Autoimmune Abnormalities of Postpartum Thyroid Diseases

The year following parturition is a critical time for the de novo appearance or exacerbation of autoimmune diseases, including autoimmune thyroid disease. The vast majority of postpartum thyroid disease consists of postpartum thyroiditis (PPT) and the minority by Graves’ disease and non-autoimmune thyroiditis. PPT has a worldwide prevalence ranging from 1 to 22% