Smith K, Molina H, Mao D, et al. Prevention of T cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy. Nat Immunol (2001) 2:64–8. doi:10.1038/83183

PubMed Abstract | CrossRef Full Text | Google Scholar

98. Wilczyński JR. Immunological analogy between allograft rejection, recurrent abortion and pre-eclampsia – the same basic mechanism? Hum Immunol (2006) 67:492–511. doi:10.1016/j.humimm.2006.04.007

PubMed Abstract | CrossRef Full Text | Google Scholar

99. Warning JC, Mccracken SA, Morris JM. A balancing act: mechanisms by which the fetus avoids rejection by the maternal immune system. Reproduction (2011) 141:715–24. doi:10.1530/REP-10-0360

PubMed Abstract | CrossRef Full Text | Google Scholar

100. Kim CJ, Romero R, Chaemsaithong P, Kim JS. Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance. Am J Obstet Gynecol (2015) 213:S53–69. doi:10.1016/j.ajog.2015.08.041

PubMed Abstract | CrossRef Full Text | Google Scholar

101. Raman K, Wang H, Troncone MJ, Khan WI, Pare G, Terry J. Overlap chronic placental inflammation is associated with a unique gene expression pattern. PLoS One (2015) 10:e0133738. doi:10.1371/journal.pone.0133738

PubMed Abstract | CrossRef Full Text | Google Scholar

102. Hyde KJ, Schust DJ. Immunologic challenges of human reproduction: an evolving story. Fertil Steril (2016) 106:499–510. doi:10.1016/j.fertnstert.2016.07.1073

PubMed Abstract | CrossRef Full Text | Google Scholar

103. Zelante T, Pieraccini G, Scaringi L, Aversa F, Romani L. Learning from other diseases: protection and pathology in chronic fungal infections. Semin Immunopathol (2016) 38:239–48. doi:10.1007/s00281-015-0523-3

PubMed Abstract | CrossRef Full Text | Google Scholar

104. Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci (2011) 1221:80–7. doi:10.1111/j.1749-6632.2010.05938.x

PubMed Abstract | CrossRef Full Text | Google Scholar

105. Racicot K, Kwon JY, Aldo P, Silasi M, Mor G. Understanding the complexity of the immune system during pregnancy. Am J Reprod Immunol (2014) 72:107–16. doi:10.1111/aji.12289

PubMed Abstract | CrossRef Full Text | Google Scholar

106. Mor G, Aldo P, Alvero AB. The unique immunological and microbial aspects of pregnancy. Nat Rev Immunol (2017) 17:469–82. doi:10.1038/nri.2017.64

CrossRef Full Text | Google Scholar

107. Hench PS. The ameliorating effect of pregnancy on chronic atrophic (infectious rheumatoid) arthritis, fibrositis and intermittent hydrarthritis. Mayo Clin Proc (1938) 13:161–7.

Google Scholar

108. Glyn J. The discovery and early use of cortisone. J R Soc Med (1998) 91:513–7. doi:10.1177/014107689809101004

CrossRef Full Text | Google Scholar

109. de Man YA, Dolhain RJ, Van De Geijn FE, Willemsen SP, Hazes JM. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum (2008) 59:1241–8. doi:10.1002/art.24003

PubMed Abstract | CrossRef Full Text | Google Scholar

110. Muñoz-Valle JF, Vazquez-Del Mercado M, García-Iglesias T, Orozco-Barocio G, Bernard-Medina G, Martínez-Bonilla G, et al. T(H)1/T(H)2 cytokine profile, metalloprotease-9 activity and hormonal status in pregnant rheumatoid arthritis and systemic lupus erythematosus patients. Clin Exp Immunol (2003) 131:377–84. doi:10.1046/j.1365-2249.2003.02059.x

PubMed Abstract | CrossRef Full Text | Google Scholar

111. Nelson JL, Hughes KA, Smith AG, Nisperos BB, Branchaud AM, Hansen JA. Maternal-fetal disparity in HLA class II alloantigens and the pregnancy-induced amelioration of rheumatoid arthritis. N Engl J Med (1993) 329:466–71. doi:10.1056/NEJM199308123290704

PubMed Abstract | CrossRef Full Text | Google Scholar

112. Chiam NP, Lim LL. Uveitis and gender: the course of uveitis in pregnancy. J Ophthalmol (2014) 2014:401915. doi:10.1155/2014/401915

PubMed Abstract | CrossRef Full Text | Google Scholar

113. James D, Steer PL, Weiner C, Gonik B, Crowther C, Robson S, editors. High Risk Pregnancy. Amsterdam: Elsevier/Saunders (2010).

Google Scholar

114. Khashan AS, Kenny LC, Laursen TM, Mahmood U, Mortensen PB, Henriksen TB, et al. Pregnancy and the risk of autoimmune disease. PLoS One (2011) 6:e19658. doi:10.1371/journal.pone.0019658

CrossRef Full Text | Google Scholar

115. Hunt JS, Petroff MG, Mcintire RH, Ober C. HLA-G and immune tolerance in pregnancy. FASEB J (2005) 19:681–93. doi:10.1096/fj.04-2078rev

PubMed Abstract | CrossRef Full Text | Google Scholar

116. Hviid TV. HLA-G in human reproduction: aspects of genetics, function and pregnancy complications. Hum Reprod Update (2006) 12:209–32. doi:10.1093/humupd/dmi048

PubMed Abstract | CrossRef Full Text | Google Scholar

117. Guleria I, Sayegh MH. Maternal acceptance of the fetus: true human tolerance. J Immunol (2007) 178:3345–51. doi:10.4049/jimmunol.178.6.3345

PubMed Abstract | CrossRef Full Text | Google Scholar

118. Dahl M, Perin TL, Djurisic S, Rasmussen M, Ohlsson J, Buus S, et al. Soluble human leukocyte antigen-G in seminal plasma is associated with HLA-G genotype: possible implications for fertility success. Am J Reprod Immunol (2014) 72:89–105. doi:10.1111/aji.12251

PubMed Abstract | CrossRef Full Text | Google Scholar

119. Lynge Nilsson L, Djurisic S, Hviid TVF. Controlling the immunological crosstalk during conception and pregnancy: HLA-G in reproduction. Front Immunol (2014) 5:198. doi:10.3389/fimmu.2014.00198

PubMed Abstract | CrossRef Full Text | Google Scholar

120. Martínez-Varea A, Pellicer B, Perales-Marin A, Pellicer A. Relationship between maternal immunological response during pregnancy and onset of preeclampsia. J Immunol Res (2014) 2014:210241. doi:10.1155/2014/210241

PubMed Abstract | CrossRef Full Text | Google Scholar

121. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell (2008) 133:775–87. doi:10.1016/j.cell.2008.05.009

PubMed Abstract | CrossRef Full Text | Google Scholar

122. Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol (2004) 5:266–71. doi:10.1038/ni1037

PubMed Abstract | CrossRef Full Text | Google Scholar

123. Guerin LR, Prins JR, Robertson SA. Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment? Hum Reprod Update (2009) 15:517–35. doi:10.1093/humupd/dmp004

PubMed Abstract | CrossRef Full Text | Google Scholar

124. Saito S. Th17 cells and regulatory T cells: new light on pathophysiology of preeclampsia. Immunol Cell Biol (2010) 88:615–7. doi:10.1038/icb.2010.68

CrossRef Full Text | Google Scholar

125. Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am J Reprod Immunol (2010) 63:601–10. doi:10.1111/j.1600-0897.2010.00852.x

PubMed Abstract | CrossRef Full Text | Google Scholar

126. Clark DA, Chaouat G. Regulatory T cells and reproduction: how do they do it? J Reprod Immunol (2012) 96:1–7. doi:10.1016/j.jri.2012.07.007

PubMed Abstract | CrossRef Full Text | Google Scholar

127. Alijotas-Reig J, Llurba E, Gris JM. Potentiating maternal immune tolerance in pregnancy: a new challenging role for regulatory T cells. Placenta (2014) 35:241–8. doi:10.1016/j.placenta.2014.02.004

PubMed Abstract | CrossRef Full Text | Google Scholar

128. Jiang TT, Chaturvedi V, Ertelt JM, Kinder JM, Clark DR, Valent AM, et al. Regulatory T cells: new keys for further unlocking the enigma of fetal tolerance and pregnancy complications. J Immunol (2014) 192:4949–56. doi:10.4049/jimmunol.1400498

PubMed Abstract | CrossRef Full Text | Google Scholar

129. La Rocca C, Carbone F, Longobardi S, Matarese G. The immunology of pregnancy: regulatory T cells control maternal immune tolerance toward the fetus. Immunol Lett (2014) 162:41–8. doi:10.1016/j.imlet.2014.06.013

CrossRef Full Text | Google Scholar

130. Clark DA. The importance of being a regulatory T cell in pregnancy. J Reprod Immunol (2016) 116:60–9. doi:10.1016/j.jri.2016.04.288

CrossRef Full Text | Google Scholar

131. Harmon AC, Cornelius DC, Amaral LM, Faulkner JL, Cunningham MW Jr, Wallace K, et al. The role of inflammation in the pathology of preeclampsia. Clin Sci (Lond) (2016) 130:409–19. doi:10.1042/CS20150702

PubMed Abstract | CrossRef Full Text | Google Scholar

132. LaMarca B, Cornelius DC, Harmon AC, Amaral LM, Cunningham MW, Faulkner JL, et al. Identifying immune mechanisms mediating the hypertension during preeclampsia. Am J Physiol Regul Integr Comp Physiol (2016) 311:R1–9. doi:10.1152/ajpregu.00052.2016

CrossRef Full Text | Google Scholar

133. Nancy P, Tagliani E, Tay CS, Asp P, Levy DE, Erlebacher A. Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface. Science (2012) 336:1317–21. doi:10.1126/science.1220030

PubMed Abstract | CrossRef Full Text | Google Scholar

134. Williams Z. Inducing tolerance to pregnancy. N Engl J Med (2012) 367:1159–61. doi:10.1056/NEJMcibr1207279

CrossRef Full Text | Google Scholar

135. Samstein RM, Josefowicz SZ, Arvey A, Treuting PM, Rudensky AY. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell (2012) 150:29–38. doi:10.1016/j.cell.2012.05.031

PubMed Abstract | CrossRef Full Text | Google Scholar

136. Somerset DA, Zheng Y, Kilby MD, Sansom DM, Drayson MT. Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset. Immunology (2004) 112:38–43. doi:10.1111/j.1365-2567.2004.01869.x

PubMed Abstract | CrossRef Full Text | Google Scholar

137. Schumacher A, Zenclussen AC. Effects of heme oxygenase-1 on innate and adaptive immune responses promoting pregnancy success and allograft tolerance. Front Pharmacol (2014) 5:288. doi:10.3389/fphar.2014.00288

CrossRef Full Text | Google Scholar

138. Carp HJA, Selmi C, Shoenfeld Y. The autoimmune bases of infertility and pregnancy loss. J Autoimmun (2012) 38:J266–74. doi:10.1016/j.jaut.2011.11.016

PubMed Abstract | CrossRef Full Text | Google Scholar

139. Mittrücker H-W, Kaufmann SHE. Mini-review: regulatory T cells and infection: suppression revisited. Eur J Immunol (2004) 34:306–12. doi:10.1002/eji.200324578

PubMed Abstract | CrossRef Full Text | Google Scholar

140. Belkaid Y. Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol (2007) 7:875–88. doi:10.1038/nri2189

PubMed Abstract | CrossRef Full Text | Google Scholar

141. Belkaid Y, Tarbell K. Regulatory T cells in the control of host-microorganism interactions. Annu Rev Immunol (2009) 27:551–89. doi:10.1146/annurev.immunol.021908.132723

CrossRef Full Text | Google Scholar

142. Maizels RM, Smith KA. Regulatory T cells in infection. Adv Immunol (2011) 112:73–136. doi:10.1016/B978-0-12-387827-4.00003-6

CrossRef Full Text | Google Scholar

143. Sanchez AM, Yang Y. The role of natural regulatory T cells in infection. Immunol Res (2011) 49:124–34. doi:10.1007/s12026-010-8176-8

CrossRef Full Text | Google Scholar

144. Berod L, Puttur F, Huehn J, Sparwasser T. Tregs in infection and vaccinology: heroes or traitors? Microb Biotechnol (2012) 5:260–9. doi:10.1111/j.1751-7915.2011.00299.x

PubMed Abstract | CrossRef Full Text | Google Scholar

145. Williams Z, Zepf D, Longtine J, Anchan R, Broadman B, Missmer SA, et al. Foreign fetal cells persist in the maternal circulation. Fertil Steril (2009) 91:2593–5. doi:10.1016/j.fertnstert.2008.02.008

PubMed Abstract | CrossRef Full Text | Google Scholar

146. Hahn S, Rusterholz C, Hösli I, Lapaire O. Cell-free nucleic acids as potential markers for preeclampsia. Placenta (2011) 32(Suppl):S17–20. doi:10.1016/j.placenta.2010.06.018

PubMed Abstract | CrossRef Full Text | Google Scholar

147. Visca E, Lapaire O, Hosli I, Hahn S. Cell-free fetal nucleic acids as prenatal biomarkers. Expert Opin Med Diagn (2011) 5:151–60. doi:10.1517/17530059.2011.554821

CrossRef Full Text | Google Scholar

148. Robertson SA, Bromfield JJ, Tremellen KP. Seminal ‘priming’ for protection from pre-eclampsia-a unifying hypothesis. J Reprod Immunol (2003) 59:253–65. doi:10.1016/S0165-0378(03)00052-4

PubMed Abstract | CrossRef Full Text | Google Scholar

149. Getz GS. Thematic review series: the immune system and atherogenesis. Bridging the innate and adaptive immune systems. J Lipid Res (2005) 46:619–22. doi:10.1194/jlr.E500002-JLR200

CrossRef Full Text | Google Scholar

150. Sarma JV, Ward PA. The complement system. Cell Tissue Res (2011) 343:227–35. doi:10.1007/s00441-010-1034-0

PubMed Abstract | CrossRef Full Text | Google Scholar

151. Kennedy MA. A brief review of the basics of immunology: the innate and adaptive response. Vet Clin North Am Small Anim Pract (2010) 40:369–79. doi:10.1016/j.cvsm.2010.01.003

PubMed Abstract | CrossRef Full Text | Google Scholar

152. Warrington R, Watson W, Kim HL, Antonetti FR. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol (2011) 7(Suppl 1):S1. doi:10.1186/1710-1492-7-S1-S1

PubMed Abstract | CrossRef Full Text | Google Scholar

153. Abbas AK, Lichtman AH, Pillai S. Basic Immunology: Functions and Disorders of the Immune System. 8th ed. St Louis, MO: Elsevier (2012).

Google Scholar

154. Abbas AK, Lichtman AH, Pillai S. Basic Immunology: Functions and Disorders of the Immune System. 5th ed. St Louis, MO: Elsevier (2016).

Google Scholar

155. Murphy K, Weaver C, editors. Janeway’s Immunobiology. New York: Garland Science (2016).

Google Scholar

156. Kell DB, Pretorius E. On the translocation of bacteria and their lipopolysaccharides between blood and peripheral locations in chronic, inflammatory diseases: the central roles of LPS and LPS-induced cell death. Integr Biol (2015) 7:1339–77. doi:10.1039/C5IB00158G

CrossRef Full Text | Google Scholar

157. Legutki JB, Magee DM, Stafford P, Johnston SA. A general method for characterization of humoral immunity induced by a vaccine or infection. Vaccine (2010) 28:4529–37. doi:10.1016/j.vaccine.2010.04.061

PubMed Abstract | CrossRef Full Text | Google Scholar

158. Stafford P, Halperin R, Legutki JB, Magee DM, Galgiani J, Johnston SA. Physical characterization of the “immunosignaturing effect”. Mol Cell Proteomics (2012) 11:M111011593. doi:10.1074/mcp.M111.011593

CrossRef Full Text | Google Scholar

159. Sykes KF, Legutki JB, Stafford P. Immunosignaturing: a critical review. Trends Biotechnol (2013) 31:45–51. doi:10.1016/j.tibtech.2012.10.012

PubMed Abstract | CrossRef Full Text | Google Scholar

160. King AE, Kelly RW, Sallenave J-M, Bocking AD, Challis JRG. Innate immune defences in the human uterus during pregnancy. Placenta (2007) 28:1099–106. doi:10.1016/j.placenta.2007.06.002

CrossRef Full Text | Google Scholar

161. Schminkey DL, Groer M. Imitating a stress response: a new hypothesis about the innate immune system’s role in pregnancy. Med Hypotheses (2014) 82:721–9. doi:10.1016/j.mehy.2014.03.013

PubMed Abstract | CrossRef Full Text | Google Scholar

162. Zhang J, Dunk C, Croy AB, Lye SJ. To serve and to protect: the role of decidual innate immune cells on human pregnancy. Cell Tissue Res (2016) 363:249–65. doi:10.1007/s00441-015-2315-4

PubMed Abstract | CrossRef Full Text | Google Scholar

163. Redman CW. Immunological aspects of pre-eclampsia. Baillieres Clin Obstet Gynaecol (1992) 6:601–15. doi:10.1016/S0950-3552(05)80012-4

PubMed Abstract | CrossRef Full Text | Google Scholar

164. Saito S, Shiozaki A, Nakashima A, Sakai M, Sasaki Y. The role of the immune system in preeclampsia. Mol Aspects Med (2007) 28:192–209. doi:10.1016/j.mam.2007.02.006

CrossRef Full Text | Google Scholar

165. Visser N, Van Rijn BB, Rijkers GT, Franx A, Bruinse HW. Inflammatory changes in preeclampsia: current understanding of the maternal innate and adaptive immune response. Obstet Gynecol Surv (2007) 62:191–201. doi:10.1097/01.ogx.0000256779.06275.c4

PubMed Abstract | CrossRef Full Text | Google Scholar

166. Brewster JA, Orsi NM, Gopichandran N, Mcshane P, Ekbote UV, Walker JJ. Gestational effects on host inflammatory response in normal and pre-eclamptic pregnancies. Eur J Obstet Gynecol Reprod Biol (2008) 140:21–6. doi:10.1016/j.ejogrb.2007.12.020

PubMed Abstract | CrossRef Full Text | Google Scholar

167. Laresgoiti-Servitje E. A leading role for the immune system in the pathophysiology of preeclampsia. J Leukoc Biol (2013) 94:247–57. doi:10.1189/jlb.1112603

CrossRef Full Text | Google Scholar

168. Perez-Sepulveda A, Torres MJ, Khoury M, Illanes SE. Innate immune system and preeclampsia. Front Immunol (2014) 5:244. doi:10.3389/fimmu.2014.00244

CrossRef Full Text | Google Scholar

169. Staff AC, Johnsen GM, Dechend R, Redman CWG. Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors. J Reprod Immunol (2014) 10(1–102):120–6. doi:10.1016/j.jri.2013.09.001

PubMed Abstract | CrossRef Full Text | Google Scholar

170. Redman CWG, Sargent IL, Taylor RN. Immunology of normal pregnancy and preeclampsia. 4th ed. Chesley’s Hypertensive Disorders in Pregnancy. (2015). p. 161–79. doi:10.1016/B978-0-12-407866-6.00008-0

CrossRef Full Text | Google Scholar

171. Parker LC, Prince LR, Sabroe I. Translational mini-review series on toll-like receptors: networks regulated by toll-like receptors mediate innate and adaptive immunity. Clin Exp Immunol (2007) 147:199–207. doi:10.1111/j.1365-2249.2006.03203.x

PubMed Abstract | CrossRef Full Text | Google Scholar

172. Trinchieri G, Sher A. Cooperation of toll-like receptor signals in innate immune defence. Nat Rev Immunol (2007) 7:179–90. doi:10.1038/nri2038

PubMed Abstract | CrossRef Full Text | Google Scholar

173. Nelson DE, Ihekwaba AEC, Elliott M, Gibney CA, Foreman BE, Nelson G, et al. Oscillations in NF-κB signalling control the dynamics of gene expression. Science (2004) 306:704–8. doi:10.1126/science.1099962

CrossRef Full Text | Google Scholar

174. Ashall L, Horton CA, Nelson DE, Paszek P, Ryan S, Sillitoe K, et al. Pulsatile stimulation determines timing and specificity of NFkappa-B-dependent transcription. Science (2009) 324:242–6. doi:10.1126/science.1164860

CrossRef Full Text | Google Scholar

175. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol (1994) 12:991–1045. doi:10.1146/annurev.iy.12.040194.005015

PubMed Abstract | CrossRef Full Text | Google Scholar

176. Anderson CC, Matzinger P. Danger: the view from the bottom of the cliff. Semin Immunol (2000) 12:231–8; discussion 257–344. doi:10.1006/smim.2000.0236

CrossRef Full Text | Google Scholar

177. Matzinger P. Essay 1: the danger model in its historical context. Scand J Immunol (2001) 54:4–9. doi:10.1046/j.1365-3083.2001.00974.x

CrossRef Full Text | Google Scholar

178. Matzinger P. The danger model: a renewed sense of self. Science (2002) 296:301–5. doi:10.1126/science.1071059

PubMed Abstract | CrossRef Full Text | Google Scholar

179. Matzinger P, Kamala T. Tissue-based class control: the other side of tolerance. Nat Rev Immunol (2011) 11:221–30. doi:10.1038/nri2940

PubMed Abstract | CrossRef Full Text | Google Scholar

180. Matzinger P. The evolution of the danger theory. Expert Rev Clin Immunol (2012) 8:311–7. doi:10.1586/eci.12.21

CrossRef Full Text | Google Scholar

181. McCarthy CM, Kenny LC. Immunostimulatory role of mitochondrial DAMPs: alarming for pre-eclampsia? Am J Reprod Immunol (2016) 76:341–7. doi:10.1111/aji.12526

PubMed Abstract | CrossRef Full Text | Google Scholar

182. Bonney EA. Preeclampsia: a view through the danger model. J Reprod Immunol (2007) 76:68–74. doi:10.1016/j.jri.2007.03.006

PubMed Abstract | CrossRef Full Text | Google Scholar

183. Sacks GP, Studena K, Sargent K, Redman CWG. Normal pregnancy and preeclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis. Am J Obstet Gynecol (1998) 179:80–6. doi:10.1016/S0002-9378(98)70254-6

PubMed Abstract | CrossRef Full Text | Google Scholar

184. Redman CWG, Sacks GP, Sargent IL. Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol (1999) 180:499–506. doi:10.1016/S0002-9378(99)70239-5

PubMed Abstract | CrossRef Full Text | Google Scholar

185. Kim YM, Romero R, Oh SY, Kim CJ, Kilburn BA, Armant DR, et al. Toll-like receptor 4: a potential link between “danger signals,” the innate immune system and preeclampsia? Am J Obstet Gynecol (2005) 193:921–7. doi:10.1016/j.ajog.2005.06.053

CrossRef Full Text | Google Scholar

186. Wang CC, Yim KW, Poon TCW, Choy KW, Chu CY, Lui WT, et al. Innate immune response by ficolin binding in apoptotic placenta is associated with the clinical syndrome of preeclampsia. Clin Chem (2007) 53:42–52. doi:10.1373/clinchem.2007.074401

PubMed Abstract | CrossRef Full Text | Google Scholar

187. Yeh CC, Chao KC, Huang SJ. Innate immunity, decidual cells, and preeclampsia. Reprod Sci (2013) 20:339–53. doi:10.1177/1933719112450330

PubMed Abstract | CrossRef Full Text | Google Scholar

188. Bounds KR, Newell-Rogers MK, Mitchell BM. Four pathways involving innate immunity in the pathogenesis of preeclampsia. Front Cardiovasc Med (2015) 2:20. doi:10.3389/fcvm.2015.00020

PubMed Abstract | CrossRef Full Text | Google Scholar

189. Triggianese P, Perricone C, Chimenti MS, De Carolis C, Perricone R. Innate immune system at the maternal-fetal interface: mechanisms of disease and targets of therapy in pregnancy syndromes. Am J Reprod Immunol (2016) 76:245–57. doi:10.1111/aji.12509

PubMed Abstract | CrossRef Full Text | Google Scholar

190. Redman CWG, Sargent IL. Pre-eclampsia, the placenta and the maternal systemic inflammatory response – a review. Placenta (2003) 24(Suppl A):S21–7. doi:10.1053/plac.2002.0930

CrossRef Full Text | Google Scholar

191. Hubel CA. Dyslipidemia and pre-eclampsia. In: Belfort MA, Lydall F, editors. Pre-Eclampsia-Aetiology and Clinical Practice. Cambridge: Cambridge University Press (2006). p. 164–82.

Google Scholar

192. Shurin MR, Lu L, Kalinski P, Stewart-Akers AM, Lotze MT. Th1/Th2 balance in cancer, transplantation and pregnancy. Springer Semin Immunopathol (1999) 21:339–59. doi:10.1007/BF00812261

CrossRef Full Text | Google Scholar

193. Saito S, Sakai M. Th1/Th2 balance in preeclampsia. J Reprod Immunol (2003) 59:161–73. doi:10.1016/S0165-0378(03)00045-7

PubMed Abstract | CrossRef Full Text | Google Scholar

194. Chaouat G. The Th1/Th2 paradigm: still important in pregnancy? Semin Immunopathol (2007) 29:95–113. doi:10.1007/s00281-007-0069-0

PubMed Abstract | CrossRef Full Text | Google Scholar

195. Short SM, Wolfner MF, Lazzaro BP. Female Drosophila melanogaster suffer reduced defense against infection due to seminal fluid components. J Insect Physiol (2012) 58:1192–201. doi:10.1016/j.jinsphys.2012.06.002

PubMed Abstract | CrossRef Full Text | Google Scholar

196. Short SM, Lazzaro BP. Reproductive status alters transcriptomic response to infection in female Drosophila melanogaster. G3 (Bethesda) (2013) 3:827–40. doi:10.1534/g3.112.005306

CrossRef Full Text | Google Scholar

197. Schjenken JE, Robertson SA. Seminal fluid signalling in the female reproductive tract: implications for reproductive success and offspring health. Adv Exp Med Biol (2015) 868:127–58. doi:10.1007/978-3-319-18881-2_6

PubMed Abstract | CrossRef Full Text | Google Scholar

198. Pejcic-Karapetrovic B, Gurnani K, Russell MS, Finlay BB, Sad S, Krishnan L. Pregnancy impairs the innate immune resistance to Salmonella typhimurium leading to rapid fatal infection. J Immunol (2007) 179:6088–96. doi:10.4049/jimmunol.179.9.6088

PubMed Abstract | CrossRef Full Text | Google Scholar

199. Sappenfield E, Jamieson DJ, Kourtis AP. Pregnancy and susceptibility to infectious diseases. Infect Dis Obstet Gynecol (2013) 2013:752852. doi:10.1155/2013/752852

CrossRef Full Text | Google Scholar

200. Kourtis AP, Read JS, Jamieson DJ. Pregnancy and infection. N Engl J Med (2014) 370:2211–8. doi:10.1056/NEJMra1213566

CrossRef Full Text | Google Scholar

201. Kraus TA, Engel SM, Sperling RS, Kellerman L, Lo Y, Wallenstein S, et al. Characterizing the pregnancy immune phenotype: results of the viral immunity and pregnancy (VIP) study. J Clin Immunol (2012) 32:300–11. doi:10.1007/s10875-011-9627-2

PubMed Abstract | CrossRef Full Text | Google Scholar

202. Pazos M, Sperling RS, Moran TM, Kraus TA. The influence of pregnancy on systemic immunity. Immunol Res (2012) 54:254–61. doi:10.1007/s12026-012-8303-9

PubMed Abstract | CrossRef Full Text | Google Scholar

203. Lynch AM, Gibbs RS, Murphy JR, Byers T, Neville MC, Giclas PC, et al. Complement activation fragment Bb in early pregnancy and spontaneous preterm birth. Am J Obstet Gynecol (2008) 199(354):e351–8. doi:10.1016/j.ajog.2008.07.044

CrossRef Full Text | Google Scholar

204. Lynch AM, Murphy JR, Byers T, Gibbs RS, Neville MC, Giclas PC, et al. Alternative complement pathway activation fragment Bb in early pregnancy as a predictor of preeclampsia. Am J Obstet Gynecol (2008) 198:385.e381–9. doi:10.1016/j.ajog.2007.10.793

CrossRef Full Text | Google Scholar

205. Lynch AM, Murphy JR, Gibbs RS, Levine RJ, Giclas PC, Salmon JE, et al. The interrelationship of complement-activation fragments and angiogenesis-related factors in early pregnancy and their association with pre-eclampsia. BJOG (2010) 117:456–62. doi:10.1111/j.1471-0528.2009.02473.x

PubMed Abstract | CrossRef Full Text | Google Scholar

206. Soto E, Romero R, Richani K, Espinoza J, Chaiworapongsa T, Nien JK, et al. Preeclampsia and pregnancies with small-for-gestational age neonates have different profiles of complement split products. J Matern Fetal Neonatal Med (2010) 23:646–57. doi:10.3109/14767050903301009

CrossRef Full Text | Google Scholar

207. Girardi G, Prohaszka Z, Bulla R, Tedesco F, Scherjon S. Complement activation in animal and human pregnancies as a model for immunological recognition. Mol Immunol (2011) 48:1621–30. doi:10.1016/j.molimm.2011.04.011

PubMed Abstract | CrossRef Full Text | Google Scholar

208. Lynch AM, Gibbs RS, Murphy JR, Giclas PC, Salmon JE, Holers VM. Early elevations of the complement activation fragment C3a and adverse pregnancy outcomes. Obs Gynecol (2011) 117:75–83. doi:10.1097/AOG.0b013e3181fc3afa

PubMed Abstract | CrossRef Full Text | Google Scholar

209. Qing X, Redecha PB, Burmeister MA, Tomlinson S, D’agati VD, Davisson RL, et al. Targeted inhibition of complement activation prevents features of preeclampsia in mice. Kidney Int (2011) 79:331–9. doi:10.1038/ki.2010.393

PubMed Abstract | CrossRef Full Text | Google Scholar

210. Buurma A, Cohen D, Veraar K, Schonkeren D, Claas FH, Bruijn JA, et al. Preeclampsia is characterized by placental complement dysregulation. Hypertension (2012) 60:1332–7. doi:10.1161/HYPERTENSIONAHA.112.194324

PubMed Abstract | CrossRef Full Text | Google Scholar

211. Wang W, Irani RA, Zhang Y, Ramin SM, Blackwell SC, Tao L, et al. Autoantibody-mediated complement C3a receptor activation contributes to the pathogenesis of preeclampsia. Hypertension (2012) 60:712–21. doi:10.1161/HYPERTENSIONAHA.112.191817

PubMed Abstract | CrossRef Full Text | Google Scholar

212. Denny KJ, Coulthard LG, Finnell RH, Callaway LK, Taylor SM, Woodruff TM. Elevated complement factor C5a in maternal and umbilical cord plasma in preeclampsia. J Reprod Immunol (2013) 97:211–6. doi:10.1016/j.jri.2012.11.006

CrossRef Full Text | Google Scholar

213. Denny KJ, Woodruff TM, Taylor SM, Callaway LK. Complement in pregnancy: a delicate balance. Am J Reprod Immunol (2013) 69:3–11. doi:10.1111/aji.12000

CrossRef Full Text | Google Scholar

214. Hoffman MC, Rumer KK, Kramer A, Lynch AM, Winn VD. Maternal and fetal alternative complement pathway activation in early severe preeclampsia. Am J Reprod Immunol (2014) 71:55–60. doi:10.1111/aji.12162

PubMed Abstract | CrossRef Full Text | Google Scholar

215. Banadakoppa M, Vidaeff AC, Yallampalli U, Ramin SM, Belfort MA, Yallampalli C. Complement split products in amniotic fluid in pregnancies subsequently developing early-onset preeclampsia. Dis Markers (2015) 2015:263109. doi:10.1155/2015/263109

PubMed Abstract | CrossRef Full Text | Google Scholar

216. He Y, Xu B, Song D, Yu F, Chen Q, Zhao M. Expression of the complement system’s activation factors in plasma of patients with early/late-onset severe pre-eclampsia. Am J Reprod Immunol (2016) 76:205–11. doi:10.1111/aji.12541

CrossRef Full Text | Google Scholar

217. Wu W, Yang H, Feng Y, Zhang P, Li S, Wang X, et al. Polymorphisms in complement genes and risk of preeclampsia in Taiyuan, China. Inflamm Res (2016) 65:837–45. doi:10.1007/s00011-016-0968-4

CrossRef Full Text | Google Scholar

218. Velickovic I, Dalloul M, Wong KA, Bakare O, Schweis F, Garala M, et al. Complement factor B activation in patients with preeclampsia. J Reprod Immunol (2015) 109:94–100. doi:10.1016/j.jri.2014.12.002

PubMed Abstract | CrossRef Full Text | Google Scholar

219. Soto E, Romero R, Vaisbuch E, Erez O, Mazaki-Tovi S, Kusanovic JP, et al. Fragment Bb: evidence for activation of the alternative pathway of the complement system in pregnant women with acute pyelonephritis. J Matern Fetal Neonatal Med (2010) 23:1085–90. doi:10.3109/14767051003649870

CrossRef Full Text | Google Scholar

220. He Y, Xu B, Song D, Yu F, Chen Q, Zhao M. Correlations between complement system’s activation factors and anti-angiogenesis factors in plasma of patients with early/late-onset severe preeclampsia. Hypertens Pregnancy (2016) 35:499–509. doi:10.1080/10641955.2016.1190845

CrossRef Full Text | Google Scholar

221. Lynch AM, Eckel RH, Murphy JR, Gibbs RS, West NA, Giclas PC, et al. Prepregnancy obesity and complement system activation in early pregnancy and the subsequent development of preeclampsia. Am J Obstet Gynecol (2012) 206:428.e421–28. doi:10.1016/j.ajog.2012.02.035

CrossRef Full Text | Google Scholar

222. Halmos A, Rigo J Jr, Szijarto J, Fust G, Prohaszka Z, Molvarec A. Circulating ficolin-2 and ficolin-3 in normal pregnancy and pre-eclampsia. Clin Exp Immunol (2012) 169:49–56. doi:10.1111/j.1365-2249.2012.04590.x

PubMed Abstract | CrossRef Full Text | Google Scholar

223. Haeger M, Bengtson A, Karlsson K, Heideman M. Complement activation and anaphylatoxin (C3a and C5a) formation in preeclampsia and by amniotic fluid. Obstet Gynecol (1989) 73:551–6.

PubMed Abstract | Google Scholar

224. Haeger M, Unander M, Bengtsson A. Complement activation in relation to development of preeclampsia. Obstet Gynecol (1991) 78:46–9.

PubMed Abstract | Google Scholar

225. Ye Y, Kong Y, Zhang Y. Complement split products C3a/C5a and receptors: are they regulated by circulating angiotensin II type 1 receptor autoantibody in severe preeclampsia? Gynecol Obstet Invest (2016) 81:28–33. doi:10.1159/000440651

PubMed Abstract | CrossRef Full Text | Google Scholar

226. Kestlerová A, Feyereisl J, Frisová V, Měchurová A, Šůla K, Zima T, et al. Immunological and biochemical markers in preeclampsia. J Reprod Immunol (2012) 96:90–4. doi:10.1016/j.jri.2012.10.002

PubMed Abstract | CrossRef Full Text | Google Scholar

227. Burwick RM, Fichorova RN, Dawood HY, Yamamoto HS, Feinberg BB. Urinary excretion of C5b-9 in severe preeclampsia: tipping the balance of complement activation in pregnancy. Hypertension (2013) 62:1040–5. doi:10.1161/HYPERTENSIONAHA.113.01420

PubMed Abstract | CrossRef Full Text | Google Scholar

228. Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT. Complement system part I – molecular mechanisms of activation and regulation. Front Immunol (2015) 6:262. doi:10.3389/fimmu.2015.00262

CrossRef Full Text | Google Scholar

229. Merle NS, Noe R, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, Roumenina LT. Complement system part II: role in immunity. Front Immunol (2015) 6:257. doi:10.3389/fimmu.2015.00257

CrossRef Full Text | Google Scholar

230. Ponnuraj K, Xu Y, Macon K, Moore D, Volanakis JE, Narayana SVL. Structural analysis of engineered Bb fragment of complement factor B: insights into the activation mechanism of the alternative pathway C3-convertase. Mol Cell (2004) 14:17–28. doi:10.1016/S1097-2765(04)00160-1

PubMed Abstract | CrossRef Full Text | Google Scholar

231. Rooijakkers SHM, Wu J, Ruyken M, Van Domselaar R, Planken KL, Tzekou A, et al. Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor. Nat Immunol (2009) 10:721–7. doi:10.1038/ni.1756

PubMed Abstract | CrossRef Full Text | Google Scholar

232. Vaisbuch E, Romero R, Erez O, Mazaki-Tovi S, Kusanovic JP, Soto E, et al. Fragment Bb in amniotic fluid: evidence for complement activation by the alternative pathway in women with intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med (2009) 22:905–16. doi:10.1080/14767050902994663

PubMed Abstract | CrossRef Full Text | Google Scholar

233. Li Q, Li YX, Stahl GL, Thurman JM, He Y, Tong HH. Essential role of factor B of the alternative complement pathway in complement activation and opsonophagocytosis during acute pneumococcal otitis media in mice. Infect Immun (2011) 79:2578–85. doi:10.1128/IAI.00168-11

PubMed Abstract | CrossRef Full Text | Google Scholar

234. Singh J, Ahmed A, Girardi G. Role of complement component C1q in the onset of preeclampsia in mice. Hypertension (2011) 58:716–24. doi:10.1161/HYPERTENSIONAHA.111.175919

PubMed Abstract | CrossRef Full Text | Google Scholar

235. Marti JJ, Herrmann U. Immunogestosis: a new etiologic concept of “essential” EPH gestosis, with special consideration of the primigravid patient; preliminary report of a clinical study. Am J Obstet Gynecol (1977) 128:489–93. doi:10.1016/0002-9378(77)90030-8

CrossRef Full Text | Google Scholar

236. Dekker G, Sukcharoen N. Etiology of preeclampsia: an update. J Med Assoc Thai (2004) 87(Suppl 3):S96–103.

PubMed Abstract | Google Scholar

237. Johansson M, Bromfield JJ, Jasper MJ, Robertson SA. Semen activates the female immune response during early pregnancy in mice. Immunology (2004) 112:290–300. doi:10.1111/j.1365-2567.2004.01876.x

PubMed Abstract | CrossRef Full Text | Google Scholar

238. Robertson SA, Guerin LR, Bromfield JJ, Branson KM, Ahlström AC, Care AS. Seminal fluid drives expansion of the CD4+CD25+ T regulatory cell pool and induces tolerance to paternal alloantigens in mice. Biol Reprod (2009) 80:1036–45. doi:10.1095/biolreprod.108.074658

CrossRef Full Text | Google Scholar

239. Larsen MH, Bzorek M, Pass MB, Larsen LG, Nielsen MW, Svendsen SG, et al. Human leukocyte antigen-G in the male reproductive system and in seminal plasma. Mol Hum Reprod (2011) 17:727–38. doi:10.1093/molehr/gar052

PubMed Abstract | CrossRef Full Text | Google Scholar

240. Hviid TVF. Human leukocyte antigen-G within the male reproductive system: implications for reproduction. Adv Exp Med Biol (2015) 868:171–90. doi:10.1007/978-3-319-18881-2_8

CrossRef Full Text | Google Scholar

241. Anderson DJ, Politch JA. Role of seminal plasma in human female reproductive failure: immunomodulation, inflammation, and infections. Adv Exp Med Biol (2015) 868:159–69. doi:10.1007/978-3-319-18881-2_7

PubMed Abstract | CrossRef Full Text | Google Scholar

242. Milardi D, Grande G, Vincenzoni F, Castagnola M, Marana R. Proteomics of human seminal plasma: identification of biomarker candidates for fertility and infertility and the evolution of technology. Mol Reprod Dev (2013) 80:350–7. doi:10.1002/mrd.22178

PubMed Abstract | CrossRef Full Text | Google Scholar

243. Drabovich AP, Saraon P, Jarvi K, Diamandis EP. Seminal plasma as a diagnostic fluid for male reproductive system disorders. Nat Rev Urol (2014) 11:278–88. doi:10.1038/nrurol.2014.74

PubMed Abstract | CrossRef Full Text | Google Scholar

244. Robertson SA. Seminal plasma and male factor signalling in the female reproductive tract. Cell Tissue Res (2005) 322:43–52. doi:10.1007/s00441-005-1127-3

PubMed Abstract | CrossRef Full Text | Google Scholar

245. Robertson SA. Seminal fluid signaling in the female reproductive tract: lessons from rodents and pigs. J Anim Sci (2007) 85:E36–44. doi:10.2527/jas.2006-578

PubMed Abstract | CrossRef Full Text | Google Scholar

246. Bromfield JJ. Seminal fluid and reproduction: much more than previously thought. J Assist Reprod Genet (2014) 31:627–36. doi:10.1007/s10815-014-0243-y

PubMed Abstract | CrossRef Full Text | Google Scholar

247. Bromfield JJ, Schjenken JE, Chin PY, Care AS, Jasper MJ, Robertson SA. Maternal tract factors contribute to paternal seminal fluid impact on metabolic phenotype in offspring. Proc Natl Acad Sci U S A (2014) 111:2200–5. doi:10.1073/pnas.1305609111

PubMed Abstract | CrossRef Full Text | Google Scholar

248. Robertson SA, Sharkey DJ. Seminal fluid and fertility in women. Fertil Steril (2016) 106:511–9. doi:10.1016/j.fertnstert.2016.07.1101

PubMed Abstract | CrossRef Full Text | Google Scholar

249. García-Montalvo IA, Mayoral Andrade G, Perez-Campos Mayoral L, Pina Canseco S, Martinez Cruz R, Martinez-Cruz M, et al. Molecules in seminal plasma related to platelets in preeclampsia. Med Hypotheses (2016) 93:27–9. doi:10.1016/j.mehy.2016.05.009

CrossRef Full Text | Google Scholar

250. Robertson SA, Guerin LR, Moldenhauer LM, Hayball JD. Activating T regulatory cells for tolerance in early pregnancy – the contribution of seminal fluid. J Reprod Immunol (2009) 83:109–16. doi:10.1016/j.jri.2009.08.003

CrossRef Full Text | Google Scholar

251. Robertson SA, Prins JR, Sharkey DJ, Moldenhauer LM. Seminal fluid and the generation of regulatory T cells for embryo implantation. Am J Reprod Immunol (2013) 69:315–30. doi:10.1111/aji.12107

PubMed Abstract | CrossRef Full Text | Google Scholar

252. Shima T, Inada K, Nakashima A, Ushijima A, Ito M, Yoshino O, et al. Paternal antigen-specific proliferating regulatory T cells are increased in uterine-draining lymph nodes just before implantation and in pregnant uterus just after implantation by seminal plasma-priming in allogeneic mouse pregnancy. J Reprod Immunol (2015) 108:72–82. doi:10.1016/j.jri.2015.02.005

PubMed Abstract | CrossRef Full Text | Google Scholar

253. Saito S, Shima T, Nakashima A, Inada K, Yoshino O. Role of paternal antigen-specific treg cells in successful implantation. Am J Reprod Immunol (2016) 75:310–6. doi:10.1111/aji.12469

PubMed Abstract | CrossRef Full Text | Google Scholar

254. Okazaki T, Akiyoshi T, Kan M, Mori M, Teshima H, Shimada M. Artificial insemination with seminal plasma improves the reproductive performance of frozen-thawed boar epididymal spermatozoa. J Androl (2012) 33:990–8. doi:10.2164/jandrol.111.015115

PubMed Abstract | CrossRef Full Text | Google Scholar

255. Bromfield JJ. A role for seminal plasma in modulating pregnancy outcomes in domestic species. Reproduction (2016) 152:R223–32. doi:10.1530/REP-16-0313

PubMed Abstract | CrossRef Full Text | Google Scholar

256. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. Br Med J (2005) 330:565–7. doi:10.1136/bmj.38380.674340.E0

PubMed Abstract | CrossRef Full Text | Google Scholar

257. Bartsch E, Medcalf KE, Park AL, Ray JG; High Risk of Pre-eclampsia Identification Group. Clinical risk factors for pre-eclampsia determined in early pregnancy: systematic review and meta-analysis of large cohort studies. BMJ (2016) 353:i1753. doi:10.1136/bmj.i1753

PubMed Abstract | CrossRef Full Text | Google Scholar

258. Bdolah Y, Elchalal U, Natanson-Yaron S, Yechiam H, Bdolah-Abram T, Greenfield C, et al. Relationship between nulliparity and preeclampsia may be explained by altered circulating soluble fms-like tyrosine kinase 1. Hypertens Pregnancy (2014) 33:250–9. doi:10.3109/10641955.2013.858745

PubMed Abstract | CrossRef Full Text | Google Scholar

259. Tandberg A, Klungsoyr K, Romundstad LB, Skjaerven R. Pre-eclampsia and assisted reproductive technologies: consequences of advanced maternal age, interbirth intervals, new partner and smoking habits. BJOG (2015) 122:915–22. doi:10.1111/1471-0528.13051

PubMed Abstract | CrossRef Full Text | Google Scholar

260. Robillard PY, Hulsey TC, Perianin J, Janky E, Miri EH, Papiernik E. Association of pregnancy-induced hypertension with duration of sexual cohabitation before conception. Lancet (1994) 344:973–5. doi:10.1016/S0140-6736(94)91638-1

CrossRef Full Text | Google Scholar

261. Einarsson JI, Sangi-Haghpeykar H, Gardner MO. Sperm exposure and development of preeclampsia. Am J Obstet Gynecol (2003) 188:1241–3. doi:10.1067/mob.2003.401

PubMed Abstract | CrossRef Full Text | Google Scholar

262. Saftlas AF, Levine RJ, Klebanoff MA, Martz KL, Ewell MG, Morris CD, et al. Abortion, changed paternity, and risk of preeclampsia in nulliparous women. Am J Epidemiol (2003) 157:1108–14. doi:10.1093/aje/kwg101

PubMed Abstract | CrossRef Full Text | Google Scholar

263. Klonoff-Cohen HS, Savitz DA, Cefalo RC, Mccann MF. An epidemiologic study of contraception and preeclampsia. JAMA (1989) 262:3143–7. doi:10.1001/jama.262.22.3143

PubMed Abstract | CrossRef Full Text | Google Scholar

264. Hernández-Valencia M, Saldaña Quezada L, Alvarez Muñoz M, Valdez Martínez E. Barrier family planning methods as risk factor which predisposes to preeclampsia. Ginecol Obstet Mex (2000) 68:333–8.

Google Scholar

265. Letur-Köenirsch H, Peigné M, Ohl J, Cédrin I, D’argent EM, Scheffler F, et al. Pregnancies issued from egg donation are associated to a higher risk of hypertensive pathologies then control ART pregnancies. Results of a large comparative cohort study. Hum Reprod (2014) 29:68–9.

Google Scholar

266. Letur H, Peigné M, Ohl J, Cédrin-Durnerin I, Mathieu-D’argent E, Scheffler F, et al. Hypertensive pathologies and egg donation pregnancies: results of a large comparative cohort study. Fertil Steril (2016) 106:284–90. doi:10.1016/j.fertnstert.2016.03.031

PubMed Abstract | CrossRef Full Text | Google Scholar

267. Tarlatzi TB, Imbert R, Alvaro Mercadal B, Demeestere I, Venetis CA, Englert Y, et al. Does oocyte donation compared with autologous oocyte IVF pregnancies have a higher risk of preeclampsia? Reprod Biomed Online (2017) 34:11–8. doi:10.1016/j.rbmo.2016.10.002

PubMed Abstract | CrossRef Full Text | Google Scholar

268. Giannubilo SR, Landi B, Ciavattini A. Preeclampsia: what could happen in a subsequent pregnancy? Obstet Gynecol Surv (2014) 69:747–62. doi:10.1097/OGX.0000000000000126

PubMed Abstract | CrossRef Full Text | Google Scholar

269. Koelman CA, Coumans ABC, Nijman HW, Doxiadis IIN, Dekker GA, Claas FHJ. Correlation between oral sex and a low incidence of preeclampsia: a role for soluble HLA in seminal fluid? J Reprod Immunol (2000) 46:155–66. doi:10.1016/S0165-0378(99)00062-5

PubMed Abstract | CrossRef Full Text | Google Scholar

270. Martin RD. A Biological Function for Oral Sex? Psychology Today (2016). Available from: https://www.psychologytoday.com/blog/how-we-do-it/201602/biological-function-oral-sex

Google Scholar

271. Saftlas AF, Olson DR, Franks AL, Atrash HK, Pokras R. Epidemiology of preeclampsia and eclampsia in the United-States, 1979–1986. Am J Obstet Gynecol (1990) 163:460–5. doi:10.1016/0002-9378(90)91176-D

CrossRef Full Text | Google Scholar

272. Zhang J, Zeisler J, Hatch MC, Berkowitz G. Epidemiology of pregnancy-induced hypertension. Epidemiol Rev (1997) 19:218–32. doi:10.1093/oxfordjournals.epirev.a017954

PubMed Abstract | CrossRef Full Text | Google Scholar

273. Lamminpää R, Vehvilainen-Julkunen K, Gissler M, Heinonen S. Preeclampsia complicated by advanced maternal age: a registry-based study on primiparous women in Finland 1997–2008. BMC Pregnancy Childbirth (2012) 12:47. doi:10.1186/1471-2393-12-47

PubMed Abstract | CrossRef Full Text | Google Scholar

274. Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates in the United States, 1980–2010: age-period-cohort analysis. BMJ (2013) 347:f6564. doi:10.1136/bmj.f6564

PubMed Abstract | CrossRef Full Text | Google Scholar

275. Carolan M. Maternal age >= 45 years and maternal and perinatal outcomes: a review of the evidence. Midwifery (2013) 29:479–89. doi:10.1016/j.midw.2012.04.001

CrossRef Full Text | Google Scholar

276. Need JA, Bell B, Meffin E, Jones WR. Pre-eclampsia in pregnancies from donor inseminations. J Reprod Immunol (1983) 5:329–38. doi:10.1016/0165-0378(83)90242-5

PubMed Abstract | CrossRef Full Text | Google Scholar

277. Smith GN, Walker M, Tessier JL, Millar KG. Increased incidence of preeclampsia in women conceiving by intrauterine insemination with donor versus partner sperm for treatment of primary infertility. Am J Obs Gynecol (1997) 177:455–8. doi:10.1016/S0002-9378(97)70215-1

PubMed Abstract | CrossRef Full Text | Google Scholar

278. Hoy J, Venn A, Halliday J, Kovacs G, Waalwyk K. Perinatal and obstetric outcomes of donor insemination using cryopreserved semen in Victoria, Australia. Hum Reprod (1999) 14:1760–4. doi:10.1093/humrep/14.7.1760

PubMed Abstract | CrossRef Full Text | Google Scholar

279. Davis JA, Gallup GG. Preeclampsia and other pregnancy complications as an adaptive response to unfamiliar semen. In: Platek SM, Shackelford TK, editors. Female Infidelity and Paternal Uncertainty: Evolutionary Perspectives on Male Anti-Cuckoldry Tactics. Cambridge: CUPpip (2006). p. 191–204.

Google Scholar

280. Gleicher N, Boler LR Jr, Norusis M, Del Granado A. Hypertensive diseases of pregnancy and parity. Am J Obstet Gynecol (1986) 154:1044–9. doi:10.1016/0002-9378(86)90747-7

PubMed Abstract | CrossRef Full Text | Google Scholar

281. Roberts JM, Redman CW. Pre-eclampsia: more than pregnancy-induced hypertension. Lancet (1993) 341:1447–51. doi:10.1016/0140-6736(93)90889-O

CrossRef Full Text | Google Scholar

282. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet (2005) 365:785–99. doi:10.1016/S0140-6736(05)71003-5

PubMed Abstract | CrossRef Full Text | Google Scholar

283. Luo ZC, An N, Xu HR, Larante A, Audibert F, Fraser WD. The effects and mechanisms of primiparity on the risk of pre-eclampsia: a systematic review. Paediatr Perinat Epidemiol (2007) 21(Suppl 1):36–45. doi:10.1111/j.1365-3016.2007.00836.x

PubMed Abstract | CrossRef Full Text | Google Scholar

284. Hernández-Díaz S, Toh S, Cnattingius S. Risk of pre-eclampsia in first and subsequent pregnancies: prospective cohort study. BMJ (2009) 338:b2255. doi:10.1136/bmj.b2255

PubMed Abstract | CrossRef Full Text | Google Scholar

285. Wu CS, Nohr EA, Bech BH, Vestergaard M, Catov JM, Olsen J. Health of children born to mothers who had preeclampsia: a population-based cohort study. Am J Obstet Gynecol (2009) 201:269.e261–269.e210. doi:10.1016/j.ajog.2009.06.060

PubMed Abstract | CrossRef Full Text | Google Scholar

286. Wikström AK, Gunnarsdóttir J, Cnattingius S. The paternal role in pre-eclampsia and giving birth to a small for gestational age infant; a population-based cohort study. BMJ Open (2012) 2:e001178. doi:10.1136/bmjopen-2012-001178

CrossRef Full Text | Google Scholar

287. English FA, Kenny LC, Mccarthy FP. Risk factors and effective management of preeclampsia. Integr Blood Press Control (2015) 8:7–12. doi:10.2147/IBPC.S50641

CrossRef Full Text | Google Scholar

288. Rich-Edwards JW, Ness RB, Roberts JM. Epidemiology of pregnancy-related hypertension. 4th ed. Chesley’s Hypertensive Disorders in Pregnancy. (2015). p. 37–55. doi:10.1016/B978-0-12-407866-6.00003-1

CrossRef Full Text | Google Scholar

289. Dildy GA III, Belfort MA, Smulian JC. Preeclampsia recurrence and prevention. Semin Perinatol (2007) 31:135–41. doi:10.1053/j.semperi.2007.03.005

CrossRef Full Text | Google Scholar

290. Conde-Agudelo A, Belizán JM. Risk factors for pre-eclampsia in a large cohort of Latin American and Caribbean women. BJOG (2000) 107:75–83. doi:10.1111/j.1471-0528.2000.tb11582.x

PubMed Abstract | CrossRef Full Text | Google Scholar

291. Feeney JG, Scott JS. Pre-eclampsia and changed paternity. Eur J Obstet Gynecol Reprod Biol (1980) 11:35–8. doi:10.1016/0028-2243(80)90051-9

PubMed Abstract | CrossRef Full Text | Google Scholar

292. Ikedife D. Eclampsia in multipara. Br Med J (1980) 280:985–6. doi:10.1136/bmj.280.6219.985-a

CrossRef Full Text | Google Scholar

293. Chng PK. Occurrence of pre-eclampsia in pregnancies to three husbands. Case report. Br J Obstet Gynaecol (1982) 89:862–3. doi:10.1111/j.1471-0528.1982.tb05042.x

CrossRef Full Text | Google Scholar

294. Robillard PY, Hulsey TC, Alexander GR, Keenan A, De Caunes F, Papiernik E. Paternity patterns and risk of preeclampsia in the last pregnancy in multiparae. J Reprod Immunol (1993) 24:1–12. doi:10.1016/0165-0378(93)90032-D

PubMed Abstract | CrossRef Full Text | Google Scholar

295. Trupin LS, Simon LP, Eskenazi B. Change in paternity: a risk factor for preeclampsia in multiparas. Epidemiology (1996) 7:240–4. doi:10.1097/00001648-199605000-00004

PubMed Abstract | CrossRef Full Text | Google Scholar

296. Robillard PY, Dekker GA, Hulsey TC. Revisiting the epidemiological standard of preeclampsia: primigravidity or primipaternity? Eur J Obstet Gynecol Reprod Biol (1999) 84:37–41. doi:10.1016/S0301-2115(98)00250-4

PubMed Abstract | CrossRef Full Text | Google Scholar

297. Tubbergen P, Lachmeijer AMA, Althuisius SM, Vlak MEJ, Van Geijn HP, Dekker GA. Change in paternity: a risk factor for preeclampsia in multiparous women? J Reprod Immunol (1999) 45:81–8. doi:10.1016/S0165-0378(99)00040-6

CrossRef Full Text | Google Scholar

298. Li DK, Wi S. Changing paternity and the risk of preeclampsia/eclampsia in the subsequent pregnancy. Am J Epidemiol (2000) 151:57–62. doi:10.1093/oxfordjournals.aje.a010122

PubMed Abstract | CrossRef Full Text | Google Scholar

299. Dekker GA, Robillard PY. Preeclampsia: a couple’s disease with maternal and fetal manifestations. Curr Pharm Des (2005) 11:699–710. doi:10.2174/1381612053381828

PubMed Abstract | CrossRef Full Text | Google Scholar

300. Deen ME, Ruurda LG, Wang J, Dekker GA. Risk factors for preeclampsia in multiparous women: primipaternity versus the birth interval hypothesis. J Matern Fetal Neonatal Med (2006) 19:79–84. doi:10.1080/14767050500361653

PubMed Abstract | CrossRef Full Text | Google Scholar

301. Dekker G, Robillard PY, Roberts C. The etiology of preeclampsia: the role of the father. J Reprod Immunol (2011) 89:126–32. doi:10.1016/j.jri.2010.12.010

PubMed Abstract | CrossRef Full Text | Google Scholar

302. Nagayama S, Ohkuchi A, Usui R, Matsubara S, Suzuki M. The role of the father in the occurrence of preeclampsia. Med J Obs Gynecol (2014) 2:1029–32.

Google Scholar

303. Robillard PY, Dekker G, Chaouat G, Scioscia M, Iacobelli S, Hulsey TC. Historical evolution of ideas on eclampsia/preeclampsia: a proposed optimistic view of preeclampsia. J Reprod Immunol (2017) 123:72–7. doi:10.1016/j.jri.2017.09.006

PubMed Abstract | CrossRef Full Text | Google Scholar

304. Trogstad LIS, Eskild A, Magnus P, Samuelsen SO, Nesheim BI. Changing paternity and time since last pregnancy; the impact on pre-eclampsia risk. A study of 547 238 women with and without previous pre-eclampsia. Int J Epidemiol (2001) 30:1317–22. doi:10.1093/ije/30.6.1317

CrossRef Full Text | Google Scholar

305. Lie RT, Rasmussen S, Brunborg H, Gjessing HK, Lie-Nielsen E, Irgens LM. Fetal and maternal contributions to risk of pre-eclampsia: population based study. BMJ (1998) 316:1343–7. doi:10.1136/bmj.316.7141.1343

CrossRef Full Text | Google Scholar

306. Triche EW, Harland KK, Field EH, Rubenstein LM, Saftlas AF. Maternal-fetal HLA sharing and preeclampsia: variation in effects by seminal fluid exposure in a case-control study of nulliparous women in Iowa. J Reprod Immunol (2014) 101-102:111–9. doi:10.1016/j.jri.2013.06.004

PubMed Abstract | CrossRef Full Text | Google Scholar

307. Saftlas AF, Rubenstein L, Prater K, Harland KK, Field E, Triche EW. Cumulative exposure to paternal seminal fluid prior to conception and subsequent risk of preeclampsia. J Reprod Immunol (2014) 101-102:104–10. doi:10.1016/j.jri.2013.07.006

PubMed Abstract | CrossRef Full Text | Google Scholar

308. Kho EM, Mccowan LM, North RA, Roberts CT, Chan E, Black MA, et al. Duration of sexual relationship and its effect on preeclampsia and small for gestational age perinatal outcome. J Reprod Immunol (2009) 82:66–73. doi:10.1016/j.jri.2009.04.011

PubMed Abstract | CrossRef Full Text | Google Scholar

309. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ (2007) 335:974. doi:10.1136/bmj.39335.385301.BE

PubMed Abstract | CrossRef Full Text | Google Scholar

310. Salha O, Sharma V, Dada T, Nugent D, Rutherford AJ, Tomlinson AJ, et al. The influence of donated gametes on the incidence of hypertensive disorders of pregnancy. Hum Reprod (1999) 14:2268–73. doi:10.1093/humrep/14.9.2268

PubMed Abstract | CrossRef Full Text | Google Scholar

311. Gelbaya TA. Short and long-term risks to women who conceive through in vitro fertilization. Hum Fertil (Camb) (2010) 13:19–27. doi:10.3109/14647270903437923

PubMed Abstract | CrossRef Full Text | Google Scholar

312. van der Hoorn ML, Lashley EE, Bianchi DW, Claas FH, Schonkeren CM, Scherjon SA. Clinical and immunologic aspects of egg donation pregnancies: a systematic review. Hum Reprod Update (2010) 16:704–12. doi:10.1093/humupd/dmq017

PubMed Abstract | CrossRef Full Text | Google Scholar

313. Masoudian P, Nasr A, De Nanassy J, Fung-Kee-Fung K, Bainbridge SA, El Demellawy D. Oocyte donation pregnancies and the risk of preeclampsia or gestational hypertension: a systematic review and metaanalysis. Am J Obstet Gynecol (2016) 214:328–39. doi:10.1016/j.ajog.2015.11.020

PubMed Abstract | CrossRef Full Text | Google Scholar

314. Porreco RP, Heyborne KD. Immunogenesis of preeclampsia: lessons from donor gametes. J Matern Fetal Neonatal Med (2017):1–7. doi:10.1080/14767058.2017.1309385

CrossRef Full Text | Google Scholar

315. Dude AM, Yeh JS, Muasher SJ. Donor oocytes are associated with preterm birth when compared to fresh autologous in vitro fertilization cycles in singleton pregnancies. Fertil Steril (2016) 106:660–5. doi:10.1016/j.fertnstert.2016.05.029

CrossRef Full Text | Google Scholar

316. Stoop D, Baumgarten M, Haentjens P, Polyzos NP, De Vos M, Verheyen G, et al. Obstetric outcome in donor oocyte pregnancies: a matched-pair analysis. Reprod Biol Endocrinol (2012) 10:42. doi:10.1186/1477-7827-10-42

PubMed Abstract | CrossRef Full Text | Google Scholar

317. Levron Y, Dviri M, Segol I, Yerushalmi GM, Hourvitz A, Orvieto R, et al. The ’immunologic theory’ of preeclampsia revisited: a lesson from donor oocyte gestations. Am J Obstet Gynecol (2014) 211(383):e381–5. doi:10.1016/j.ajog.2014.03.044

PubMed Abstract | CrossRef Full Text | Google Scholar

318. Fox NS, Roman AS, Saltzman DH, Hourizadeh T, Hastings J, Rebarber A. Risk factors for preeclampsia in twin pregnancies. Am J Perinatol (2014) 31:163–6. doi:10.1055/s-0033-1343775

PubMed Abstract | CrossRef Full Text | Google Scholar

319. Thomopoulos C, Salamalekis G, Kintis K, Andrianopoulou I, Michalopoulou H, Skalis G, et al. Risk of hypertensive disorders in pregnancy following assisted reproductive technology: overview and meta-analysis. J Clin Hypertens (Greenwich) (2017) 19:173–83. doi:10.1111/jch.12945

PubMed Abstract | CrossRef Full Text | Google Scholar

320. Blázquez A, García D, Rodríguez A, Vassena R, Figueras F, Vernaeve V. Is oocyte donation a risk factor for preeclampsia? A systematic review and meta-analysis. J Assist Reprod Genet (2016) 33:855–63. doi:10.1007/s10815-016-0701-9

CrossRef Full Text | Google Scholar

321. Klatsky PC, Delaney SS, Caughey AB, Tran ND, Schattman GL, Rosenwaks Z. The role of embryonic origin in preeclampsia: a comparison of autologous in vitro fertilization and ovum donor pregnancies. Obstet Gynecol (2010) 116:1387–92. doi:10.1097/AOG.0b013e3181fb8e59

PubMed Abstract | CrossRef Full Text | Google Scholar

322. Kroon B, Hart RJ, Wong BM, Ford E, Yazdani A. Antibiotics prior to embryo transfer in ART. Cochrane Database Syst Rev (2012) (3):CD008995. doi:10.1002/14651858.CD008995.pub2

CrossRef Full Text | Google Scholar

323. Sibai BM, Mercer B, Sarinoglu C. Severe preeclampsia in the second trimester: recurrence risk and long-term prognosis. Am J Obstet Gynecol (1991) 165:1408–12. doi:10.1016/S0002-9378(12)90773-5

PubMed Abstract | CrossRef Full Text | Google Scholar

324. van Rijn BB, Hoeks LB, Bots ML, Franx A, Bruinse HW. Outcomes of subsequent pregnancy after first pregnancy with early-onset preeclampsia. Am J Obstet Gynecol (2006) 195:723–8. doi:10.1016/j.ajog.2006.06.044

PubMed Abstract | CrossRef Full Text | Google Scholar

325. Mostello D, Kallogjeri D, Tungsiripat R, Leet T. Recurrence of preeclampsia: effects of gestational age at delivery of the first pregnancy, body mass index, paternity, and interval between births. Am J Obstet Gynecol (2008) 199(55):e51–7. doi:10.1016/j.ajog.2007.11.058

PubMed Abstract | CrossRef Full Text | Google Scholar

326. Rasmussen S, Irgens LM, Albrechtsen S, Dalaker K. Predicting preeclampsia in the second pregnancy from low birth weight in the first pregnancy. Obstet Gynecol (2000) 96:696–700. doi:10.1097/00006250-200011000-00010

PubMed Abstract | CrossRef Full Text | Google Scholar

327. Thevaranjan N, Puchta A, Schulz C, Naidoo A, Szamosi JC, Verschoor CP, et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe (2017) 21(455–466):e454. doi:10.1016/j.chom.2017.03.002

PubMed Abstract | CrossRef Full Text | Google Scholar

328. Astin M, Scott JR, Worley RJ. Pre-eclampsia/eclampsia: a fatal father factor. Lancet (1981) 2:533. doi:10.1016/S0140-6736(81)90925-9

CrossRef Full Text | Google Scholar

329. Wang JX, Knottnerus AM, Schuit G, Norman RJ, Chan A, Dekker GA. Surgically obtained sperm, and risk of gestational hypertension and pre-eclampsia. Lancet (2002) 359:673–4. doi:10.1016/S0140-6736(02)07804-2

CrossRef Full Text | Google Scholar

330. Le Ray C, Scherier S, Anselem O, Marszalek A, Tsatsaris V, Cabrol D, et al. Association between oocyte donation and maternal and perinatal outcomes in women aged 43 years or older. Hum Reprod (2012) 27:896–901. doi:10.1093/humrep/der469

PubMed Abstract | CrossRef Full Text | Google Scholar

331. González-Comadran M, Avila JU, Tascón AS, Jimenéz R, Solà I, Brassesco M, et al. The impact of donor insemination on the risk of preeclampsia: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol (2014) 182:160–6. doi:10.1016/j.ejogrb.2014.09.022

CrossRef Full Text | Google Scholar

332. Thomopoulos C, Tsioufis C, Michalopoulou H, Makris T, Papademetriou V, Stefanadis C. Assisted reproductive technology and pregnancy-related hypertensive complications: a systematic review. J Hum Hypertens (2013) 27:148–57. doi:10.1038/jhh.2012.13

PubMed Abstract | CrossRef Full Text | Google Scholar

333. Baud D, Greub G. Intracellular bacteria and adverse pregnancy outcomes. Clin Microbiol Infect (2011) 17:1312–22. doi:10.1111/j.1469-0691.2011.03604.x

CrossRef Full Text | Google Scholar

334. Vigliani MB, Bakardjiev AI. Intracellular organisms as placental invaders. Fetal Matern Med Rev (2014) 25:332–8. doi:10.1017/S0965539515000066

PubMed Abstract | CrossRef Full Text | Google Scholar

335. Parnell LA, Briggs CM, Cao B, Delannoy-Bruno O, Schrieffer AE, Mysorekar IU. Microbial communities in placentas from term normal pregnancy exhibit spatially variable profiles. Sci Rep (2017) 7:11200. doi:10.1038/s41598-017-11514-4

PubMed Abstract | CrossRef Full Text | Google Scholar

336. Wu H, Estill MS, Shershebnev A, Suvorov A, Krawetz SA, Whitcomb BW, et al. Preconception urinary phthalate concentrations and sperm DNA methylation profiles among men undergoing IVF treatment: a cross-sectional study. Hum Reprod (2017) 32(11):2159–69. doi:10.1093/humrep/dex283

CrossRef Full Text | Google Scholar

337. Verstraelen H, Senok AC. Vaginal lactobacilli, probiotics, and IVF. Reprod Biomed Online (2005) 11:674–5. doi:10.1016/S1472-6483(10)61683-5

PubMed Abstract | CrossRef Full Text | Google Scholar

338. Sirota I, Zarek SM, Segars JH. Potential influence of the microbiome on infertility and assisted reproductive technology. Semin Reprod Med (2014) 32:35–42. doi:10.1055/s-0033-1361821

PubMed Abstract | CrossRef Full Text | Google Scholar

339. Reid G, Brigidi P, Burton JP, Contractor N, Duncan S, Fargier E, et al. Microbes central to human reproduction. Am J Reprod Immunol (2015) 73:1–11. doi:10.1111/aji.12319

PubMed Abstract | CrossRef Full Text | Google Scholar

340. Xie F, Hu Y, Magee LA, Money DM, Patrick DM, Brunham RM, et al. Chlamydia pneumoniae infection in preeclampsia. Hypertens Pregnancy (2010) 29:468–77. doi:10.3109/10641950903242642

CrossRef Full Text | Google Scholar

341. Heine RP, Ness RB, Roberts JM. Seroprevalence of antibodies to Chlamydia pneumoniae in women with preeclampsia. Obstet Gynecol (2003) 101:221–6. doi:10.1016/S0029-7844(02)02591-7

CrossRef Full Text | Google Scholar

342. El-Shourbagy MAA, El-Refaie TA, Sayed KKA, Wahba KAH, El-Din ASS, Fathy MM. Impact of seroconversion and antichlamydial treatment on the rate of pre-eclampsia among Egyptian primigravidae. Int J Gynaecol Obstet (2011) 113:137–40. doi:10.1016/j.ijgo.2010.11.014

PubMed Abstract | CrossRef Full Text | Google Scholar

343. Mosbah A, Nabiel Y. Helicobacter pylori, Chlamydiae pneumoniae and trachomatis as probable etiological agents of preeclampsia. J Matern Fetal Neonat Med (2016) 29:1607–12. doi:10.3109/14767058.2015.1056146

CrossRef Full Text | Google Scholar

344. Gomez LM, Parry S. Trophoblast infection with Chlamydia pneumoniae and adverse pregnancy outcomes associated with placental dysfunction. Am J Obstet Gynecol (2009) 200(526):e521–7. doi:10.1016/j.ajog.2009.03.001

PubMed Abstract | CrossRef Full Text | Google Scholar

345. Haggerty CL, Klebanoff MA, Panum I, Uldum SA, Bass DC, Olsen J, et al. Prenatal Chlamydia trachomatis infection increases the risk of preeclampsia. Pregnancy Hypertens (2013) 3:151–4. doi:10.1016/j.preghy.2013.03.002

CrossRef Full Text | Google Scholar

346. Haggerty CL, Panum I, Uldum SA, Bass DC, Olsen J, Darville T, et al. Chlamydia trachomatis infection may increase the risk of preeclampsia. Pregnancy Hypertens (2013) 3:28–33. doi:10.1016/j.preghy.2012.09.002

CrossRef Full Text | Google Scholar

347. Xie F, Hu Y, Magee LA, Money DM, Patrick DM, Krajden M, et al. An association between cytomegalovirus infection and pre-eclampsia: a case-control study and data synthesis. Acta Obstet Gynecol Scand (2010) 89:1162–7. doi:10.3109/00016349.2010.499449

CrossRef Full Text | Google Scholar

348. Xie F, Von Dadelszen P, Nadeau J. CMV infection, TLR-2 and -4 expression, and cytokine profiles in early-onset preeclampsia with HELLP syndrome. Am J Reprod Immunol (2014) 71:379–86. doi:10.1111/aji.12199

PubMed Abstract | CrossRef Full Text | Google Scholar

349. Ponzetto A, Cardaropoli S, Piccoli E, Rolfo A, Gennero L, Kanduc D, et al. Pre-eclampsia is associated with Helicobacter pylori seropositivity in Italy. J Hypertens (2006) 24:2445–9. doi:10.1097/HJH.0b013e3280109e8c

PubMed Abstract | CrossRef Full Text | Google Scholar

350. Panarelli M, Sattar N. Pre-eclampsia associated with Helicobacter pylori seropositivity. J Hypertens (2006) 24:2353–4. doi:10.1097/HJH.0b013e3280113638

CrossRef Full Text | Google Scholar

351. Tersigni C, Franceschi F, Todros T, Cardaropoli S, Scambia G, Di Simone N. Insights into the role of Helicobacter pylori infection in preeclampsia: from the bench to the bedside. Front Immunol (2014) 5:484. doi:10.3389/fimmu.2014.00484

CrossRef Full Text | Google Scholar

352. Üstün Y, Engin-Üstün Y, Ozkaplan E, Otlu B, Sait Tekerekoğlu M. Association of Helicobacter pylori infection with systemic inflammation in preeclampsia. J Matern Fetal Neonatal Med (2010) 23:311–4. doi:10.3109/14767050903121456

PubMed Abstract | CrossRef Full Text | Google Scholar

353. Aksoy H, Ozkan A, Aktas F, Borekci B. Helicobacter pylori seropositivity and its relationship with serum malondialdehyde and lipid profile in preeclampsia. J Clin Lab Anal (2009) 23:219–22. doi:10.1002/jcla.20330

PubMed Abstract | CrossRef Full Text | Google Scholar

354. Cardaropoli S, Rolfo A, Todros T. Helicobacter pylori and pregnancy-related disorders. World J Gastroenterol (2014) 20:654–64. doi:10.3748/wjg.v20.i3.654

PubMed Abstract | CrossRef Full Text | Google Scholar

355. Pugliese A, Beltramo T, Todros T, Cardaropoli S, Ponzetto A. Interleukin-18 and gestosis: correlation with Helicobacter pylori seropositivity. Cell Biochem Funct (2008) 26:817–9. doi:10.1002/cbf.1503

PubMed Abstract | CrossRef Full Text | Google Scholar

356. Cardaropoli S, Giuffrida D, Piazzese A, Todros T. Helicobacter pylori seropositivity and pregnancy-related diseases: a prospective cohort study. J Reprod Immunol (2015) 109:41–7. doi:10.1016/j.jri.2015.02.004

PubMed Abstract | CrossRef Full Text | Google Scholar

357. Cardaropoli S, Rolfo A, Piazzese A, Ponzetto A, Todros T. Helicobacter pylori’s virulence and infection persistence define pre-eclampsia complicated by fetal growth retardation. World J Gastroenterol (2011) 17:5156–65. doi:10.3748/wjg.v17.i47.5156

PubMed Abstract | CrossRef Full Text | Google Scholar

358. den Hollander WJ, Schalekamp-Timmermans S, Holster IL, Jaddoe VW, Hofman A, Moll HA, et al. Helicobacter pylori colonization and pregnancies complicated by preeclampsia, spontaneous prematurity, and small for gestational age birth. Helicobacter (2017) 22:e12364. doi:10.1111/hel.12364

CrossRef Full Text | Google Scholar

359. Sansone M, Sarno L, Saccone G, Berghella V, Maruotti GM, Migliucci A, et al. Risk of preeclampsia in human immunodeficiency virus-infected pregnant women. Obstet Gynecol (2016) 127:1027–32. doi:10.1097/AOG.0000000000001424

PubMed Abstract | CrossRef Full Text | Google Scholar

360. McDonnold M, Dunn H, Hester A, Pacheco LD, Hankins GD, Saade GR, et al. High risk human papillomavirus at entry to prenatal care and risk of preeclampsia. Am J Obstet Gynecol (2014) 210(138):e131–5. doi:10.1016/j.ajog.2013.09.040

CrossRef Full Text | Google Scholar

361. Hill JA, Devoe LD, Bryans CI Jr. Frequency of asymptomatic bacteriuria in preeclampsia. Obstet Gynecol (1986) 67:529–32.

PubMed Abstract | Google Scholar

362. Hsu CD, Witter FR. Urogenital infection in preeclampsia. Int J Gynaecol Obstet (1995) 49:271–5. doi:10.1016/0020-7292(95)02373-K

PubMed Abstract | CrossRef Full Text | Google Scholar

363. Mittendorf R, Lain KY, Williams MA, Walker CK. Preeclampsia. A nested, case-control study of risk factors and their interactions. J Reprod Med (1996) 41:491–6.

Google Scholar

364. Easter SR, Cantonwine DE, Zera CA, Lim KH, Parry SI, Mcelrath TF. Urinary tract infection during pregnancy, angiogenic factor profiles, and risk of preeclampsia. Am J Obs Gynecol (2016) 214:387.e1–7. doi:10.1016/j.ajog.2015.09.101

CrossRef Full Text | Google Scholar

365. Mazor-Dray E, Levy A, Schlaeffer F, Sheiner E. Maternal urinary tract infection: is it independently associated with adverse pregnancy outcome? J Matern Fetal Neonatal Med (2009) 22:124–8. doi:10.1080/14767050802488246

CrossRef Full Text | Google Scholar

366. Minassian C, Thomas SL, Williams DJ, Campbell O, Smeeth L. Acute maternal infection and risk of pre-eclampsia: a population-based case-control study. PLoS One (2013) 8:e73047. doi:10.1371/journal.pone.0073047

CrossRef Full Text | Google Scholar

367. Rezavand N, Veisi F, Zangane M, Amini R, Almasi A. Association between asymptomatic bacteriuria and pre-eclampsia. Glob J Health Sci (2016) 8:235–9. doi:10.5539/gjhs.v8n7p235

CrossRef Full Text | Google Scholar

368. Karmon A, Sheiner E. The relationship between urinary tract infection during pregnancy and preeclampsia: causal, confounded or spurious? Arch Gynecol Obstet (2008) 277:479–81. doi:10.1007/s00404-008-0643-2

PubMed Abstract | CrossRef Full Text | Google Scholar

369. Villar J, Carroli G, Wojdyla D, Abalos E, Giordano D, Ba’aqeel H, et al. Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions? Am J Obstet Gynecol (2006) 194:921–31. doi:10.1016/j.ajog.2005.10.813

CrossRef Full Text | Google Scholar

370. Bánhidy F, Ács N, Puhó EH, Czeizel AE. Pregnancy complications and birth outcomes of pregnant women with urinary tract infections and related drug treatments. Scand J Infect Dis (2007) 39:390–7. doi:10.1080/00365540601087566

PubMed Abstract | CrossRef Full Text | Google Scholar

371. Ide M, Papapanou PN. Epidemiology of association between maternal periodontal disease and adverse pregnancy outcomes – systematic review. J Periodontol (2013) 84:S181–94. doi:10.1902/jop.2013.134009

CrossRef Full Text | Google Scholar

372. Dunlop AL, Mulle JG, Ferranti EP, Edwards S, Dunn AB, Corwin EJ. Maternal microbiome and pregnancy outcomes that impact infant health: a review. Adv Neonatal Care (2015) 15:377–85. doi:10.1097/ANC.0000000000000218

PubMed Abstract | CrossRef Full Text | Google Scholar

373. Doron MW, Makhlouf RA, Katz VL, Lawson EE, Stiles AD. Increased incidence of sepsis at birth in neutropenic infants of mothers with preeclampsia. J Pediatr (1994) 125:452–8. doi:10.1016/S0022-3476(05)83294-9

CrossRef Full Text | Google Scholar

374. Wei B-J, Chen Y-J, Yu L, Wu B. Periodontal disease and risk of preeclampsia: a meta-analysis of observational studies. PLoS One (2013) 8:e70901. doi:10.1371/journal.pone.0070901

PubMed Abstract | CrossRef Full Text | Google Scholar

375. Shetty M, Shetty PK, Ramesh A, Thomas B, Prabhu S, Rao A. Periodontal disease in pregnancy is a risk factor for preeclampsia. Acta Obstet Gynecol Scand (2010) 89:718–21. doi:10.3109/00016341003623738

PubMed Abstract | CrossRef Full Text | Google Scholar

376. Kumar A, Basra M, Begum N, Rani V, Prasad S, Lamba AK, et al. Association of maternal periodontal health with adverse pregnancy outcome. J Obstet Gynaecol Res (2013) 39:40–5. doi:10.1111/j.1447-0756.2012.01957.x

CrossRef Full Text | Google Scholar

377. Amarasekara R, Jayasekara RW, Senanayake H, Dissanayake VHW. Microbiome of the placenta in pre-eclampsia supports the role of bacteria in the multifactorial cause of pre-eclampsia. J Obstet Gynaecol Res (2015) 41:662–9. doi:10.1111/jog.12619

PubMed Abstract | CrossRef Full Text | Google Scholar

378. Hlimi T. Association of anemia, pre-eclampsia and eclampsia with seasonality: a realist systematic review. Health Place (2015) 31:180–92. doi:10.1016/j.healthplace.2014.12.003

PubMed Abstract | CrossRef Full Text | Google Scholar

379. Brabin BJ, Johnson PM. Placental malaria and pre-eclampsia through the looking glass backwards? J Reprod Immunol (2005) 65:1–15. doi:10.1016/j.jri.2004.09.006

PubMed Abstract | CrossRef Full Text | Google Scholar

380. Anya SE. Seasonal variation in the risk and causes of maternal death in the Gambia: malaria appears to be an important factor. Am J Trop Med Hyg (2004) 70:510–3.

PubMed Abstract | Google Scholar

381. Sartelet H, Rogier C, Milko-Sartelet I, Angel G, Michel G. Malaria associated pre-eclampsia in Senegal. Lancet (1996) 347:1121. doi:10.1016/S0140-6736(96)90321-9

CrossRef Full Text | Google Scholar

382. Silasi M, Cardenas I, Kwon JY, Racicot K, Aldo P, Mor G. Viral infections during pregnancy. Am J Reprod Immunol (2015) 73:199–213. doi:10.1111/aji.12355

CrossRef Full Text | Google Scholar

383. Racicot K, Mor G. Risks associated with viral infections during pregnancy. J Clin Invest (2017) 127:1591–9. doi:10.1172/JCI87490

PubMed Abstract | CrossRef Full Text | Google Scholar

384. Keck C, Gerber-Schafer C, Clad A, Wilhelm C, Breckwoldt M. Seminal tract infections: impact on male fertility and treatment options. Hum Reprod Update (1998) 4:891–903. doi:10.1093/humupd/4.6.891

PubMed Abstract | CrossRef Full Text | Google Scholar

385. Ochsendorf FR. Sexually transmitted infections: impact on male fertility. Andrologia (2008) 40:72–5. doi:10.1111/j.1439-0272.2007.00825.x

PubMed Abstract | CrossRef Full Text | Google Scholar

386. Swidsinski A, Dörffel Y, Loening-Baucke V, Mendling W, Verstraelen H, Dieterle S, et al. Desquamated epithelial cells covered with a polymicrobial biofilm typical for bacterial vaginosis are present in randomly selected cryopreserved donor semen. FEMS Immunol Med Microbiol (2010) 59:399–404. doi:10.1111/j.1574-695X.2010.00688.x

PubMed Abstract | CrossRef Full Text | Google Scholar

387. Gallo MF, Warner L, King CC, Sobel JD, Klein RS, Cu-Uvin S, et al. Association between semen exposure and incident bacterial vaginosis. Infect Dis Obstet Gynecol (2011) 2011:842652. doi:10.1155/2011/842652

PubMed Abstract | CrossRef Full Text | Google Scholar

388. Paavonen J, Eggert-Kruse W. Chlamydia trachomatis: impact on human reproduction. Hum Reprod Update (1999) 5:433–47. doi:10.1093/humupd/5.5.433

PubMed Abstract | CrossRef Full Text | Google Scholar

389. Rando OJ, Simmons RA. I’m eating for two: parental dietary effects on offspring metabolism. Cell (2015) 161:93–105. doi:10.1016/j.cell.2015.02.021

PubMed Abstract | CrossRef Full Text | Google Scholar

390. Dehghan Marvast L, Aflatoonian A, Talebi AR, Ghasemzadeh J, Pacey AA. Semen inflammatory markers and Chlamydia trachomatis infection in male partners of infertile couples. Andrologia (2016) 48:729–36. doi:10.1111/and.12501

PubMed Abstract | CrossRef Full Text | Google Scholar

391. López-Hurtado M, Velazco-Fernández M, Pedraza-Sánchez MJE, Flores-Salazar VR, Villagrana Zesati R, Guerra-Infante FM. Molecular detection of Chlamydia trachomatis and semen quality of sexual partners of infertile women. Andrologia (2017) e12812. doi:10.1111/and.12812

PubMed Abstract | CrossRef Full Text | Google Scholar

392. Delwart EL, Mullins JI, Gupta P, Learn GH Jr, Holodniy M, Katzenstein D, et al. Human immunodeficiency virus type 1 populations in blood and semen. J Virol (1998) 72:617–23.

PubMed Abstract | Google Scholar

393. Winter AJ, Taylor S, Workman J, White D, Ross JD, Swan AV, et al. Asymptomatic urethritis and detection of HIV-1 RNA in seminal plasma. Sex Transm Infect (1999) 75:261–3. doi:10.1136/sti.75.4.261

CrossRef Full Text | Google Scholar

394. Pilcher CD, Joaki G, Hoffman IF, Martinson FE, Mapanje C, Stewart PW, et al. Amplified transmission of HIV-1: comparison of HIV-1 concentrations in semen and blood during acute and chronic infection. AIDS (2007) 21:1723–30. doi:10.1097/QAD.0b013e3281532c82

PubMed Abstract | CrossRef Full Text | Google Scholar

395. Hladik F, McElrath MJ. Setting the stage: host invasion by HIV. Nat Rev Immunol (2008) 8:447–57. doi:10.1038/nri2302

PubMed Abstract | CrossRef Full Text | Google Scholar

396. Liu CM, Osborne BJW, Hungate BA, Shahabi K, Huibner S, Lester R, et al. The semen microbiome and its relationship with local immunology and viral load in HIV infection. PloS Path (2014) 10:e1004262. doi:10.1371/journal.ppat.1004262

CrossRef Full Text | Google Scholar

397. Rametse CL, Olivier AJ, Masson L, Barnabas S, Mckinnon LR, Ngcapu S, et al. Role of semen in altering the balance between inflammation and tolerance in the female genital tract: does it contribute to HIV risk? Viral Immunol (2014) 27:200–6. doi:10.1089/vim.2013.0136

PubMed Abstract | CrossRef Full Text | Google Scholar

398. Gruber F, Lipozencic J, Kehler T. History of venereal diseases from antiquity to the renaissance. Acta Dermatovenerol Croat (2015) 23:1–11.

PubMed Abstract | Google Scholar

399. Sherman JK, Rosenfeld J. Importance of frozen-stored human semen in the spread of gonorrhea. Fertil Steril (1975) 26:1043–7. doi:10.1016/S0015-0282(16)41468-8

PubMed Abstract | CrossRef Full Text | Google Scholar

400. Zheng H. Analysis of the antigen-antibody specificity in the semen of patients with Neisseria gonorrhoeae. Chin Med Sci J (1997) 12:47–9.

PubMed Abstract | Google Scholar

401. Isbey SF, Alcorn TM, Davis RH, Haizlip J, Leone PA, Cohen MS. Characterisation of Neisseria gonorrhoeae in semen during urethral infection in men. Genitourin Med (1997) 73:378–82.

PubMed Abstract | Google Scholar

402. Kertséz G. A new method of inoculation to prove the infectivity of the semen in latent syphilis. Br J Dermatol Syph (1931) 43:588–92. doi:10.1111/j.1365-2133.1931.tb09454.x

CrossRef Full Text | Google Scholar

403. Adeoba A. Interpretation of positive serological tests for syphilis in pregnancy. Br J Vener Dis (1967) 43:249–58.

Google Scholar

404. Burchell AN, Allen VG, Gardner SL, Moravan V, Tan DHS, Grewal R, et al. High incidence of diagnosis with syphilis co-infection among men who have sex with men in an HIV cohort in Ontario, Canada. BMC Infect Dis (2015) 15:356. doi:10.1186/s12879-015-1098-2

CrossRef Full Text | Google Scholar

405. Punjabi U, Wyns C, Mahmoud A, Vernelen K, China B, Verheyen G. Fifteen years of Belgian experience with external quality assessment of semen analysis. Andrology (2016) 4:1084–93. doi:10.1111/andr.12230

PubMed Abstract | CrossRef Full Text | Google Scholar

406. Trompoukis C, Kalaitzis C, Giannakopoulos S, Sofikitis N, Touloupidis S. Semen and the diagnosis of infertility in Aristotle. Andrologia (2007) 39:33–7. doi:10.1111/j.1439-0272.2006.00757.x

PubMed Abstract | CrossRef Full Text | Google Scholar

407. Jungwirth A, Diemer T, Dohle GR, Giwercman A, Kopa Z, Krausz C, et al. Guidelines on Male Infertility. Eur Assoc Urol (2015).

Google Scholar

408. Mändar R, Punab M, Borovkova N, Lapp E, Kiiker R, Korrovits P, et al. Complementary seminovaginal microbiome in couples. Res Microbiol (2015) 166:440–7. doi:10.1016/j.resmic.2015.03.009

PubMed Abstract | CrossRef Full Text | Google Scholar

409. Fowlkes DM, Dooher GB, O’Leary WM. Evidence by scanning electron microscopy for an association between spermatozoa and T-mycoplasmas in men of infertile marriage. Fertil Steril (1975) 26:1203–11. doi:10.1016/S0015-0282(16)41536-0

CrossRef Full Text | Google Scholar

410. Fowlkes DM, Macleod J, O’Leary WM. T-mycoplasmas and human infertility: correlation of infection with alterations in seminal parameters. Fertil Steril (1975) 26:1212–8. doi:10.1016/S0015-0282(16)41537-2

CrossRef Full Text | Google Scholar

411. Rehewy MS, Hafez ES, Thomas A, Brown WJ. Aerobic and anaerobic bacterial flora in semen from fertile and infertile groups of men. Arch Androl (1979) 2:263–8. doi:10.3109/01485017908987323

PubMed Abstract | CrossRef Full Text | Google Scholar

412. Swenson CE, Toth A, Toth C, Wolfgruber L, O’Leary WM. Asymptomatic bacteriospermia in infertile men. Andrologia (1980) 12:7–11. doi:10.1111/j.1439-0272.1980.tb00567.x

PubMed Abstract | CrossRef Full Text | Google Scholar

413. Mogra N, Dhruva A, Kothari LK. Non-specific seminal tract infection and male infertility: a bacteriological study. J Postgrad Med (1981) 27:99–104.

PubMed Abstract | Google Scholar

414. Busolo F, Zanchetta R, Lanzone E, Cusinato R. Microbial flora in semen of asymptomatic infertile men. Andrologia (1984) 16:269–75. doi:10.1111/j.1439-0272.1984.tb00282.x

PubMed Abstract | CrossRef Full Text | Google Scholar

415. Naessens A, Foulon W, Debrucker P, Devroey P, Lauwers S. Recovery of microorganisms in semen and relationship to semen evaluation. Fertil Steril (1986) 45:101–5. doi:10.1016/S0015-0282(16)49105-3

PubMed Abstract | CrossRef Full Text | Google Scholar

416. Eggert-Kruse W, Rohr G, Strock W, Pohl S, Schwalbach B, Runnebaum B. Anaerobes in ejaculates of subfertile men. Hum Reprod Update (1995) 1:462–78. doi:10.1093/humupd/1.5.462

PubMed Abstract | CrossRef Full Text | Google Scholar

417. Merino G, Carranza-Lira S, Murrieta S, Rodriguez L, Cuevas E, Moran C. Bacterial infection and semen characteristics in infertile men. Arch Androl (1995) 35:43–7. doi:10.3109/01485019508987852

PubMed Abstract | CrossRef Full Text | Google Scholar

418. Jarvi K, Lacroix JM, Jain A, Dumitru I, Heritz D, Mittelman MW. Polymerase chain reaction-based detection of bacteria in semen. Fertil Steril (1996) 66:463–7. doi:10.1016/S0015-0282(16)58520-3

PubMed Abstract | CrossRef Full Text | Google Scholar

419. Lacroix JM, Jarvi K, Batra SD, Heritz DM, Mittelman MW. PCR-based technique for the detection of bacteria in semen and urine. J Microbiol Meth (1996) 26:61–71. doi:10.1016/0167-7012(96)00844-5

CrossRef Full Text | Google Scholar

420. Byrn RA, Kiessling AA. Analysis of human immunodeficiency virus in semen: indications of a genetically distinct virus reservoir. J Reprod Immunol (1998) 41:161–76. doi:10.1016/S0165-0378(98)00056-4

PubMed Abstract | CrossRef Full Text | Google Scholar

421. Cardoso EM, Santoianni JE, De Paulis AN, Andrada JA, Predari SC, Arregger AL. Improvement of semen quality in infected asymptomatic infertile male after bacteriological cure. Medicina (B Aires) (1998) 58:160–4.

PubMed Abstract | Google Scholar

422. Köhn FM, Erdmann I, Oeda T, El Mulla KF, Schiefer HG, Schill WB. Influence of urogenital infections on sperm functions. Andrologia (1998) 30(Suppl 1):73–80. doi:10.1111/j.1439-0272.1998.tb02829.x

CrossRef Full Text | Google Scholar

423. Onemu SO, Ibeh IN. Studies on the significance of positive bacterial semen cultures in male fertility in Nigeria. Int J Fertil Womens Med (2001) 46:210–4.

PubMed Abstract | Google Scholar

424. Esfandiari N, Saleh RA, Abdoos M, Rouzrokh A, Nazemian Z. Positive bacterial culture of semen from infertile men with asymptomatic leukocytospermia. Int J Fertil Womens Med (2002) 47:265–70.

PubMed Abstract | Google Scholar

425. Sanocka D, Fraczek M, Jedrzejczak P, Szumala-Kakol A, Kurpisz M. Male genital tract infection: an influence of leukocytes and bacteria on semen. J Reprod Immunol (2004) 62:111–24. doi:10.1016/j.jri.2003.10.005

PubMed Abstract | CrossRef Full Text | Google Scholar

426. Sanocka-Maciejewska D, Ciupińska M, Kurpisz M. Bacterial infection and semen quality. J Reprod Immunol (2005) 67:51–6. doi:10.1016/j.jri.2005.06.003

PubMed Abstract | CrossRef Full Text | Google Scholar

427. Gdoura R, Kchaou W, Chaari C, Znazen A, Keskes L, Rebai T, et al. Ureaplasma urealyticum, Ureaplasma parvum, Mycoplasma hominis and Mycoplasma genitalium infections and semen quality of infertile men. BMC Infect Dis (2007) 7:129. doi:10.1186/1471-2334-7-129

PubMed Abstract | CrossRef Full Text | Google Scholar

428. Ikechukwu O, George E, Sabinus AE, Florence O. Role of enriched media in bacterial isolation from semen and effect of microbial infection on semen quality: a study on 100 infertile men. Pak J Med Sci (2007) 23:885–8.

Google Scholar

429. Kiessling AA, Desmarais BM, Yin HZ, Loverde J, Eyre RC. Detection and identification of bacterial DNA in semen. Fertil Steril (2008) 90:1744–56. doi:10.1016/j.fertnstert.2007.08.083

PubMed Abstract | CrossRef Full Text | Google Scholar

430. Pellati D, Mylonakis I, Bertoloni G, Fiore C, Andrisani A, Ambrosini G, et al. Genital tract infections and infertility. Eur J Obstet Gynecol Reprod Biol (2008) 140:3–11. doi:10.1016/j.ejogrb.2008.03.009

CrossRef Full Text | Google Scholar

431. Moretti E, Capitani S, Figura N, Pammolli A, Federico MG, Giannerini V, et al. The presence of bacteria species in semen and sperm quality. J Assist Reprod Genet (2009) 26:47–56. doi:10.1007/s10815-008-9283-5

CrossRef Full Text | Google Scholar

432. Kokab A, Akhondi MM, Sadeghi MR, Modarresi MH, Aarabi M, Jennings R, et al. Raised inflammatory markers in semen from men with asymptomatic chlamydial infection. J Androl (2010) 31:114–20. doi:10.2164/jandrol.109.008300

PubMed Abstract | CrossRef Full Text | Google Scholar

433. Onemu SO, Ogbimi AO, Ophori EA. Microbiology and semen indices of sexually-active males in Benin City, Edo State, Nigeria. J Bacteriol Res (2010) 2:55–9.

Google Scholar

434. Uneke CJ, Ugwuoru CD. Antibiotic susceptibility of urogenital microbial profile of infertile men in South-eastern Nigeria. Andrologia (2010) 42:268–73. doi:10.1111/j.1439-0272.2009.00988.x

PubMed Abstract | CrossRef Full Text | Google Scholar

435. De Francesco MA, Negrini R, Ravizzola G, Galli P, Manca N. Bacterial species present in the lower male genital tract: a five-year retrospective study. Eur J Contracept Reprod Health Care (2011) 16:47–53. doi:10.3109/13625187.2010.533219

PubMed Abstract | CrossRef Full Text | Google Scholar

436. Hamada A, Agarwal A, Sharma R, French DB, Ragheb A, Sabanegh ES Jr. Empirical treatment of low-level leukocytospermia with doxycycline in male infertility patients. Urology (2011) 78:1320–5. doi:10.1016/j.urology.2011.08.062

PubMed Abstract | CrossRef Full Text | Google Scholar

437. Isaiah IN, Nche BT, Nwagu IG, Nnanna II. Current studies on bacterospermia the leading cause of male infertility: a protégé and potential threat towards mans extinction. N Am J Med Sci (2011) 3:562–4. doi:10.4297/najms.2011.3559

PubMed Abstract | CrossRef Full Text | Google Scholar

438. La Vignera S, Vicari E, Condorelli RA, D’agata R, Calogero AE. Male accessory gland infection and sperm parameters (review). Int J Androl (2011) 34:e330–47. doi:10.1111/j.1365-2605.2011.01200.x

CrossRef Full Text | Google Scholar

439. Momoh ARM, Idonije BO, Nwoke EO, Osifo UC, Okhai O, Omoroguiwa A, et al. Pathogenic bacteria-a probable cause of primary infertility among couples in Ekpoma. J Microbiol Biotechnol Res (2011) 1:66–71.

Google Scholar

440. Kaur S, Prabha V. Infertility as a consequence of spermagglutinating Staphylococcus aureus colonization in genital tract of female mice. PLoS One (2012) 7:e52325. doi:10.1371/journal.pone.0052325

PubMed Abstract | CrossRef Full Text | Google Scholar

441. Rusz A, Pilatz A, Wagenlehner F, Linn T, Diemer T, Schuppe HC, et al. Influence of urogenital infections and inflammation on semen quality and male fertility. World J Urol (2012) 30:23–30. doi:10.1007/s00345-011-0726-8

PubMed Abstract | CrossRef Full Text | Google Scholar

442. Salmeri M, Valenti D, La Vignera S, Bellanca S, Morello A, Toscano MA, et al. Prevalence of Ureaplasma urealyticum and Mycoplasma hominis infection in unselected infertile men. J Chemother (2012) 24:81–6. doi:10.1179/1120009X12Z.00000000021

PubMed Abstract | CrossRef Full Text | Google Scholar

443. Nabi A, Khalili MA, Halvaei I, Ghasemzadeh J, Zare E. Seminal bacterial contaminations: probable factor in unexplained recurrent pregnancy loss. Iran J Reprod Med (2013) 11:925–32.

PubMed Abstract | Google Scholar

444. Sleha R, Boštíková V, Salavec M, Mosio P, Kusáková E, Kukla R, et al. Bacterial infection as a cause of infertility in humans(paper in Czech). Epidemiol Mikrobiol Imunol (2013) 62:26–32.

Google Scholar

445. La Vignera S, Condorelli RA, Vicari E, Salmeri M, Morgia G, Favilla V, et al. Microbiological investigation in male infertility: a practical overview. J Med Microbiol (2014) 63:1–14. doi:10.1099/jmm.0.062968-0

PubMed Abstract | CrossRef Full Text | Google Scholar

446. Weng SL, Chiu CM, Lin FM, Huang WC, Liang C, Yang T, et al. Bacterial communities in semen from men of infertile couples: metagenomic sequencing reveals relationships of seminal microbiota to semen quality. PLoS One (2014) 9:e110152. doi:10.1371/journal.pone.0110152

PubMed Abstract | CrossRef Full Text | Google Scholar

447. Fraczek M, Kurpisz M. Mechanisms of the harmful effects of bacterial semen infection on ejaculated human spermatozoa: potential inflammatory markers in semen. Folia Histochem Cytobiol (2015) 53:201–17. doi:10.5603/fhc.a2015.0019

PubMed Abstract | CrossRef Full Text | Google Scholar

448. Vander H, Prabha V. Evaluation of fertility outcome as a consequence of intravaginal inoculation with sperm-impairing micro-organisms in a mouse model. J Med Microbiol (2015) 64:344–7. doi:10.1099/jmm.0.000036

PubMed Abstract | CrossRef Full Text | Google Scholar

449. Fraczek M, Hryhorowicz M, Gill K, Zarzycka M, Gaczarzewicz D, Jedrzejczak P, et al. The effect of bacteriospermia and leukocytospermia on conventional and nonconventional semen parameters in healthy young normozoospermic males. J Reprod Immunol (2016) 118:18–27. doi:10.1016/j.jri.2016.08.006

PubMed Abstract | CrossRef Full Text | Google Scholar

450. Ruggeri M, Cannas S, Cubeddu M, Molicotti P, Piras GL, Dessole S, et al. Bacterial agents as a cause of infertility in humans. New Microbiol (2016) 39:206–9.

PubMed Abstract | Google Scholar

451. Shiadeh MN, Niyyati M, Fallahi S, Rostami A. Human parasitic protozoan infection to infertility: a systematic review. Parasitol Res (2016) 115:469–77. doi:10.1007/s00436-015-4827-y

PubMed Abstract | CrossRef Full Text | Google Scholar

452. Vicari LO, Castiglione R, Salemi M, Vicari BO, Mazzarino MC, Vicari E. Effect of levofloxacin treatment on semen hyperviscosity in chronic bacterial prostatitis patients. Andrologia (2016) 48:380–8. doi:10.1111/and.12456

PubMed Abstract | CrossRef Full Text | Google Scholar

453. Ahmadi MH, Mirsalehian A, Sadighi Gilani MA, Bahador A, Talebi M. Asymptomatic infection with Mycoplasma hominis negatively affects semen parameters and leads to male infertility as confirmed by improved semen parameters after antibiotic treatment. Urology (2017) 100:97–102. doi:10.1016/j.urology.2016.11.018

PubMed Abstract | CrossRef Full Text | Google Scholar

454. Kjaergaard N, Kristensen B, Hansen ES, Farholt S, Schønheyder HC, Uldbjerg N, et al. Microbiology of semen specimens from males attending a fertility clinic. APMIS (1997) 105:566–70. doi:10.1111/j.1699-0463.1997.tb05054.x

PubMed Abstract | CrossRef Full Text | Google Scholar

455. Hillier SL, Rabe LK, Muller CH, Zarutskie P, Kuzan FB, Stenchever MA. Relationship of bacteriologic characteristics to semen indices in men attending an infertility clinic. Obstet Gynecol (1990) 75:800–4.

PubMed Abstract | Google Scholar

456. Dieterle S. Urogenital infections in reproductive medicine. Andrologia (2008) 40:117–9. doi:10.1111/j.1439-0272.2008.00833.x

PubMed Abstract | CrossRef Full Text | Google Scholar

457. Vilvanathan S, Kandasamy B, Jayachandran AL, Sathiyanarayanan S, Tanjore Singaravelu V, Krishnamurthy V, et al. Bacteriospermia and its impact on basic semen parameters among infertile men. Interdiscip Perspect Infect Dis (2016) 2016:2614692. doi:10.1155/2016/2614692

PubMed Abstract | CrossRef Full Text | Google Scholar

458. Liversedge NH, Jenkins JM, Keay SD, Mclaughlin EA, Al-Sufyan H, Maile LA, et al. Antibiotic treatment based on seminal cultures from asymptomatic male partners in in-vitro fertilization is unnecessary and may be detrimental. Hum Reprod (1996) 11:1227–31. doi:10.1093/oxfordjournals.humrep.a019361

PubMed Abstract | CrossRef Full Text | Google Scholar

459. Bhandari P, Rishi P, Prabha V. Positive effect of probiotic Lactobacillus plantarum in reversing the LPS induced infertility in mouse model. J Med Microbiol (2016) 65:345–50. doi:10.1099/jmm.0.000230

CrossRef Full Text | Google Scholar

460. Hou D, Zhou X, Zhong X, Settles ML, Herring J, Wang L, et al. Microbiota of the seminal fluid from healthy and infertile men. Fertil Steril (2013) 100:1261–9. doi:10.1016/j.fertnstert.2013.07.1991

PubMed Abstract | CrossRef Full Text | Google Scholar

461. Javurek AB, Spollen WG, Ali AMM, Johnson SA, Lubahn DB, Bivens NJ, et al. Discovery of a novel seminal fluid microbiome and influence of estrogen receptor alpha genetic status. Sci Rep (2016) 6. doi:10.1038/srep23027

CrossRef Full Text | Google Scholar

462. Craig LB, Peck JD, Xu J, Sankaranarayanan K, Warinner C, Hansen KR, et al. Characterizing the semen microbiome and associations with semen parameters: the Chasm study. Fertil Steril (2015) 104:E66. doi:10.1016/j.fertnstert.2015.07.202

CrossRef Full Text | Google Scholar

463. Deen GF, Knust B, Broutet N, Sesay FR, Formenty P, Ross C, et al. Ebola RNA persistence in semen of ebola virus disease survivors – preliminary report. N Engl J Med (2015). doi:10.1056/NEJMoa1511410

CrossRef Full Text | Google Scholar

464. Soka MJ, Choi MJ, Baller A, White S, Rogers E, Purpura LJ, et al. Prevention of sexual transmission of ebola in Liberia through a national semen testing and counselling programme for survivors: an analysis of ebola virus RNA results and behavioural data. Lancet Glob Health (2016) 4:e736–43. doi:10.1016/S2214-109X(16)30175-9

PubMed Abstract | CrossRef Full Text | Google Scholar

465. Thorson A, Formenty P, Lofthouse C, Broutet N. Systematic review of the literature on viral persistence and sexual transmission from recovered ebola survivors: evidence and recommendations. BMJ Open (2016) 6:e008859. doi:10.1136/bmjopen-2015-008859

PubMed Abstract | CrossRef Full Text | Google Scholar

466. Sissoko D, Duraffour S, Kerber R, Kolie JS, Beavogui AH, Camara AM, et al. Persistence and clearance of ebola virus RNA from seminal fluid of ebola virus disease survivors: a longitudinal analysis and modelling study. Lancet Glob Health (2017) 5:e80–8. doi:10.1016/S2214-109X(16)30243-1

PubMed Abstract | CrossRef Full Text | Google Scholar

467. Klatt NR, Cheu R, Birse K, Zevin AS, Perner M, Noël-Romas L, et al. Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women. Science (2017) 356:938–45. doi:10.1126/science.aai9383

PubMed Abstract | CrossRef Full Text | Google Scholar

468. Ma W, Li S, Ma S, Jia L, Zhang F, Zhang Y, et al. Zika virus causes testis damage and leads to male infertility in mice. Cell (2016) 167:1511–24.e1510. doi:10.1016/j.cell.2016.11.016

PubMed Abstract | CrossRef Full Text | Google Scholar

469. Baud D, Musso D, Vouga M, Alves MP, Vulliemoz N. Zika virus: a new threat to human reproduction. Am J Reprod Immunol (2017) 77:e12614. doi:10.1111/aji.12614

PubMed Abstract | CrossRef Full Text | Google Scholar

470. Hamer DH, Wilson ME, Jean J, Chen LH. Epidemiology, prevention, and potential future treatments of sexually transmitted zika virus infection. Curr Infect Dis Rep (2017) 19:16. doi:10.1007/s11908-017-0571-z

PubMed Abstract | CrossRef Full Text | Google Scholar

471. Ohri M, Prabha V. Isolation of a sperm-agglutinating factor from Staphylococcus aureus isolated from a woman with unexplained infertility. Fertil Steril (2005) 84:1539–41. doi:10.1016/j.fertnstert.2005.05.030

PubMed Abstract | CrossRef Full Text | Google Scholar

472. Diemer T, Huwe P, Ludwig M, Hauck EW, Weidner W. Urogenital infection and sperm motility. Andrologia (2003) 35:283–7. doi:10.1111/j.1439-0272.2003.tb00858.x

PubMed Abstract | CrossRef Full Text | Google Scholar

473. Prabha V, Sandhu R, Kaur S, Kaur K, Sarwal A, Mavuduru RS, et al. Mechanism of sperm immobilization by Escherichia coli. Adv Urol (2010) 2010:240268. doi:10.1155/2010/240268

PubMed Abstract | CrossRef Full Text | Google Scholar

474. Fraczek M, Wiland E, Piasecka M, Boksa M, Gaczarzewicz D, Szumala-Kakol A, et al. Fertilizing potential of ejaculated human spermatozoa during in vitro semen bacterial infection. Fertil Steril (2014) 102(711–719):e711. doi:10.1016/j.fertnstert.2014.06.002

CrossRef Full Text | Google Scholar

475. Kaur K, Prabha V. Spermagglutinating Escherichia coli and its role in infertility: in vivo study. Microb Pathog (2014) 6(9–70):33–8. doi:10.1016/j.micpath.2014.03.010

PubMed Abstract | CrossRef Full Text | Google Scholar

476. Pretorius E, Mbotwe S, Bester J, Robinson CJ, Kell DB. Acute induction of anomalous and amyloidogenic blood clotting by molecular amplification of highly substoichiometric levels of bacterial lipopolysaccharide. J R Soc Interface (2016) 123:20160539. doi:10.1098/rsif.2016.0539

CrossRef Full Text | Google Scholar

477. Kell DB, Pretorius E. Proteins behaving badly. Substoichiometric molecular control and amplification of the initiation and nature of amyloid fibril formation: lessons from and for blood clotting. Progr Biophys Mol Biol (2017) 123:16–41. doi:10.1016/j.pbiomolbio.2016.08.006

CrossRef Full Text | Google Scholar

478. Pretorius E, Page MJ, Hendricks L, Nkosi NB, Benson SR, Kell DB. Both Lipopolysaccharide and Lipoteichoic Acids Potently Induce Anomalous Fibrin Amyloid Formation: Assessment with Novel Amytracker™ Stains. bioRxiv preprint. bioRxiv, 143867 (2017). doi:10.1101/143867

CrossRef Full Text | Google Scholar

479. Gupta S, Prabha V. Human sperm interaction with Staphylococcus aureus: a molecular approach. J Pathog (2012) 2012:816536. doi:10.1155/2012/816536

PubMed Abstract | CrossRef Full Text | Google Scholar

480. Enwuru CA, Iwalokun B, Enwuru VN, Ezechi O, Oluwadun A. The effect of presence of facultative bacteria species on semen and sperm quality of men seeking fertility care. Afr J Urol (2016) 22:213–22. doi:10.1016/j.afju.2016.03.010

CrossRef Full Text | Google Scholar

481. Anway MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors and mate fertility. Science (2005) 308:1466–9. doi:10.1126/science.1108190

CrossRef Full Text | Google Scholar

482. Fenech M. Micronuclei and their association with sperm abnormalities, infertility, pregnancy loss, pre-eclampsia and intra-uterine growth restriction in humans. Mutagenesis (2011) 26:63–7. doi:10.1093/mutage/geq084

PubMed Abstract | CrossRef Full Text | Google Scholar

483. Pandian Z, Bhattacharya S, Templeton A. Review of unexplained infertility and obstetric outcome: a 10 year review. Hum Reprod (2001) 16:2593–7. doi:10.1093/humrep/16.12.2593

PubMed Abstract | CrossRef Full Text | Google Scholar

484. Trogstad L, Magnus P, Moffett A, Stoltenberg C. The effect of recurrent miscarriage and infertility on the risk of pre-eclampsia. BJOG (2009) 116:108–13. doi:10.1111/j.1471-0528.2008.01978.x

PubMed Abstract | CrossRef Full Text | Google Scholar

485. Basso O, Baird DD. Infertility and preterm delivery, birthweight, and Caesarean section: a study within the Danish National Birth Cohort. Hum Reprod (2003) 18:2478–84. doi:10.1093/humrep/deg444

PubMed Abstract | CrossRef Full Text | Google Scholar

486. Basso O, Weinberg CR, Baird DD, Wilcox AJ, Olsen J. Subfecundity as a correlate of preeclampsia: a study within the Danish National Birth Cohort. Am J Epidemiol (2003) 157:195–202. doi:10.1093/aje/kwf194

PubMed Abstract | CrossRef Full Text | Google Scholar

487. Sohrabvand F, Jafari M, Shariat M, Haghollahi F, Lotfi M. Frequency and epidemiologic aspects of male infertility. Acta Med Iran (2015) 53:231–5.

PubMed Abstract | Google Scholar

488. Dobson PD, Kell DB. Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule? Nat Rev Drug Disc (2008) 7:205–20. doi:10.1038/nrd2438

CrossRef Full Text | Google Scholar

489. Kell DB, Dobson PD, Bilsland E, Oliver SG. The promiscuous binding of pharmaceutical drugs and their transporter-mediated uptake into cells: what we (need to) know and how we can do so. Drug Disc Today (2013) 18:218–39. doi:10.1016/j.drudis.2012.11.008

PubMed Abstract | CrossRef Full Text | Google Scholar

490. Kell DB, Oliver SG. How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion. Front Pharmacol (2014) 5:231. doi:10.3389/fphar.2014.00231

PubMed Abstract | CrossRef Full Text | Google Scholar

491. Pajovic B, Radojevic N, Vukovic M, Stjepcevic A. Semen analysis before and after antibiotic treatment of asymptomatic Chlamydia- and Ureaplasma-related pyospermia. Andrologia (2013) 45:266–71. doi:10.1111/and.12004

PubMed Abstract | CrossRef Full Text | Google Scholar

492. Schoor RA. Prostatitis and male infertility: evidence and links. Curr Urol Rep (2002) 3:324–9. doi:10.1007/s11934-002-0058-8

PubMed Abstract | CrossRef Full Text | Google Scholar

493. Everaert K, Mahmoud A, Depuydt C, Maeyaert M, Comhaire F. Chronic prostatitis and male accessory gland infection – is there an impact on male infertility (diagnosis and therapy)? Andrologia (2003) 35:325–30. doi:10.1111/j.1439-0272.2003.tb00867.x

CrossRef Full Text | Google Scholar

494. La Vignera S, Condorelli R, Vicari E, D’agata R, Calogero AE. High frequency of sexual dysfunction in patients with male accessory gland infections. Andrologia (2012) 44(Suppl 1):438–46. doi:10.1111/j.1439-0272.2011.01202.x

PubMed Abstract | CrossRef Full Text | Google Scholar

495. Alshahrani S, Mcgill J, Agarwal A. Prostatitis and male infertility. J Reprod Immunol (2013) 100:30–6. doi:10.1016/j.jri.2013.05.004

CrossRef Full Text | Google Scholar

496. La Vignera S, Vicari E, Condorelli RA, Franchina C, Scalia G, Morgia G, et al. Prevalence of human papilloma virus infection in patients with male accessory gland infection. Reprod Biomed Online (2015) 30:385–91. doi:10.1016/j.rbmo.2014.12.016

PubMed Abstract | CrossRef Full Text | Google Scholar

497. Estemalik J, Demko C, Bissada NF, Joshi N, Bodner D, Shankar E, et al. Simultaneous detection of oral pathogens in subgingival plaque and prostatic fluid of men with periodontal and prostatic diseases. J Periodontol (2017) 88:823–29. doi:10.1902/jop.2017.160477

PubMed Abstract | CrossRef Full Text | Google Scholar

498. Hedger MP. Toll-like receptors and signalling in spermatogenesis and testicular responses to inflammation – a perspective. J Reprod Immunol (2011) 88:130–41. doi:10.1016/j.jri.2011.01.010

CrossRef Full Text | Google Scholar

499. Bhushan S, Schuppe HC, Fijak M, Meinhardt A. Testicular infection: microorganisms, clinical implications and host-pathogen interaction. J Reprod Immunol (2009) 83:164–7. doi:10.1016/j.jri.2009.07.007

CrossRef Full Text | Google Scholar

500. Bhushan S, Schuppe HC, Tchatalbachev S, Fijak M, Weidner W, Chakraborty T, et al. Testicular innate immune defense against bacteria. Mol Cell Endocrinol (2009) 306:37–44. doi:10.1016/j.mce.2008.10.017

CrossRef Full Text | Google Scholar

501. Chen B, Yu L, Wang J, Li C, Zhao K, Zhang H. Involvement of prokineticin 2 and prokineticin receptor 1 in lipopolysaccharide-induced testitis in rats. Inflammation (2016) 39:534–42. doi:10.1007/s10753-015-0277-z

PubMed Abstract | CrossRef Full Text | Google Scholar

502. Lipsky BA. Prostatitis and urinary tract infection in men: what’s new; what’s true? Am J Med (1999) 106:327–34. doi:10.1016/S0002-9343(99)00017-0

PubMed Abstract | CrossRef Full Text | Google Scholar

503. Lipsky BA, Byren I, Hoey CT. Treatment of bacterial prostatitis. Clin Infect Dis (2010) 50:1641–52. doi:10.1086/652861

PubMed Abstract | CrossRef Full Text | Google Scholar

504. Vicari E, Calogero AE, Condorelli RA, Vicari LO, La Vignera S. Male accessory gland infection frequency in infertile patients with chronic microbial prostatitis and irritable bowel syndrome. Int J Androl (2012) 35:183–9. doi:10.1111/j.1365-2605.2011.01216.x

CrossRef Full Text | Google Scholar

505. Wagenlehner FME, Pilatz A, Bschleipfer T, Diemer T, Linn T, Meinhardt A, et al. Bacterial prostatitis. World J Urol (2013) 31:711–6. doi:10.1007/s00345-013-1055-x

PubMed Abstract | CrossRef Full Text | Google Scholar

506. Krebs J, Bartel P, Pannek J. Bacterial persistence in the prostate after antibiotic treatment of chronic bacterial prostatitis in men with spinal cord injury. Urology (2014) 83:515–20. doi:10.1016/j.urology.2013.11.023

CrossRef Full Text | Google Scholar

507. Krebs J, Bartel P, Pannek J. Chronic bacterial prostatitis in men with spinal cord injury. World J Urol (2014) 32:1579–85. doi:10.1007/s00345-013-1235-8

CrossRef Full Text | Google Scholar

508. Wagenlehner FME, Weidner W, Pilatz A, Naber KG. Urinary tract infections and bacterial prostatitis in men. Curr Opin Infect Dis (2014) 27:97–101. doi:10.1097/QCO.0000000000000024

PubMed Abstract | CrossRef Full Text | Google Scholar

509. Videčnik Zorman J, Matičič M, Jeverica S, Smrkolj T. Diagnosis and treatment of bacterial prostatitis. Acta Dermatovenereol (2015) 24:25–9.

Google Scholar

510. Condorelli RA, Vicari E, Mongioi LM, Russo GI, Morgia G, La Vignera S, et al. Human papilloma virus infection in patients with male accessory gland infection: usefulness of the ultrasound evaluation. Int J Endocrinol (2016) 2016:9174609. doi:10.1155/2016/9174609

PubMed Abstract | CrossRef Full Text | Google Scholar

511. Gill BC, Shoskes DA. Bacterial prostatitis. Curr Opin Infect Dis (2016) 29:86–91. doi:10.1097/QCO.0000000000000222

CrossRef Full Text | Google Scholar

512. Krieger JN, Thumbikat P. Bacterial prostatitis: bacterial virulence, clinical outcomes, and new directions. Microbiol Spectr (2016) 4(1):UTI-0004-2012. doi:10.1128/microbiolspec.UTI-0004-2012

CrossRef Full Text | Google Scholar

513. Alvarado-Esquivel C, Pacheco-Vega SJ, Hernández-Tinoco J, Centeno-Tinoco MM, Beristain-Garcia I, Sánchez-Anguiano LF, et al. Miscarriage history and Toxoplasma gondii infection: a cross-sectional study in women in Durango City, Mexico. Eur J Microbiol Immunol (Bp) (2014) 4:117–22. doi:10.1556/EuJMI.4.2014.2.4

PubMed Abstract | CrossRef Full Text | Google Scholar

514. Giakoumelou S, Wheelhouse N, Cuschieri K, Entrican G, Howie SEM, Horne AW. The role of infection in miscarriage. Hum Reprod Update (2015). doi:10.1093/humupd/dmv041

CrossRef Full Text | Google Scholar

515. van der Eijk AA, Van Genderen PJ, Verdijk RM, Reusken CB, Mogling R, Van Kampen JJ, et al. Miscarriage associated with zika virus infection. N Engl J Med (2016) 375:1002–4. doi:10.1056/NEJMc1605898

CrossRef Full Text | Google Scholar

516. McDonald HM, Chambers HM. Intrauterine infection and spontaneous midgestation abortion: is the spectrum of microorganisms similar to that in preterm labor? Infect Dis Obstet Gynecol (2000) 8:220–7. doi:10.1155/S1064744900000314

PubMed Abstract | CrossRef Full Text | Google Scholar

517. Romero R, Espinoza J, Mazor M. Can endometrial infection/inflammation explain implantation failure, spontaneous abortion, and preterm birth after in vitro fertilization? Fertil Steril (2004) 82:799–804. doi:10.1016/j.fertnstert.2004.05.076

PubMed Abstract | CrossRef Full Text | Google Scholar

518. Conde-Ferráez L, Chan May ADA, Carrillo-Martínez JR, Ayora-Talavera G, González-Losa MDR. Human papillomavirus infection and spontaneous abortion: a case-control study performed in Mexico. Eur J Obstet Gynecol Reprod Biol (2013) 170:468–73. doi:10.1016/j.ejogrb.2013.07.002

PubMed Abstract | CrossRef Full Text | Google Scholar

519. Wang H, Cao Q, Ge J, Liu C, Ma Y, Meng Y, et al. LncRNA-regulated infection and inflammation pathways associated with pregnancy loss: genome wide differential expression of lncRNAs in early spontaneous abortion. Am J Reprod Immunol (2014) 72:359–75. doi:10.1111/aji.12275

PubMed Abstract | CrossRef Full Text | Google Scholar

520. Ahmadi A, Khodabandehloo M, Ramazanzadeh R, Farhadifar F, Roshani D, Ghaderi E, et al. The relationship between Chlamydia trachomatis genital infection and spontaneous abortion. J Reprod Infertil (2016) 17:110–6.

PubMed Abstract | Google Scholar

521. Ambühl LMM, Baandrup U, Dybkaer K, Blaakaer J, Uldbjerg N, Sørensen S. Human papillomavirus infection as a possible cause of spontaneous abortion and spontaneous preterm delivery. Infect Dis Obstet Gynecol (2016) 2016:3086036. doi:10.1155/2016/3086036

PubMed Abstract | CrossRef Full Text | Google Scholar

522. Golding B, Scott DE, Scharf O, Huang LY, Zaitseva M, Lapham C, et al. Immunity and protection against Brucella abortus. Microbes Infect (2001) 3:43–8. doi:10.1016/S1286-4579(00)01350-2

PubMed Abstract | CrossRef Full Text | Google Scholar

523. Corbel MJ, Elberg SS, Cosivi O. Brucellosis in Humans and Animals. Geneva: World Health Organization (2006).

Google Scholar

524. Oliveira SC, De Oliveira FS, Macedo GC, De Almeida LA, Carvalho NB. The role of innate immune receptors in the control of Brucella abortus infection: toll-like receptors and beyond. Microbes Infect (2008) 10:1005–9. doi:10.1016/j.micinf.2008.07.005

PubMed Abstract | CrossRef Full Text | Google Scholar

525. Kuster CE, Althouse GC. The impact of bacteriospermia on boar sperm storage and reproductive performance. Theriogenology (2016) 85:21–6. doi:10.1016/j.theriogenology.2015.09.049

CrossRef Full Text | Google Scholar

526. Dorneles EMS, Sriranganathan N, Lage AP. Recent advances in Brucella abortus vaccines. Vet Res (2015) 46:76. doi:10.1186/s13567-015-0199-7

PubMed Abstract | CrossRef Full Text | Google Scholar

527. Brown VG, Schollum LM, Jarvis BDW. Microbiology of bovine semen and artificial breeding practices under New-Zealand conditions. NZ J Agric Res (1974) 17:431–2. doi:10.1080/00288233.1974.10421030

CrossRef Full Text | Google Scholar

528. Schollum LM. The Microbiology of Bovine Serum and the Antimicrobial Activity of Bovine Seminal Plasma [PhD thesis]. Palmerston North: Massey University (1977).

Google Scholar

529. Yániz JL, Marco-Aguado MA, Mateos JA, Santolaria P. Bacterial contamination of ram semen, antibiotic sensitivities, and effects on sperm quality during storage at 15 degrees C. Anim Reprod Sci (2010) 122:142–9. doi:10.1016/j.anireprosci.2010.08.006

CrossRef Full Text | Google Scholar

530. Gaczarzewicz D, Udała J, Piasecka M, Błaszczyk B, Stankiewicz T. Bacterial contamination of boar semen and its relationship to sperm quality preserved in commercial extender containing gentamicin sulfate. Pol J Vet Sci (2016) 19:451–9. doi:10.1515/pjvs-2016-0057

PubMed Abstract | CrossRef Full Text | Google Scholar

531. Romero R, Mazor M, Wu YK, Sirtori M, Oyarzun E, Mitchell MD, et al. Infection in the pathogenesis of preterm labor. Semin Perinatol (1988) 12:262–79.

Google Scholar

532. Toth M, Witkin SS, Ledger W, Thaler H. The role of infection in the etiology of preterm birth. Obstet Gynecol (1988) 71:723–6.

PubMed Abstract | Google Scholar

533. Cassell GH, Waites KB, Watson HL, Crouse DT, Harasawa R. Ureaplasma urealyticum intrauterine infection: role in prematurity and disease in newborns. Clin Microbiol Rev (1993) 6:69–87. doi:10.1128/CMR.6.1.69

PubMed Abstract | CrossRef Full Text | Google Scholar

534. McGregor JA, French JI, Jones W, Milligan K, Mckinney PJ, Patterson E, et al. Bacterial vaginosis is associated with prematurity and vaginal fluid mucinase and sialidase: results of a controlled trial of topical clindamycin cream. Am J Obstet Gynecol (1994) 170:1048–59; discussion 1059–60. doi:10.1016/S0002-9378(94)70098-2

PubMed Abstract | CrossRef Full Text | Google Scholar

535. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med (2000) 342:1500–7. doi:10.1056/NEJM200005183422007

CrossRef Full Text | Google Scholar

536. Gonçalves LF, Chaiworapongsa T, Romero R. Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev (2002) 8:3–13. doi:10.1002/mrdd.10008

PubMed Abstract | CrossRef Full Text | Google Scholar

537. Gerber S, Vial Y, Hohlfeld P, Witkin SS. Detection of Ureaplasma urealyticum in second-trimester amniotic fluid by polymerase chain reaction correlates with subsequent preterm labor and delivery. J Infect Dis (2003) 187:518–21. doi:10.1086/368205

CrossRef Full Text | Google Scholar

538. Gardella C, Riley DE, Hitti J, Agnew K, Krieger JN, Eschenbach D. Identification and sequencing of bacterial rDNAs in culture-negative amniotic fluid from women in premature labor. Am J Perinatol (2004) 21:319–23. doi:10.1055/s-2004-831884

PubMed Abstract | CrossRef Full Text | Google Scholar

539. Espinoza J, Erez O, Romero R. Preconceptional antibiotic treatment to prevent preterm birth in women with a previous preterm delivery. Am J Obstet Gynecol (2006) 194:630–7. doi:10.1016/j.ajog.2005.11.050

PubMed Abstract | CrossRef Full Text | Google Scholar

540. Lee SE, Romero R, Kim CJ, Shim SS, Yoon BH. Funisitis in term pregnancy is associated with microbial invasion of the amniotic cavity and intra-amniotic inflammation. J Matern Fetal Neonatal Med (2006) 19:693–7. doi:10.1080/14767050600927353

PubMed Abstract | CrossRef Full Text | Google Scholar

541. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet (2008) 371:75–84. doi:10.1016/S0140-6736(08)60074-4

PubMed Abstract | CrossRef Full Text | Google Scholar

542. Check JH. A practical approach to the prevention of miscarriage part 4-role of infection. Clin Exp Obstet Gyn (2010) 37:252–5.

Google Scholar

543. Bastek JA, Gómez LM, Elovitz MA. The role of inflammation and infection in preterm birth. Clin Perinatol (2011) 38:385–406. doi:10.1016/j.clp.2011.06.003

PubMed Abstract | CrossRef Full Text | Google Scholar

544. Johnson HL, Ghanem KG, Zenilman JM, Erbelding EJ. Sexually transmitted infections and adverse pregnancy outcomes among women attending inner city public sexually transmitted diseases clinics. Sex Transm Dis (2011) 38:167–71. doi:10.1097/OLQ.0b013e3181f2e85f

PubMed Abstract | CrossRef Full Text | Google Scholar

545. Manzoni P, Rizzollo S, Decembrino L, Ruffinazzi G, Rossi Ricci A, Gallo E, et al. Recent advances in prevention of sepsis in the premature neonates in NICU. Early Hum Dev (2011) 87(Suppl 1):S31–3. doi:10.1016/j.earlhumdev.2011.01.008

CrossRef Full Text | Google Scholar

546. Rours GIJG, Duijts L, Moll HA, Arends LR, De Groot R, Jaddoe VW, et al. Chlamydia trachomatis infection during pregnancy associated with preterm delivery: a population-based prospective cohort study. Eur J Epidemiol (2011) 26:493–502. doi:10.1007/s10654-011-9586-1

CrossRef Full Text | Google Scholar

547. Jefferson KK. The bacterial etiology of preterm birth. Adv Appl Microbiol (2012) 80:1–22. doi:10.1016/B978-0-12-394381-1.00001-5

PubMed Abstract | CrossRef Full Text | Google Scholar

548. Lee SYR, Leung CW. Histological chorioamnionitis – implication for bacterial colonization, laboratory markers of infection, and early onset sepsis in very-low-birth-weight neonates. J Matern Fetal Neonatal Med (2012) 25:364–8. doi:10.3109/14767058.2011.579208

PubMed Abstract | CrossRef Full Text | Google Scholar

549. Shinar S, Skornick-Rapaport A, Rimon E. Placental abruption remote from term associated with Q fever infection. Obstet Gynecol (2012) 120:503–5. doi:10.1097/AOG.0b013e318260590f

PubMed Abstract | CrossRef Full Text | Google Scholar

550. Subramaniam A, Abramovici A, Andrews WW, Tita AT. Antimicrobials for preterm birth prevention: an overview. Infect Dis Obs Gynecol (2012). doi:10.1155/2012/157159

CrossRef Full Text | Google Scholar

551. Aagaard K, Ma J, Antony KM, Ganu R, Petrosino J, Versalovic J. The placenta harbors a unique microbiome. Sci Transl Med (2014) 6:237ra265. doi:10.1126/scitranslmed.3008599

PubMed Abstract | CrossRef Full Text | Google Scholar

552. Joergensen JS, Kjaer Weile LK, Lamont RF. The early use of appropriate prophylactic antibiotics in susceptible women for the prevention of preterm birth of infectious etiology. Expert Opin Pharmacother (2014) 15:2173–91. doi:10.1517/14656566.2014.950225

PubMed Abstract | CrossRef Full Text | Google Scholar

553. Allen-Daniels MJ, Serrano MG, Pflugner LP, Fettweis JM, Prestosa MA, Koparde VN, et al. Identification of a gene in Mycoplasma hominis associated with preterm birth and microbial burden in intraamniotic infection. Am J Obstet Gynecol (2015) 212:779.e1–779.e13. doi:10.1016/j.ajog.2015.01.032

CrossRef Full Text | Google Scholar

554. de Andrade Ramos B, Kanninen TT, Sisti G, Witkin SS. Microorganisms in the female genital tract during pregnancy: tolerance versus pathogenesis. Am J Reprod Immunol (2015) 73:383–9. doi:10.1111/aji.12326

PubMed Abstract | CrossRef Full Text | Google Scholar

555. Kacerovsky M, Vrbacky F, Kutova R, Pliskova L, Andrys C, Musilova I, et al. Cervical microbiota in women with preterm prelabor rupture of membranes. PLoS One (2015) 10:e0126884. doi:10.1371/journal.pone.0126884

CrossRef Full Text | Google Scholar

556. Lamont RF. Advances in the prevention of infection-related preterm birth. Front Immunol (2015) 6:566. doi:10.3389/fimmu.2015.00566

PubMed Abstract | CrossRef Full Text | Google Scholar

557. Lis R, Rowhani-Rahbar A, Manhart LE. Mycoplasma genitalium infection and female reproductive tract disease: a meta-analysis. Clin Infect Dis (2015) 61:418–26. doi:10.1093/cid/civ312

PubMed Abstract | CrossRef Full Text | Google Scholar

558. Pammi M, Weisman LE. Late-onset sepsis in preterm infants: update on strategies for therapy and prevention. Expert Rev Anti Infect Ther (2015) 13:487–504. doi:10.1586/14787210.2015.1008450

PubMed Abstract | CrossRef Full Text | Google Scholar

559. Ueno T, Niimi H, Yoneda N, Yoneda S, Mori M, Tabata H, et al. Eukaryote-made thermostable DNA polymerase enables rapid PCR-based detection of mycoplasma, ureaplasma and other bacteria in the amniotic fluid of preterm labor cases. PLoS One (2015) 10:e0129032. doi:10.1371/journal.pone.0129032

PubMed Abstract | CrossRef Full Text | Google Scholar

560. Frey HA, Klebanoff MA. The epidemiology, etiology, and costs of preterm birth. Semin Fetal Neonatal Med (2016) 21:68–73. doi:10.1016/j.siny.2015.12.011

PubMed Abstract | CrossRef Full Text | Google Scholar

561. Nadeau HCG, Subramaniam A, Andrews WW. Infection and preterm birth. Semin Fetal Neonatal Med (2016) 21:100–5. doi:10.1016/j.siny.2015.12.008

PubMed Abstract | CrossRef Full Text | Google Scholar

562. Vinturache AE, Gyamfi-Bannerman C, Hwang J, Mysorekar IU, Jacobsson B; Preterm Birth International Collaborative (Prebic). Maternal microbiome – a pathway to preterm birth. Semin Fetal Neonatal Med (2016) 21:94–9. doi:10.1016/j.siny.2016.02.004

CrossRef Full Text | Google Scholar

563. Yoneda S, Shiozaki A, Yoneda N, Ito M, Shima T, Fukuda K, et al. Antibiotic therapy increases the risk of preterm birth in preterm labor without intra-amniotic microbes, but may prolong the gestation period in preterm labor with microbes, evaluated by rapid and high-sensitive PCR system. Am J Reprod Immunol (2016) 75:440–50. doi:10.1111/aji.12484

PubMed Abstract | CrossRef Full Text | Google Scholar

564. García-Velasco JA, Menabrito M, Catalán IB. What fertility specialists should know about the vaginal microbiome: a review. Reprod Biomed Online (2017) 35:103–12. doi:10.1016/j.rbmo.2017.04.005

CrossRef Full Text | Google Scholar

565. van Well GTJ, Daalderop LA, Wolfs T, Kramer BW. Human perinatal immunity in physiological conditions and during infection. Mol Cell Pediatr (2017) 4:4. doi:10.1186/s40348-017-0070-1

PubMed Abstract | CrossRef Full Text | Google Scholar

566. Zini A, Boman JM, Belzile E, Ciampi A. Sperm DNA damage is associated with an increased risk of pregnancy loss after IVF and ICSI: systematic review and meta-analysis. Hum Reprod (2008) 23:2663–8. doi:10.1093/humrep/den321

CrossRef Full Text | Google Scholar

567. Gil-Villa AM, Cardona-Maya W, Agarwal A, Sharma R, Cadavid Á. Assessment of sperm factors possibly involved in early recurrent pregnancy loss. Fertil Steril (2010) 94:1465–72. doi:10.1016/j.fertnstert.2009.05.042

PubMed Abstract | CrossRef Full Text | Google Scholar

568. Brahem S, Mehdi M, Landolsi H, Mougou S, Elghezal H, Saad A. Semen parameters and sperm DNA fragmentation as causes of recurrent pregnancy loss. Urology (2011) 78:792–6. doi:10.1016/j.urology.2011.05.049

PubMed Abstract | CrossRef Full Text | Google Scholar

569. Shina A, Carp HJA. Recurrent pregnancy loss – beyond evidence based medicine. Gynecol Endocrinol (2012) 28:991–2. doi:10.3109/09513590.2012.683083

PubMed Abstract | CrossRef Full Text | Google Scholar

570. Lewis SEM, John Aitken R, Conner SJ, Iuliis GD, Evenson DP, Henkel R, et al. The impact of sperm DNA damage in assisted conception and beyond: recent advances in diagnosis and treatment. Reprod Biomed Online (2013) 27:325–37. doi:10.1016/j.rbmo.2013.06.014

PubMed Abstract | CrossRef Full Text | Google Scholar

571. Simon L, Proutski I, Stevenson M, Jennings D, Mcmanus J, Lutton D, et al. Sperm DNA damage has a negative association with live-birth rates after IVF. Reprod Biomed Online (2013) 26:68–78. doi:10.1016/j.rbmo.2012.09.019

PubMed Abstract | CrossRef Full Text | Google Scholar

572. Wang R, Zhou H, Zhang Z, Dai R, Geng D, Liu R. The impact of semen quality, occupational exposure to environmental factors and lifestyle on recurrent pregnancy loss. J Assist Reprod Genet (2013) 30:1513–8. doi:10.1007/s10815-013-0091-1

PubMed Abstract | CrossRef Full Text | Google Scholar

573. Belloc S, Benkhalifa M, Cohen-Bacrie M, Dalleac A, Chahine H, Amar E, et al. Which isolated sperm abnormality is most related to sperm DNA damage in men presenting for infertility evaluation. J Assist Reprod Genet (2014) 31:527–32. doi:10.1007/s10815-014-0194-3

PubMed Abstract | CrossRef Full Text | Google Scholar

574. Bonney EA, Brown SA. To drive or be driven: the path of a mouse model of recurrent pregnancy loss. Reproduction (2014) 147:R153–67. doi:10.1530/REP-13-0583

PubMed Abstract | CrossRef Full Text | Google Scholar

575. Kavitha P, Malini SS. Positive association of sperm dysfunction in the pathogenesis of recurrent pregnancy loss. J Clin Diagn Res (2014) 8:OC07–10. doi:10.7860/JCDR/2014/9109.5172

PubMed Abstract | CrossRef Full Text | Google Scholar

576. Zhao J, Zhang Q, Wang Y, Li Y. Whether sperm deoxyribonucleic acid fragmentation has an effect on pregnancy and miscarriage after in vitro fertilization/intracytoplasmic sperm injection: a systematic review and meta-analysis. Fertil Steril (2014) 102:998–1005.e1008. doi:10.1016/j.fertnstert.2014.06.033

CrossRef Full Text | Google Scholar

577. Bronson R, editor. The Male Role in Pregnancy Loss and Embryo Implantation Failure. Berlin: Springer (2015).

Google Scholar

578. Esteves SC, Sánchez-Martin F, Sánchez-Martin P, Schneider DT, Gosálvez J. Comparison of reproductive outcome in oligozoospermic men with high sperm DNA fragmentation undergoing intracytoplasmic sperm injection with ejaculated and testicular sperm. Fertil Steril (2015) 104:1398–405. doi:10.1016/j.fertnstert.2015.08.028

CrossRef Full Text | Google Scholar

579. Zidi-Jrah I, Hajlaoui A, Mougou-Zerelli S, Kammoun M, Meniaoui I, Sallem A, et al. Relationship between sperm aneuploidy, sperm DNA integrity, chromatin packaging, traditional semen parameters, and recurrent pregnancy loss. Fertil Steril (2016) 105:58–64. doi:10.1016/j.fertnstert.2015.09.041

PubMed Abstract | CrossRef Full Text | Google Scholar

580. Simon L, Zini A, Dyachenko A, Ciampi A, Carrell DT. A systematic review and meta-analysis to determine the effect of sperm DNA damage on in vitro fertilization and intracytoplasmic sperm injection outcome. Asian J Androl (2017) 19:80–90. doi:10.4103/1008-682X.182822

PubMed Abstract | CrossRef Full Text | Google Scholar

581. Agarwal A, Majzoub A, Esteves SC, Ko E, Ramasamy R, Zini A. Clinical utility of sperm DNA fragmentation testing: practice recommendations based on clinical scenarios. Transl Androl Urol (2016) 5:935–50. doi:10.21037/tau.2016.10.03

PubMed Abstract | CrossRef Full Text | Google Scholar

582. Usmani S, Liu HC, Pilcher CD, Witkowska HE, Kirchhoff F, Greene WC, et al. HIV-enhancing amyloids are prevalent in fresh semen and are a determinant for semen’s ability to enhance HIV infection: relevance for HIV transmission. AIDS Res Hum Retroviruses (2014) 30:A183–4. doi:10.1089/aid.2014.5392.abstract

CrossRef Full Text | Google Scholar

583. Binder NK, Sheedy JR, Hannan NJ, Gardner DK. Male obesity is associated with changed spermatozoa Cox4i1 mRNA level and altered seminal vesicle fluid composition in a mouse model. Mol Hum Reprod (2015) 21:424–34. doi:10.1093/molehr/gav010

PubMed Abstract | CrossRef Full Text | Google Scholar

584. Gil-Villa AM, Cardona-Maya W, Agarwal A, Sharma R, Cadavid Á. Role of male factor in early recurrent embryo loss: do antioxidants have any effect? Fertil Steril (2009) 92:565–71. doi:10.1016/j.fertnstert.2008.07.1715

CrossRef Full Text | Google Scholar

585. Shiva M, Gautam AK, Verma Y, Shivgotra V, Doshi H, Kumar S. Association between sperm quality, oxidative stress, and seminal antioxidant activity. Clin Biochem (2011) 44:319–24. doi:10.1016/j.clinbiochem.2010.11.009

PubMed Abstract | CrossRef Full Text | Google Scholar

586. Agarwal A, Durairajanayagam D, Halabi J, Peng J, Vazquez-Levin M. Proteomics, oxidative stress and male infertility. Reprod Biomed Online (2014) 29:32–58. doi:10.1016/j.rbmo.2014.02.013

CrossRef Full Text | Google Scholar

587. Durairajanayagam D, Agarwal A, Ong C, Prashast P. Lycopene and male infertility. Asian J Androl (2014) 16:420–5. doi:10.4103/1008-682X.126384

CrossRef Full Text | Google Scholar

588. Ko EY, Sabanegh ES Jr, Agarwal A. Male infertility testing: reactive oxygen species and antioxidant capacity. Fertil Steril (2014) 102:1518–27. doi:10.1016/j.fertnstert.2014.10.020

PubMed Abstract | CrossRef Full Text | Google Scholar

589. Cruz DF, Lume C, Silva JV, Nunes A, Castro I, Silva R, et al. Oxidative stress markers: can they be used to evaluate human sperm quality? Turk J Urol (2015) 41:198–207. doi:10.5152/tud.2015.06887

CrossRef Full Text | Google Scholar

590. Agarwal A, Roychoudhury S, Sharma R, Gupta S, Majzoub A, Sabanegh E. Diagnostic application of oxidation-reduction potential assay for measurement of oxidative stress: clinical utility in male factor infertility. Reprod Biomed Online (2017) 34:48–57. doi:10.1016/j.rbmo.2016.10.008

PubMed Abstract | CrossRef Full Text | Google Scholar

591. Agarwal A, Wang SM. Clinical relevance of oxidation-reduction potential in the evaluation of male infertility. Urology (2017) 104:84–9. doi:10.1016/j.urology.2017.02.016

PubMed Abstract | CrossRef Full Text | Google Scholar

592. Bouziat R, Hinterleitner R, Brown JJ, Stencel-Baerenwald JE, Ikizler M, Mayassi T, et al. Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science (2017) 356:44–50. doi:10.1126/science.aah5298

PubMed Abstract | CrossRef Full Text | Google Scholar

593. Verdu EF, Caminero A. How infection can incite sensitivity to food. Science (2017) 356:29–30. doi:10.1126/science.aan1500

CrossRef Full Text | Google Scholar

594. Ludvigsson JF, Montgomery SM, Ekbom A. Celiac disease and risk of adverse fetal outcome: a population-based cohort study. Gastroenterology (2005) 129:454–63. doi:10.1016/j.gastro.2005.05.065

CrossRef Full Text | Google Scholar

595. Wolf H, Ilsen A, Van Pampus MG, Sahebdien S, Pena S, Von Blomberg ME. Celiac serology in women with severe pre-eclampsia or delivery of a small for gestational age neonate. Int J Gynaecol Obstet (2008) 103:175–7. doi:10.1016/j.ijgo.2008.05.024

CrossRef Full Text | Google Scholar

596. Bast A, O’Bryan T, Bast E. Celiac disease and reproductive health. Practical Gastroenterol (2009):10–21.

Google Scholar

597. Özgör B, Selimoğlu MA. Coeliac disease and reproductive disorders. Scand J Gastroenterol (2010) 45:395–402. doi:10.3109/00365520903508902

CrossRef Full Text | Google Scholar

598. Soni S, Badawy SZ. Celiac disease and its effect on human reproduction: a review. J Reprod Med (2010) 55:3–8.

Google Scholar

599. Tersigni C, Castellani R, De Waure C, Fattorossi A, De Spirito M, Gasbarrini A, et al. Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms. Hum Reprod Update (2014) 20:582–93. doi:10.1093/humupd/dmu007

CrossRef Full Text | Google Scholar

600. Moleski SM, Lindenmeyer CC, Veloski JJ, Miller RS, Miller CL, Kastenberg D, et al. Increased rates of pregnancy complications in women with celiac disease. Ann Gastroenterol (2015) 28:236–40.

PubMed Abstract | Google Scholar

601. Saccone G, Berghella V, Sarno L, Maruotti GM, Cetin I, Greco L, et al. Celiac disease and obstetric complications: a systematic review and metaanalysis. Am J Obstet Gynecol (2016) 214:225–34. doi:10.1016/j.ajog.2015.09.080

PubMed Abstract | CrossRef Full Text | Google Scholar

602. Byberg KK, Ogland B, Eide GE, Øymar K. Birth after preeclamptic pregnancies: association with allergic sensitization and allergic rhinoconjunctivitis in late childhood; a historically matched cohort study. BMC Pediatr (2014) 14:101. doi:10.1186/1471-2431-14-101

PubMed Abstract | CrossRef Full Text | Google Scholar

603. Liu AH. Revisiting the hygiene hypothesis for allergy and asthma. J Allergy Clin Immunol (2015) 136:860–5. doi:10.1016/j.jaci.2015.08.012

PubMed Abstract | CrossRef Full Text | Google Scholar

604. Stokholm J, Sevelsted A, Anderson UD, Bisgaard H. Preeclampsia associates with asthma, allergy, and eczema in childhood. Am J Respir Crit Care Med (2017) 195:614–21. doi:10.1164/rccm.201604-0806OC

PubMed Abstract | CrossRef Full Text | Google Scholar

605. Omer SB, Goodman D, Steinhoff MC, Rochat R, Klugman KP, Stoll BJ, et al. Maternal influenza immunization and reduced likelihood of prematurity and small for gestational age births: a retrospective cohort study. PLoS Med (2011) 8:e1000441. doi:10.1371/journal.pmed.1000441

PubMed Abstract | CrossRef Full Text | Google Scholar

606. Adedinsewo DA, Noory L, Bednarczyk RA, Steinhoff MC, Davis R, Ogbuanu C, et al. Impact of maternal characteristics on the effect of maternal influenza vaccination on fetal outcomes. Vaccine (2013) 31:5827–33. doi:10.1016/j.vaccine.2013.09.071

PubMed Abstract | CrossRef Full Text | Google Scholar

607. Richards JL, Hansen C, Bredfeldt C, Bednarczyk RA, Steinhoff MC, Adjaye-Gbewonyo D, et al. Neonatal outcomes after antenatal influenza immunization during the 2009 H1N1 influenza pandemic: impact on preterm birth, birth weight, and small for gestational age birth. Clin Infect Dis (2013) 56:1216–22. doi:10.1093/cid/cit045

PubMed Abstract | CrossRef Full Text | Google Scholar

608. Olsen SJ, Mirza SA, Vonglokham P, Khanthamaly V, Chitry B, Pholsena V, et al. The effect of influenza vaccination on birth outcomes in a cohort of pregnant women in Lao PDR, 2014–2015. Clin Infect Dis (2016) 63:487–94. doi:10.1093/cid/ciw290

PubMed Abstract | CrossRef Full Text | Google Scholar

609. Phadke VK, Steinhoff MC, Omer SB, Macdonald NE. Maternal influenza immunization and adverse birth outcomes: using data and practice to inform theory and research design. Am J Epidemiol (2016) 184:789–92. doi:10.1093/aje/kww110

PubMed Abstract | CrossRef Full Text | Google Scholar

610. Leslie M. Can flu shots help women get pregnant? Science (2017) 355:1247–8. doi:10.1126/science.355.6331.1247

CrossRef Full Text | Google Scholar

611. Nordin JD, Kharbanda EO, Vazquez Benitez G, Lipkind H, Vellozzi C, Destefano F, et al. Maternal influenza vaccine and risks for preterm or small for gestational age birth. J Pediatr (2014) 164:1051–7.e1052. doi:10.1016/j.jpeds.2014.01.037

PubMed Abstract | CrossRef Full Text | Google Scholar

612. Bratton KN, Wardle MT, Orenstein WA, Omer SB. Maternal influenza immunization and birth outcomes of stillbirth and spontaneous abortion: a systematic review and meta-analysis. Clin Infect Dis (2015) 60:e11–9. doi:10.1093/cid/ciu915

PubMed Abstract | CrossRef Full Text | Google Scholar

613. Coenders A, Koopmans NK, Broekhuijsen K, Groen H, Karstenberg-Kramer JMA, Van Goor K, et al. Adjuvanted vaccines in pregnancy: no evidence for effect of the adjuvanted H1N1/09 vaccination on occurrence of preeclampsia or intra-uterine growth restriction. Eur J Obstet Gynecol Reprod Biol (2015) 187:14–9. doi:10.1016/j.ejogrb.2015.01.011

PubMed Abstract | CrossRef Full Text | Google Scholar

614. Munoz FM, Greisinger AJ, Wehmanen OA, Mouzoon ME, Hoyle JC, Smith FA, et al. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol (2005) 192:1098–106. doi:10.1016/j.ajog.2004.12.019

CrossRef Full Text | Google Scholar

615. Mak TK, Mangtani P, Leese J, Watson JM, Pfeifer D. Influenza vaccination in pregnancy: current evidence and selected national policies. Lancet Infect Dis (2008) 8:44–52. doi:10.1016/S1473-3099(07)70311-0

PubMed Abstract | CrossRef Full Text | Google Scholar

616. Tamma PD, Ault KA, Del Rio C, Steinhoff MC, Halsey NA, Omer SB. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol (2009) 201:547–52. doi:10.1016/j.ajog.2009.09.034

CrossRef Full Text | Google Scholar

617. Yamaguchi K, Hisano M, Isojima S, Irie S, Arata N, Watanabe N, et al. Relationship of Th1/Th2 cell balance with the immune response to influenza vaccine during pregnancy. J Med Virol (2009) 81:1923–8. doi:10.1002/jmv.21620

PubMed Abstract | CrossRef Full Text | Google Scholar

618. Bednarczyk RA, Adjaye-Gbewonyo D, Omer SB. Safety of influenza immunization during pregnancy for the fetus and the neonate. Am J Obstet Gynecol (2012) 207:S38–46. doi:10.1016/j.ajog.2012.07.002

CrossRef Full Text | Google Scholar

619. Jamieson DJ, Kissin DM, Bridges CB, Rasmussen SA. Benefits of influenza vaccination during pregnancy for pregnant women. Am J Obstet Gynecol (2012) 207:S17–20. doi:10.1016/j.ajog.2012.06.070

PubMed Abstract | CrossRef Full Text | Google Scholar

620. Kharbanda EO, Vazquez-Benitez G, Shi WX, Lipkind H, Naleway A, Molitor B, et al. Assessing the safety of influenza immunization during pregnancy: the Vaccine Safety Datalink. Am J Obstet Gynecol (2012) 207:S47–51. doi:10.1016/j.ajog.2012.06.073

PubMed Abstract | CrossRef Full Text | Google Scholar

621. Moro PL, Tepper NK, Grohskopf LA, Vellozzi C, Broder K. Safety of seasonal influenza and influenza A (H1N1) 2009 monovalent vaccines in pregnancy. Expert Rev Vaccines (2012) 11:911–21. doi:10.1586/erv.12.72

CrossRef Full Text | Google Scholar

622. Pasternak B, Svanström H, Mølgaard-Nielsen D, Krause TG, Emborg HD, Melbye M, et al. Risk of adverse fetal outcomes following administration of a pandemic influenza A(H1N1) vaccine during pregnancy. JAMA (2012) 308:165–74. doi:10.1001/jama.2012.6131

CrossRef Full Text | Google Scholar

623. Pasternak B, Svanström H, Mølgaard-Nielsen D, Krause TG, Emborg HD, Melbye M, et al. Vaccination against pandemic A/H1N1 2009 influenza in pregnancy and risk of fetal death: cohort study in Denmark. BMJ (2012) 344:e2794. doi:10.1136/bmj.e2794

CrossRef Full Text | Google Scholar

624. Beau AB, Hurault-Delarue C, Vidal S, Guitard C, Vayssière C, Petiot D, et al. Pandemic A/H1N1 influenza vaccination during pregnancy: a comparative study using the EFEMERIS database. Vaccine (2014) 32:1254–8. doi:10.1016/j.vaccine.2014.01.021

PubMed Abstract | CrossRef Full Text | Google Scholar

625. Keller-Stanislawski B, Englund JA, Kang G, Mangtani P, Neuzil K, Nohynek H, et al. Safety of immunization during pregnancy: a review of the evidence of selected inactivated and live attenuated vaccines. Vaccine (2014) 32:7057–64. doi:10.1016/j.vaccine.2014.09.052

PubMed Abstract | CrossRef Full Text | Google Scholar

626. Naleway AL, Irving SA, Henninger ML, Li DK, Shifflett P, Ball S, et al. Safety of influenza vaccination during pregnancy: a review of subsequent maternal obstetric events and findings from two recent cohort studies. Vaccine (2014) 32:3122–7. doi:10.1016/j.vaccine.2014.04.021

PubMed Abstract | CrossRef Full Text | Google Scholar

627. Vaughn DW, Seifert H, Hepburn A, Dewe W, Li P, Drame M, et al. Safety of AS03-adjuvanted inactivated split virion A(H1N1)pdm09 and H5N1 influenza virus vaccines administered to adults: pooled analysis of 28 clinical trials. Hum Vaccin Immunother (2014) 10:2942–57. doi:10.4161/21645515.2014.972149

PubMed Abstract | CrossRef Full Text | Google Scholar

628. Baum U, Leino T, Gissler M, Kilpi T, Jokinen J. Perinatal survival and health after maternal influenza A(H1N1)pdm09 vaccination: a cohort study of pregnancies stratified by trimester of vaccination. Vaccine (2015) 33:4850–7. doi:10.1016/j.vaccine.2015.07.061

PubMed Abstract | CrossRef Full Text | Google Scholar

629. Fabiani M, Bella A, Rota MC, Clagnan E, Gallo T, D’amato M, et al. A/H1N1 pandemic influenza vaccination: a retrospective evaluation of adverse maternal, fetal and neonatal outcomes in a cohort of pregnant women in Italy. Vaccine (2015) 33:2240–7. doi:10.1016/j.vaccine.2015.03.041

PubMed Abstract | CrossRef Full Text | Google Scholar

630. Fell DB, Platt RW, Lanes A, Wilson K, Kaufman JS, Basso O, et al. Fetal death and preterm birth associated with maternal influenza vaccination: systematic review. BJOG (2015) 122:17–26. doi:10.1111/1471-0528.12977

PubMed Abstract | CrossRef Full Text | Google Scholar

631. Ludvigsson JF, Ström P, Lundholm C, Cnattingius S, Ekbom A, Örtqvist Å, et al. Maternal vaccination against H1N1 influenza and offspring mortality: population based cohort study and sibling design. BMJ (2015) 351:h5585. doi:10.1136/bmj.h5585

PubMed Abstract | CrossRef Full Text | Google Scholar

632. Savitz DA, Fell DB, Ortiz JR, Bhat N. Does influenza vaccination improve pregnancy outcome? Methodological issues and research needs. Vaccine (2015) 33:6430–5. doi:10.1016/j.vaccine.2015.08.041

CrossRef Full Text | Google Scholar

633. Walls T, Graham P, Petousis-Harris H, Hill L, Austin N. Infant outcomes after exposure to Tdap vaccine in pregnancy: an observational study. BMJ Open (2016) 6:e009536. doi:10.1136/bmjopen-2015-009536

PubMed Abstract | CrossRef Full Text | Google Scholar

634. Donegan K, King B, Bryan P. Safety of pertussis vaccination in pregnant women in UK: observational study. BMJ (2014) 349:g4219. doi:10.1136/bmj.g4219

PubMed Abstract | CrossRef Full Text | Google Scholar

635. Kharbanda EO, Vazquez-Benitez G, Lipkind HS, Klein NP, Cheetham TC, Naleway AL, et al. Maternal Tdap vaccination: coverage and acute safety outcomes in the vaccine safety datalink, 2007–2013. Vaccine (2016) 34:968–73. doi:10.1016/j.vaccine.2015.12.046

PubMed Abstract | CrossRef Full Text | Google Scholar

636. Petousis-Harris H, Walls T, Watson D, Paynter J, Graham P, Turner N. Safety of Tdap vaccine in pregnant women: an observational study. BMJ Open (2016) 6:e010911. doi:10.1136/bmjopen-2015-010911

PubMed Abstract | CrossRef Full Text | Google Scholar

637. Wheeler CM, Skinner SR, Del Rosario-Raymundo MR, Garland SM, Chatterjee A, Lazcano-Ponce E, et al. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 7-year follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. Lancet Infect Dis (2016) 16:1154–68. doi:10.1016/S1473-3099(16)30120-7

PubMed Abstract | CrossRef Full Text | Google Scholar

638. Raj RS, Bonney EA, Phillippe M. Influenza, immune system, and pregnancy. Reprod Sci (2014) 21:1434–51. doi:10.1177/1933719114537720

PubMed Abstract | CrossRef Full Text | Google Scholar

639. Staff AC, Benton SJ, Von Dadelszen P, Roberts JM, Taylor RN, Powers RW, et al. Redefining preeclampsia using placenta-derived biomarkers. Hypertension (2013) 61:932–42. doi:10.1161/HYPERTENSIONAHA.111.00250

CrossRef Full Text | Google Scholar

640. Scheminske M, Henninger M, Irving SA, Thompson M, Williams J, Shifflett P, et al. The association between influenza vaccination and other preventative health behaviors in a cohort of pregnant women. Health Educ Behav (2015) 42:402–8. doi:10.1177/1090198114560021

PubMed Abstract | CrossRef Full Text | Google Scholar

641. Steinhoff MC, Omer SB, Roy E, El Arifeen S, Raqib R, Dodd C, et al. Neonatal outcomes after influenza immunization during pregnancy: a randomized controlled trial. CMAJ (2012) 184:645–53. doi:10.1503/cmaj.110754

CrossRef Full Text | Google Scholar

642. Porter TF, Lacoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev (2006):CD000112. doi:10.1002/14651858.CD000112.pub2

CrossRef Full Text | Google Scholar

643. Wong LF, Porter TF, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev (2014):CD000112. doi:10.1002/14651858.CD000112.pub3

CrossRef Full Text | Google Scholar

644. Jørgensen KT, Pedersen BV, Jacobsen S, Biggar RJ, Frisch M. National cohort study of reproductive risk factors for rheumatoid arthritis in Denmark: a role for hyperemesis, gestational hypertension and pre-eclampsia? Ann Rheum Dis (2010) 69:358–63. doi:10.1136/ard.2008.099945

PubMed Abstract | CrossRef Full Text | Google Scholar

645. Ebringer A, Rashid T, Wilson C. Rheumatoid arthritis, Proteus, anti-CCP antibodies and Karl Popper. Autoimmun Rev (2010) 9:216–23. doi:10.1016/j.autrev.2009.10.006

PubMed Abstract | CrossRef Full Text | Google Scholar

646. Ebringer A. Rheumatoid Arthritis and Proteus. London: Springer (2012).

Google Scholar

647. Ebringer A, Rashid T. Rheumatoid arthritis is caused by a Proteus urinary tract infection. APMIS (2014) 122:363–8. doi:10.1111/apm.12154

PubMed Abstract | CrossRef Full Text | Google Scholar

648. Pretorius E, Akeredolu O-O, Soma P, Kell DB. Major involvement of bacterial components in rheumatoid arthritis and its accompanying oxidative stress, systemic inflammation and hypercoagulability. Exp Biol Med (2017) 242:355–73. doi:10.1177/1535370216681549

CrossRef Full Text | Google Scholar

649. Wang G, Li X, Wang Z. APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Res (2016) 44:D1087–93. doi:10.1093/nar/gkv1278

PubMed Abstract | CrossRef Full Text | Google Scholar

650. Zasloff M. Antimicrobial peptides of multicellular organisms. Nature (2002) 415:389–95. doi:10.1038/415389a

PubMed Abstract | CrossRef Full Text | Google Scholar

651. Auvynet C, Rosenstein Y. Multifunctional host defense peptides: antimicrobial peptides, the small yet big players in innate and adaptive immunity. FEBS J (2009) 276:6497–508. doi:10.1111/j.1742-4658.2009.07360.x

PubMed Abstract | CrossRef Full Text | Google Scholar

652. Gustafsson A, Olin AI, Ljunggren L. LPS interactions with immobilized and soluble antimicrobial peptides. Scand J Clin Lab Invest (2010) 70:194–200. doi:10.3109/00365511003663622

PubMed Abstract | CrossRef Full Text | Google Scholar

653. Lee SH, Jun HK, Lee HR, Chung CP, Choi BK. Antibacterial and lipopolysaccharide (LPS)-neutralising activity of human cationic antimicrobial peptides against periodontopathogens. Int J Antimicrob Agents (2010) 35:138–45. doi:10.1016/j.ijantimicag.2009.09.024

PubMed Abstract | CrossRef Full Text | Google Scholar

654. Kościuczuk EM, Lisowski P, Jarczak J, Strzałkowska N, Jóźwik A, Horbańczuk J, et al. Cathelicidins: family of antimicrobial peptides. A review. Mol Biol Rep (2012) 39:10957–70. doi:10.1007/s11033-012-1997-x

CrossRef Full Text | Google Scholar

655. Seo MD, Won HS, Kim JH, Mishig-Ochir T, Lee BJ. Antimicrobial peptides for therapeutic applications: a review. Molecules (2012) 17:12276–86. doi:10.3390/molecules171012276

PubMed Abstract | CrossRef Full Text | Google Scholar

656. Zhao J, Zhao C, Liang G, Zhang M, Zheng J. Engineering antimicrobial peptides with improved antimicrobial and hemolytic activities. J Chem Inf Model (2013) 53:3280–96. doi:10.1021/ci400477e

PubMed Abstract | CrossRef Full Text | Google Scholar

657. Ashby M, Petkova A, Hilpert K. Cationic antimicrobial peptides as potential new therapeutic agents in neonates and children: a review. Curr Opin Infect Dis (2014) 27:258–67. doi:10.1097/QCO.0000000000000057

PubMed Abstract | CrossRef Full Text | Google Scholar

658. Waghu FH, Gopi L, Barai RS, Ramteke P, Nizami B, Idicula-Thomas S. CAMP: collection of sequences and structures of antimicrobial peptides. Nucleic Acids Res (2014) 42:D1154–8. doi:10.1093/nar/gkt1157

PubMed Abstract | CrossRef Full Text | Google Scholar

659. Wang G. Human antimicrobial peptides and proteins. Pharmaceuticals (Basel) (2014) 7:545–94. doi:10.3390/ph7050545

CrossRef Full Text | Google Scholar

660. Kido EA, Pandolfi V, Houllou-Kido LM, Andrade PP, Marcelino FC, Nepomuceno AL, et al. Plant antimicrobial peptides: an overview of SuperSAGE transcriptional profile and a functional review. Curr Protein Pept Sci (2010) 11:220–30. doi:10.2174/138920310791112110

PubMed Abstract | CrossRef Full Text | Google Scholar

661. Li W, Tailhades J, O’brien-Simpson NM, Separovic F, Otvos L Jr, Hossain MA, et al. Proline-rich antimicrobial peptides: potential therapeutics against antibiotic-resistant bacteria. Amino Acids (2014) 46:2287–94. doi:10.1007/s00726-014-1820-1

PubMed Abstract | CrossRef Full Text | Google Scholar

662. Kosikowska P, Lesner A. Antimicrobial peptides (AMPs) as drug candidates: a patent review (2003–2015). Expert Opin Ther Pat (2016) 26:689–702. doi:10.1080/13543776.2016.1176149

PubMed Abstract | CrossRef Full Text | Google Scholar

663. Kang HK, Kim C, Seo CH, Park Y. The therapeutic applications of antimicrobial peptides (AMPs): a patent review. J Microbiol (2017) 55:1–12. doi:10.1007/s12275-017-6452-1

CrossRef Full Text | Google Scholar

664. Yoshio H, Tollin M, Gudmundsson GH, Lagercrantz H, Jornvall H, Marchini G, et al. Antimicrobial polypeptides of human vernix caseosa and amniotic fluid: implications for newborn innate defense. Pediatr Res (2003) 53:211–6. doi:10.1203/01.PDR.0000047471.47777.B0

PubMed Abstract | CrossRef Full Text | Google Scholar

665. Frew L, Stock SJ. Antimicrobial peptides and pregnancy. Reproduction (2011) 141:725–35. doi:10.1530/REP-10-0537

CrossRef Full Text | Google Scholar

666. Kai-Larsen Y, Gudmundsson GH, Agerberth B. A review of the innate immune defence of the human foetus and newborn, with the emphasis on antimicrobial peptides. Acta Paediatr (2014) 103:1000–8. doi:10.1111/apa.12700

PubMed Abstract | CrossRef Full Text | Google Scholar

667. Tribe RM. Small peptides with a big role: antimicrobial peptides in the pregnant female reproductive tract. Am J Reprod Immunol (2015) 74:123–5. doi:10.1111/aji.12379

PubMed Abstract | CrossRef Full Text | Google Scholar

668. Yarbrough VL, Winkle S, Herbst-Kralovetz MM. Antimicrobial peptides in the female reproductive tract: a critical component of the mucosal immune barrier with physiological and clinical implications. Hum Reprod Update (2015) 21:353–77. doi:10.1093/humupd/dmu065

PubMed Abstract | CrossRef Full Text | Google Scholar

669. Yedery RD, Reddy KVR. Antimicrobial peptides as microbicidal contraceptives: prophecies for prophylactics – a mini review. Eur J Contracept Reprod Health Care (2005) 10:32–42. doi:10.1080/13625180500035124

CrossRef Full Text | Google Scholar

670. Zairi A, Tangy F, Bouassida K, Hani K. Dermaseptins and magainins: antimicrobial peptides from frogs’ skin-new sources for a promising spermicides microbicides-a mini review. J Biomed Biotechnol (2009) 2009:452567. doi:10.1155/2009/452567

PubMed Abstract | CrossRef Full Text | Google Scholar

671. Schulze M, Junkes C, Mueller P, Speck S, Ruediger K, Dathe M, et al. Effects of cationic antimicrobial peptides on liquid-preserved boar spermatozoa. PLoS One (2014) 9:e100490. doi:10.1371/journal.pone.0100490

PubMed Abstract | CrossRef Full Text | Google Scholar

672. Speck S, Courtiol A, Junkes C, Dathe M, Müller K, Schulze M. Cationic synthetic peptides: assessment of their antimicrobial potency in liquid preserved boar semen. PLoS One (2014) 9:e105949. doi:10.1371/journal.pone.0105949

PubMed Abstract | CrossRef Full Text | Google Scholar

673. Schulze M, Grobbel M, Müller K, Junkes C, Dathe M, Rüdiger K, et al. Challenges and limits using antimicrobial peptides in boar semen preservation. Reprod Domest Anim (2015) 50(Suppl 2):5–10. doi:10.1111/rda.12553

PubMed Abstract | CrossRef Full Text | Google Scholar

674. Schulze M, Dathe M, Waberski D, Müller K. Liquid storage of boar semen: current and future perspectives on the use of cationic antimicrobial peptides to replace antibiotics in semen extenders. Theriogenology (2016) 85:39–46. doi:10.1016/j.theriogenology.2015.07.016

PubMed Abstract | CrossRef Full Text | Google Scholar

675. Bussalleu E, Sancho S, Briz MD, Yeste M, Bonet S. Do antimicrobial peptides PR-39, PMAP-36 and PMAP-37 have any effect on bacterial growth and quality of liquid-stored boar semen? Theriogenology (2017) 89:235–43. doi:10.1016/j.theriogenology.2016.11.017

CrossRef Full Text | Google Scholar

676. Easterhoff D, Ontiveros F, Brooks LR, Kim Y, Ross B, Silva JN, et al. Semen-derived enhancer of viral infection (SEVI) binds bacteria, enhances bacterial phagocytosis by macrophages, and can protect against vaginal infection by a sexually transmitted bacterial pathogen. Antimicrob Agents Chemother (2013) 57:2443–50. doi:10.1128/AAC.02464-12

PubMed Abstract | CrossRef Full Text | Google Scholar

677. Edström AML, Malm J, Frohm B, Martellini JA, Giwercman A, Mörgelin M, et al. The major bactericidal activity of human seminal plasma is zinc-dependent and derived from fragmentation of the semenogelins. J Immunol (2008) 181:3413–21. doi:10.4049/jimmunol.181.5.3413

PubMed Abstract | CrossRef Full Text | Google Scholar

678. Zhao H, Lee WH, Shen JH, Li H, Zhang Y. Identification of novel semenogelin I-derived antimicrobial peptide from liquefied human seminal plasma. Peptides (2008) 29:505–11. doi:10.1016/j.peptides.2008.01.009

PubMed Abstract | CrossRef Full Text | Google Scholar

679. Yenugu S, Hamil KG, Birse CE, Ruben SM, French FS, Hall SH. Antibacterial properties of the sperm-binding proteins and peptides of human epididymis 2 (HE2) family; salt sensitivity, structural dependence and their interaction with outer and cytoplasmic membranes of Escherichia coli. Biochem J (2003) 372:473–83. doi:10.1042/BJ20030225

PubMed Abstract | CrossRef Full Text | Google Scholar

680. Avellar MCW, Honda L, Hamil KG, Yenugu S, Grossman G, Petrusz P, et al. Differential expression and antibacterial activity of epididymis protein 2 isoforms in the male reproductive tract of human and rhesus monkey (Macaca mulatta). Biol Reprod (2004) 71:1453–60. doi:10.1095/biolreprod.104.031740

PubMed Abstract | CrossRef Full Text | Google Scholar

681. Sørensen OE, Gram L, Johnsen AH, Andersson E, Bangsbøll S, Tjabringa GS, et al. Processing of seminal plasma hCAP-18 to ALL-38 by gastricsin: a novel mechanism of generating antimicrobial peptides in vagina. J Biol Chem (2003) 278:28540–6. doi:10.1074/jbc.M301608200

PubMed Abstract | CrossRef Full Text | Google Scholar

682. Williams RJ. Biochemical Individuality. New York: John Wiley (1956).

Google Scholar

683. Ayres JS, Freitag N, Schneider DS. Identification of Drosophila mutants altering defense of and endurance to Listeria monocytogenes infection. Genetics (2008) 178:1807–15. doi:10.1534/genetics.107.083782

PubMed Abstract | CrossRef Full Text | Google Scholar

684. Schneider DS, Ayres JS. Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases. Nat Rev Immunol (2008) 8:889–95. doi:10.1038/nri2432

PubMed Abstract | CrossRef Full Text | Google Scholar

685. Råberg L, Graham AL, Read AF. Decomposing health: tolerance and resistance to parasites in animals. Philos Trans R Soc Lond B Biol Sci (2009) 364:37–49. doi:10.1098/rstb.2008.0184

PubMed Abstract | CrossRef Full Text | Google Scholar

686. Ayres JS, Schneider DS. Tolerance of infections. Annu Rev Immunol (2012) 30:271–94. doi:10.1146/annurev-immunol-020711-075030

PubMed Abstract | CrossRef Full Text | Google Scholar

687. Medzhitov R, Schneider DS, Soares MP. Disease tolerance as a defense strategy. Science (2012) 335:936–41. doi:10.1126/science.1214935

PubMed Abstract | CrossRef Full Text | Google Scholar

688. Råberg L. How to live with the enemy: understanding tolerance to parasites. PLoS Biol (2014) 12:e1001989. doi:10.1371/journal.pbio.1001989

PubMed Abstract | CrossRef Full Text | Google Scholar

689. Palaferri Schieber AM, Lee YM, Chang MW, Leblanc M, Collins B, Downes M, et al. Disease tolerance mediated by microbiome E. coli involves inflammasome and IGF-1 signaling. Science (2015) 350:558–63. doi:10.1126/science.aac6468

PubMed Abstract | CrossRef Full Text | Google Scholar

690. Kogut MH, Arsenault RJ. Immunometabolic phenotype alterations associated with the induction of disease tolerance and persistent asymptomatic infection of Salmonella in the chicken intestine. Front Immunol (2017) 8:372. doi:10.3389/fimmu.2017.00372

PubMed Abstract | CrossRef Full Text | Google Scholar

691. Meunier I, Kaufmann E, Downey J, Divangahi M. Unravelling the networks dictating host resistance versus tolerance during pulmonary infections. Cell Tissue Res (2017) 367:525–36. doi:10.1007/s00441-017-2572-5

PubMed Abstract | CrossRef Full Text | Google Scholar

692. Longo VD, Finch CE. Evolutionary medicine: from dwarf model systems to healthy centenarians? Science (2003) 299:1342–6. doi:10.1126/science.1077991

PubMed Abstract | CrossRef Full Text | Google Scholar

693. Gluckman P, Beedle A, Hanson M. Principles of Evolutionary Medicine. Oxford: Oxford University Press (2009).

Google Scholar

694. Rühli FJ, Henneberg M. New perspectives on evolutionary medicine: the relevance of microevolution for human health and disease. BMC Med (2013) 11:115. doi:10.1186/1741-7015-11-115

CrossRef Full Text | Google Scholar

695. Svensson EI, Råberg L. Resistance and tolerance in animal enemy-victim coevolution. Trends Ecol Evol (2010) 25:267–74. doi:10.1016/j.tree.2009.12.005

PubMed Abstract | CrossRef Full Text | Google Scholar

696. Ayres JS. Cooperative microbial tolerance behaviors in host-microbiota mutualism. Cell (2016) 165:1323–31. doi:10.1016/j.cell.2016.05.049

PubMed Abstract | CrossRef Full Text | Google Scholar

697. Ayres JS. Microbes dress for success: tolerance or resistance? Trends Microbiol (2017) 25:1–3. doi:10.1016/j.tim.2016.11.006

PubMed Abstract | CrossRef Full Text | Google Scholar

698. Rangan KJ, Pedicord VA, Wang YC, Kim B, Lu Y, Shaham S, et al. A secreted bacterial peptidoglycan hydrolase enhances tolerance to enteric pathogens. Science (2016) 353:1434–7. doi:10.1126/science.aaf3552

PubMed Abstract | CrossRef Full Text | Google Scholar

699. Than NG, Balogh A, Romero R, Kárpáti É, Erez O, Szilágyi A, et al. Placental protein 13 (PP13) – a placental immunoregulatory galectin protecting pregnancy. Front Immunol (2014) 5:348. doi:10.3389/fimmu.2014.00348

CrossRef Full Text | Google Scholar

700. Than NG, Sumegi B, Than GN, Berente Z, Bohn H. Isolation and sequence analysis of a cDNA encoding human placental tissue protein 13 (PP13), a new lysophospholipase, homologue of human eosinophil Charcot-Leyden Crystal protein. Placenta (1999) 20:703–10. doi:10.1053/plac.1999.0436

PubMed Abstract | CrossRef Full Text | Google Scholar

701. Visegrády B, Than NG, Kilár F, Sümegi B, Than GN, Bohn H. Homology modelling and molecular dynamics studies of human placental tissue protein 13 (galectin-13). Protein Eng (2001) 14:875–80. doi:10.1093/protein/14.11.875

PubMed Abstract | CrossRef Full Text | Google Scholar

702. Bohn H, Kraus W, Winckler W. Purification and characterization of two new soluble placental tissue proteins (PP13 and PP17). Oncodev Biol Med (1983) 4:343–50.

PubMed Abstract | Google Scholar

703. Than NG, Pick E, Bellyei S, Szigeti A, Burger O, Berente Z, et al. Functional analyses of placental protein 13/galectin-13. Eur J Biochem (2004) 271:1065–78. doi:10.1111/j.1432-1033.2004.04004.x

PubMed Abstract | CrossRef Full Text | Google Scholar

704. Than NG, Romero R, Goodman M, Weckle A, Xing J, Dong Z, et al. A primate subfamily of galectins expressed at the maternal-fetal interface that promote immune cell death. Proc Natl Acad Sci U S A (2009) 106:9731–6. doi:10.1073/pnas.0903568106

PubMed Abstract | CrossRef Full Text | Google Scholar

705. Romero R, Kusanovic JP, Than NG, Erez O, Gotsch F, Espinoza J, et al. First-trimester maternal serum PP13 in the risk assessment for preeclampsia. Am J Obstet Gynecol (2008) 199:122.e121–122.e111. doi:10.1016/j.ajog.2008.01.013

PubMed Abstract | CrossRef Full Text | Google Scholar

706. Cowans NJ, Stamatopoulou A, Khalil A, Spencer K. PP13 as a marker of pre-eclampsia: a two platform comparison study. Placenta (2011) 32(Suppl):S37–41. doi:10.1016/j.placenta.2010.08.014

PubMed Abstract | CrossRef Full Text | Google Scholar

707. De Muro P, Capobianco G, Lepedda AJ, Nieddu G, Formato M, Tram NHQ, et al. Plasma PP13 and urinary GAGs/PGs as early markers of pre-eclampsia. Arch Gynecol Obstet (2016) 294:959–65. doi:10.1007/s00404-016-4111-0

PubMed Abstract | CrossRef Full Text | Google Scholar

708. Than NG, Abdul Rahman O, Magenheim R, Nagy B, Fule T, Hargitai B, et al. Placental protein 13 (galectin-13) has decreased placental expression but increased shedding and maternal serum concentrations in patients presenting with preterm pre-eclampsia and HELLP syndrome. Virchows Arch (2008) 453:387–400. doi:10.1007/s00428-008-0658-x

CrossRef Full Text | Google Scholar

709. Bruiners N, Bosman M, Postma A, Gebhardt S, Rebello G, Sammar M, et al. Promoter variant-98A-C of the LGALS13 gene and pre-eclampsia. Proceedings of the 8th World Congress of Perinatal Medicine. Florence (2007). p. 371–4.

Google Scholar

710. Than NG, Erez O, Wildman DE, Tarca AL, Edwin SS, Abbas A, et al. Severe preeclampsia is characterized by increased placental expression of galectin-1. J Matern Fetal Neonatal Med (2008) 21:429–42. doi:10.1080/14767050802041961

CrossRef Full Text | Google Scholar

711. Vasta GR. Roles of galectins in infection. Nat Rev Microbiol (2009) 7:424–38. doi:10.1038/nrmicro2146

PubMed Abstract | CrossRef Full Text | Google Scholar

712. Poltorak A, He XL, Smirnova I, Liu MY, Van Huffel C, Du X, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science (1998) 282:2085–8. doi:10.1126/science.282.5396.2085

CrossRef Full Text | Google Scholar

713. Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, et al. Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol (1999) 162:3749–52.

Google Scholar

714. Lien E, Means TK, Heine H, Yoshimura A, Kusumoto S, Fukase K, et al. Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide. J Clin Invest (2000) 105:497–504. doi:10.1172/JCI8541

PubMed Abstract | CrossRef Full Text | Google Scholar

715. Schwandner R, Dziarski R, Wesche H, Rothe M, Kirschning CJ. Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem (1999) 274:17406–9. doi:10.1074/jbc.274.25.17406

CrossRef Full Text | Google Scholar

716. Underhill DM, Ozinsky A, Hajjar AM, Stevens A, Wilson CB, Bassetti M, et al. The toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature (1999) 401:811–5. doi:10.1038/44605

PubMed Abstract | CrossRef Full Text | Google Scholar

717. Ishii KJ, Akira S. Toll-like receptors and sepsis. Curr Infect Dis Rep (2004) 6:361–6. doi:10.1007/s11908-004-0034-1

CrossRef Full Text | Google Scholar

718. Zähringer U, Lindner B, Inamura S, Heine H, Alexander C. TLR2 - promiscuous or specific? A critical re-evaluation of a receptor expressing apparent broad specificity. Immunobiology (2008) 213:205–24. doi:10.1016/j.imbio.2008.02.005

CrossRef Full Text | Google Scholar

719. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity (2011) 34:637–50. doi:10.1016/j.immuni.2011.05.006

CrossRef Full Text | Google Scholar

720. Kumar H, Kawai T, Akira S. Pathogen recognition by the innate immune system. Int Rev Immunol (2011) 30:16–34. doi:10.3109/08830185.2010.529976

PubMed Abstract | CrossRef Full Text | Google Scholar

721. Oliveira-Nascimento L, Massari P, Wetzler LM. The role of TLR2 in infection and immunity. Front Immunol (2012) 3:79. doi:10.3389/fimmu.2012.00079

PubMed Abstract | CrossRef Full Text | Google Scholar

722. Alexander SPA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M, et al. The concise guide to pharmacology 2013/14: catalytic receptors. Br J Pharmacol (2013) 170:1676–705. doi:10.1111/bph.12449

PubMed Abstract | CrossRef Full Text | Google Scholar

723. Kumar S, Ingle H, Prasad DV, Kumar H. Recognition of bacterial infection by innate immune sensors. Crit Rev Microbiol (2013) 39:229–46. doi:10.3109/1040841X.2012.706249

CrossRef Full Text | Google Scholar

724. Liu Y, Yin H, Zhao M, Lu Q. TLR2 and TLR4 in autoimmune diseases: a comprehensive review. Clin Rev Allergy Immunol (2014) 47:136–47. doi:10.1007/s12016-013-8402-y

CrossRef Full Text | Google Scholar

725. Jiménez-Dalmaroni MJ, Gerswhin ME, Adamopoulos IE. The critical role of toll-like receptors – from microbial recognition to autoimmunity: a comprehensive review. Autoimmun Rev (2016) 15:1–8. doi:10.1016/j.autrev.2015.08.009

CrossRef Full Text | Google Scholar

726. Mukherjee S, Karmakar S, Babu SP. TLR2 and TLR4 mediated host immune responses in major infectious diseases: a review. Braz J Infect Dis (2016) 20:193–204. doi:10.1016/j.bjid.2015.10.011

PubMed Abstract | CrossRef Full Text | Google Scholar

727. Tinsley JH, Chiasson VL, Mahajan A, Young KJ, Mitchell BM. Toll-like receptor 3 activation during pregnancy elicits preeclampsia-like symptoms in rats. Am J Hypertens (2009) 22:1314–9. doi:10.1038/ajh.2009.185

PubMed Abstract | CrossRef Full Text | Google Scholar

728. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell (2006) 124:783–801. doi:10.1016/j.cell.2006.02.015

CrossRef Full Text | Google Scholar

729. Schroder K, Muruve DA, Tschopp J. Innate immunity: cytoplasmic DNA sensing by the AIM2 inflammasome. Curr Biol (2009) 19:R262–5. doi:10.1016/j.cub.2009.02.011

PubMed Abstract | CrossRef Full Text | Google Scholar

730. Sauer JD, Witte CE, Zemansky J, Hanson B, Lauer P, Portnoy DA. Listeria monocytogenes triggers AIM2-mediated pyroptosis upon infrequent bacteriolysis in the macrophage cytosol. Cell Host Microbe (2010) 7:412–9. doi:10.1016/j.chom.2010.04.004

PubMed Abstract | CrossRef Full Text | Google Scholar

731. Barber GN. Cytoplasmic DNA innate immune pathways. Immunol Rev (2011) 243:99–108. doi:10.1111/j.1600-065X.2011.01051.x

CrossRef Full Text | Google Scholar

732. Konno H, Barber GN. The STING controlled cytosolic-DNA activated innate immune pathway and microbial disease. Microbes Infect (2014) 16:998–1001. doi:10.1016/j.micinf.2014.10.002

PubMed Abstract | CrossRef Full Text | Google Scholar

733. Paludan SR. Activation and regulation of DNA-driven immune responses. Microbiol Mol Biol Rev (2015) 79:225–41. doi:10.1128/MMBR.00061-14

PubMed Abstract | CrossRef Full Text | Google Scholar

734. Girling JE, Hedger MP. Toll-like receptors in the gonads and reproductive tract: emerging roles in reproductive physiology and pathology. Immunol Cell Biol (2007) 85:481–9. doi:10.1038/sj.icb.7100086

PubMed Abstract | CrossRef Full Text | Google Scholar

735. van Rijn BB, Franx A, Steegers EAP, De Groot CJM, Bertina RM, Pasterkamp G, et al. Maternal TLR4 and NOD2 gene variants, pro-inflammatory phenotype and susceptibility to early-onset preeclampsia and HELLP syndrome. PLoS One (2008) 3:e1865. doi:10.1371/journal.pone.0001865

PubMed Abstract | CrossRef Full Text | Google Scholar

736. Riley JK, Nelson DM. Toll-like receptors in pregnancy disorders and placental dysfunction. Clin Rev Allergy Immunol (2010) 39:185–93. doi:10.1007/s12016-009-8178-2

PubMed Abstract | CrossRef Full Text | Google Scholar

737. Pineda A, Verdin-Terán SL, Camacho A, Moreno-Fierros L. Expression of toll-like receptor TLR-2, TLR-3, TLR-4 and TLR-9 is increased in placentas from patients with preeclampsia. Arch Med Res (2011) 42:382–91. doi:10.1016/j.arcmed.2011.08.003

PubMed Abstract | CrossRef Full Text | Google Scholar

738. Panda B, Panda A, Ueda I, Abrahams VM, Norwitz ER, Stanic AK, et al. Dendritic cells in the circulation of women with preeclampsia demonstrate a pro-inflammatory bias secondary to dysregulation of TLR receptors. J Reprod Immunol (2012) 94:210–5. doi:10.1016/j.jri.2012.01.008

PubMed Abstract | CrossRef Full Text | Google Scholar

739. Zhang L, Yang H. Expression and localization of TLR4 and its negative regulator tollip in the placenta of early-onset and late-onset preeclampsia. Hypertens Pregnancy (2012) 31:218–27. doi:10.3109/10641955.2011.642434

PubMed Abstract | CrossRef Full Text | Google Scholar

740. Amirchaghmaghi E, Taghavi SA, Shapouri F, Saeidi S, Rezaei A, Aflatoonian R. The role of toll like receptors in pregnancy. Int J Fertil Steril (2013) 7:147–54.

Google Scholar

741. Zhu Y, Wu M, Wu CY, Xia GQ. Role of progesterone in TLR4-MyD88-dependent signaling pathway in pre-eclampsia. J Huazhong Univ Sci Technolog Med Sci (2013) 33:730–4. doi:10.1007/s11596-013-1188-6

PubMed Abstract | CrossRef Full Text | Google Scholar

742. Koga K, Izumi G, Mor G, Fujii T, Osuga Y. Toll-like receptors at the maternal-fetal interface in normal pregnancy and pregnancy complications. Am J Reprod Immunol (2014) 72:192–205. doi:10.1111/aji.12258

PubMed Abstract | CrossRef Full Text | Google Scholar

743. Xue PP, Zheng MM, Gong P, Lin CM, Zhou JJ, Li YJ, et al. Single administration of ultra-low-dose lipopolysaccharide in rat early pregnancy induces TLR4 activation in the placenta contributing to preeclampsia. PLoS One (2015) 10:e0124001. doi:10.1371/journal.pone.0124001

CrossRef Full Text | Google Scholar

744. Gong P, Liu M, Hong G, Li Y, Xue P, Zheng M, et al. Curcumin improves LPS-induced preeclampsia-like phenotype in rat by inhibiting the TLR4 signaling pathway. Placenta (2016) 41:45–52. doi:10.1016/j.placenta.2016.03.002

PubMed Abstract | CrossRef Full Text | Google Scholar

745. Kulikova GV, Nizyaeva NV, Nagovitsina MN, Lyapin VM, Loginova NS, Kan NE, et al. Specific features of TLR4 expression in structural elements of placenta in patients with preeclampsia. Bull Exp Biol Med (2016) 160:718–21. doi:10.1007/s10517-016-3259-8

PubMed Abstract | CrossRef Full Text | Google Scholar

746. Faas MM, Schuiling GA, Baller JF, Visscher CA, Bakker WW. A new animal model for human preeclampsia: ultra-low-dose endotoxin infusion in pregnant rats. Am J Obstet Gynecol (1994) 171:158–64. doi:10.1016/0002-9378(94)90463-4

PubMed Abstract | CrossRef Full Text | Google Scholar

747. Fujita Y, Mihara T, Okazaki T, Shitanaka M, Kushino R, Ikeda C, et al. Toll-like receptors (TLR) 2 and 4 on human sperm recognize bacterial endotoxins and mediate apoptosis. Hum Reprod (2011) 26:2799–806. doi:10.1093/humrep/der234

PubMed Abstract | CrossRef Full Text | Google Scholar

748. Li N, Wang T, Han D. Structural, cellular and molecular aspects of immune privilege in the testis. Front Immunol (2012) 3:152. doi:10.3389/fimmu.2012.00152

PubMed Abstract | CrossRef Full Text | Google Scholar

749. Saeidi S, Shapouri F, Amirchaghmaghi E, Hoseinifar H, Sabbaghian M, Sadighi Gilani MA, et al. Sperm protection in the male reproductive tract by toll-like receptors. Andrologia (2014) 46:784–90. doi:10.1111/and.12149

PubMed Abstract | CrossRef Full Text | Google Scholar

750. Hagan S, Khurana N, Chandra S, Abdel-Mageed AB, Mondal D, Hellstrom WJ, et al. Differential expression of novel biomarkers (TLR-2, TLR-4, COX-2, and Nrf-2) of inflammation and oxidative stress in semen of leukocytospermia patients. Andrology (2015) 3:848–55. doi:10.1111/andr.12074

CrossRef Full Text | Google Scholar

751. Kunjara S, Greenbaum AL, Wang DY, Caro HN, Mclean P, Redman CWG, et al. Inositol phosphoglycans and signal transduction systems in pregnancy in preeclampsia and diabetes: evidence for a significant regulatory role in preeclampsia at placental and systemic levels. Mol Genet Metab (2000) 69:144–58. doi:10.1006/mgme.2000.2964

PubMed Abstract | CrossRef Full Text | Google Scholar

752. Williams PJ, Gumaa K, Scioscia M, Redman CW, Rademacher TW. Inositol phosphoglycan P-type in preeclampsia: a novel marker? Hypertension (2007) 49:84–9. doi:10.1161/01.HYP.0000251301.12357.ba

CrossRef Full Text | Google Scholar

753. Scioscia M, Paine MA, Gumaa K, Rodeck CH, Rademacher TW. Release of inositol phosphoglycan P-type by the human placenta following insulin stimulus: a multiple comparison between preeclampsia, intrauterine growth restriction, and gestational hypertension. J Matern Fetal Neonatal Med (2008) 21:581–5. doi:10.1080/14767050802199934

PubMed Abstract | CrossRef Full Text | Google Scholar

754. Scioscia M, Gumaa K, Rademacher TW. The link between insulin resistance and preeclampsia: new perspectives. J Reprod Immunol (2009) 82:100–5. doi:10.1016/j.jri.2009.04.009

CrossRef Full Text | Google Scholar

755. Scioscia M, Gumaa K, Selvaggi LE, Rodeck CH, Rademacher TW. Increased inositol phosphoglycan P-type in the second trimester in pregnant women with type 2 and gestational diabetes mellitus. J Perinat Med (2009) 37:469–71. doi:10.1515/JPM.2009.082

CrossRef Full Text | Google Scholar

756. Paine MA, Scioscia M, Williams PJ, Gumaa K, Rodeck CH, Rademacher TW. Urinary inositol phosphoglycan P-type as a marker for prediction of preeclampsia and novel implications for the pathophysiology of this disorder. Hypertens Pregnancy (2010) 29:375–84. doi:10.3109/10641950903242667

PubMed Abstract | CrossRef Full Text | Google Scholar

757. Scioscia M, Williams PJ, Gumaa K, Fratelli N, Zorzi C, Rademacher TW. Inositol phosphoglycans and preeclampsia: from bench to bedside. J Reprod Immunol (2011) 89:173–7. doi:10.1016/j.jri.2011.03.001

PubMed Abstract | CrossRef Full Text | Google Scholar

758. Scioscia M, Robillard PY, Hall DR, Rademacher LH, Williams PJ, Rademacher TW. Inositol phosphoglycan P-type in infants of preeclamptic mothers. J Matern Fetal Neonatal Med (2012) 25:193–5. doi:10.3109/14767058.2011.557789

CrossRef Full Text | Google Scholar

759. Scioscia M, Siwetz M, Fascilla F, Huppertz B. Placental expression of D-chiro-inositol phosphoglycans in preeclampsia. Placenta (2012) 33:882–4. doi:10.1016/j.placenta.2012.07.007

CrossRef Full Text | Google Scholar

760. Scioscia M, Siwetz M, Campana C, Huppertz B. Differences in d-chiro-inositol-phosphoglycan expression between first and third trimester human placenta. Pregnancy Hypertens (2013) 3:1–2. doi:10.1016/j.preghy.2012.10.001

CrossRef Full Text | Google Scholar

761. Scioscia M, Nigro M, Montagnani M. The putative metabolic role of d-chiro inositol phosphoglycan in human pregnancy and preeclampsia. J Reprod Immunol (2014) 101-102:140–7. doi:10.1016/j.jri.2013.05.006

CrossRef Full Text | Google Scholar

762. Kunjara S, Mclean P, Rademacher L, Rademacher TW, Fascilla F, Bettocchi S, et al. Putative key role of inositol messengers in endothelial cells in preeclampsia. Int J Endocrinol (2016) 2016:7695648. doi:10.1155/2016/7695648

PubMed Abstract | CrossRef Full Text | Google Scholar

763. Pretorius E, Bester J, Kell DB. A bacterial component to Alzheimer-type dementia seen via a systems biology approach that links iron dysregulation and inflammagen shedding to disease. J Alzheimers Dis (2016) 53:1237–56. doi:10.3233/JAD-160318

CrossRef Full Text | Google Scholar

764. Kell DB, Pretorius E. To what extent are the terminal stages of sepsis, septic shock, SIRS, and multiple organ dysfunction syndrome actually driven by a toxic prion/amyloid form of fibrin? Semin Thromb Hemost (2017). doi:10.1055/s-0037-1604108

CrossRef Full Text | Google Scholar

765. Pretorius E, Mbotwe S, Kell DB. Lipopolysaccharide-binding protein (LBP) reverses the amyloid state of fibrin seen in plasma of type 2 diabetics with cardiovascular comorbidities. Sci Rep (2017) 7:9680. doi:10.1038/s41598-017-09860-4

CrossRef Full Text | Google Scholar

766. Pretorius E, Page MJ, Engelbrecht L, Ellis GC, Kell DB. Substantial fibrin amyloidogenesis in type 2 diabetes assessed using amyloid-selective fluorescent stains. Cardiovasc Diabetol (2017) 16:141. doi:10.1186/s12933-017-0624-5

CrossRef Full Text | Google Scholar

767. Cervera R, Balasch J. Bidirectional effects on autoimmunity and reproduction. Hum Reprod Update (2008) 14:359–66. doi:10.1093/humupd/dmn013

CrossRef Full Text | Google Scholar

768. Heilmann L, Schorsch M, Hahn T, Fareed J. Antiphospholipid syndrome and pre-eclampsia. Semin Thromb Hemost (2011) 37:141–5. doi:10.1055/s-0030-1270341

PubMed Abstract | CrossRef Full Text | Google Scholar

769. Chen Q, Guo F, Hensby-Bennett S, Stone P, Chamley L. Antiphospholipid antibodies prolong the activation of endothelial cells induced by necrotic trophoblastic debris: implications for the pathogenesis of preeclampsia. Placenta (2012) 33:810–5. doi:10.1016/j.placenta.2012.07.019

PubMed Abstract | CrossRef Full Text | Google Scholar

770. Lefkou E, Mamopoulos A, Fragakis N, Dagklis T, Vosnakis C, Nounopoulos E, et al. Clinical improvement and successful pregnancy in a preeclamptic patient with antiphospholipid syndrome treated with pravastatin. Hypertension (2014) 63:e118–9. doi:10.1161/HYPERTENSIONAHA.114.03115

CrossRef Full Text | Google Scholar

771. van Hoorn ME, Hague WM, Van Pampus MG, Bezemer D, De Vries JIP, Investigators F. Low-molecular-weight heparin and aspirin in the prevention of recurrent early-onset pre-eclampsia in women with antiphospholipid antibodies: the FRUIT-RCT. Eur J Obstet Gynecol Reprod Biol (2016) 197:168–73. doi:10.1016/j.ejogrb.2015.12.011

PubMed Abstract | CrossRef Full Text | Google Scholar

772. Asherson RA, Cervera R. Antiphospholipid antibodies and infections. Ann Rheum Dis (2003) 62:388–93. doi:10.1136/ard.62.5.388

CrossRef Full Text | Google Scholar

773. Shoenfeld Y, Blank M, Cervera R, Font J, Raschi E, Meroni PL. Infectious origin of the antiphospholipid syndrome. Ann Rheum Dis (2006) 65:2–6. doi:10.1136/ard.2005.045443

CrossRef Full Text | Google Scholar

774. Amin NM. Antiphospholipid syndromes in infectious diseases. Hematol Oncol Clin North Am (2008) 22:131–143, vii–viii. doi:10.1016/j.hoc.2007.10.001

CrossRef Full Text | Google Scholar

775. Sène D, Piette JC, Cacoub P. Antiphospholipid antibodies, antiphospholipid syndrome and infections. Autoimmun Rev (2008) 7:272–7. doi:10.1016/j.autrev.2007.10.001

PubMed Abstract | CrossRef Full Text | Google Scholar

776. García-Carrasco M, Galarza-Maldonado C, Mendoza-Pinto C, Escarcega RO, Cervera R. Infections and the antiphospholipid syndrome. Clin Rev Allergy Immunol (2009) 36:104–8. doi:10.1007/s12016-008-8103-0

CrossRef Full Text | Google Scholar

777. Zinger H, Sherer Y, Goddard G, Berkun Y, Barzilai O, Agmon-Levin N, et al. Common infectious agents prevalence in antiphospholipid syndrome. Lupus (2009) 18:1149–53. doi:10.1177/0961203309345738

PubMed Abstract | CrossRef Full Text | Google Scholar

778. Krone KA, Allen KL, Mccrae KR. Impaired fibrinolysis in the antiphospholipid syndrome. Curr Rheumatol Rep (2010) 12:53–7. doi:10.1007/s11926-009-0075-4

CrossRef Full Text | Google Scholar

779. Martínez-Zamora MA, Tassies D, Carmona F, Espinosa G, Cervera R, Reverter JC, et al. Clot lysis time and thrombin activatable fibrinolysis inhibitor in severe preeclampsia with or without associated antiphospholipid antibodies. J Reprod Immunol (2010) 86:133–40. doi:10.1016/j.jri.2010.05.002

PubMed Abstract | CrossRef Full Text | Google Scholar

780. Lockshin MD. Anticoagulation in management of antiphospholipid antibody syndrome in pregnancy. Clin Lab Med (2013) 33:367–76. doi:10.1016/j.cll.2013.01.001

CrossRef Full Text | Google Scholar

781. Lockshin MD. Pregnancy and antiphospholipid syndrome. Am J Reprod Immunol (2013) 69:585–7. doi:10.1111/aji.12071

CrossRef Full Text | Google Scholar

782. Meroni PL, Chighizola CB, Rovelli F, Gerosa M. Antiphospholipid syndrome in 2014: more clinical manifestations, novel pathogenic players and emerging biomarkers. Arthritis Res Ther (2014) 16:209. doi:10.1186/ar4549

PubMed Abstract | CrossRef Full Text | Google Scholar

783. Buhimschi IA, Nayeri UA, Zhao G, Shook LL, Pensalfini A, Funai EF, et al. Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia. Sci Transl Med (2014) 6:245ra292. doi:10.1126/scitranslmed.3008808

PubMed Abstract | CrossRef Full Text | Google Scholar

784. Jonas SM, Deserno TM, Buhimschi CS, Makin J, Choma MA, Buhimschi IA. Smartphone-based diagnostic for preeclampsia: an mHealth solution for administering the Congo Red Dot (CRD) test in settings with limited resources. J Am Med Inform Assoc (2016) 23:166–73. doi:10.1093/jamia/ocv015

PubMed Abstract | CrossRef Full Text | Google Scholar

785. Kouza M, Banerji A, Kolinski A, Buhimschi IA, Kloczkowski A. Oligomerization of FVFLM peptides and their ability to inhibit beta amyloid peptides aggregation: consideration as a possible model. Phys Chem Chem Phys (2017) 19:2990–9. doi:10.1039/c6cp07145g

PubMed Abstract | CrossRef Full Text | Google Scholar

786. Clark EAS, Silver RM, Branch DW. Do antiphospholipid antibodies cause preeclampsia and HELLP syndrome? Curr Rheumatol Rep (2007) 9:219–25. doi:10.1007/s11926-007-0035-9

CrossRef Full Text | Google Scholar

787. Saccone G, Berghella V, Maruotti GM, Ghi T, Rizzo G, Simonazzi G, et al. Antiphospholipid antibody profile based obstetric outcomes of primary antiphospholipid syndrome: the PREGNANTS study. Am J Obstet Gynecol (2017) 216:525.e521–525.e512. doi:10.1016/j.ajog.2017.01.026

CrossRef Full Text | Google Scholar

788. Horvath SE, Daum G. Lipids of mitochondria. Prog Lipid Res (2013) 52:590–614. doi:10.1016/j.plipres.2013.07.002

CrossRef Full Text | Google Scholar

789. Mejia EM, Nguyen H, Hatch GM. Mammalian cardiolipin biosynthesis. Chem Phys Lipids (2014) 179:11–6. doi:10.1016/j.chemphyslip.2013.10.001

PubMed Abstract | CrossRef Full Text | Google Scholar

790. Ren M, Phoon CKL, Schlame M. Metabolism and function of mitochondrial cardiolipin. Prog Lipid Res (2014) 55:1–16. doi:10.1016/j.plipres.2014.04.001

PubMed Abstract | CrossRef Full Text | Google Scholar

791. Hatch GM. Cardiolipin: biosynthesis, remodeling and trafficking in the heart and mammalian cells (review). Int J Mol Med (1998) 1:33–41.

PubMed Abstract | Google Scholar

792. Saini-Chohan HK, Holmes MG, Chicco AJ, Taylor WA, Moore RL, Mccune SA, et al. Cardiolipin biosynthesis and remodeling enzymes are altered during development of heart failure. J Lipid Res (2009) 50:1600–8. doi:10.1194/jlr.M800561-JLR200

PubMed Abstract | CrossRef Full Text | Google Scholar

793. Chaban Y, Boekema EJ, Dudkina NV. Structures of mitochondrial oxidative phosphorylation supercomplexes and mechanisms for their stabilisation. Biochim Biophys Acta (2014) 1837:418–26. doi:10.1016/j.bbabio.2013.10.004

PubMed Abstract | CrossRef Full Text |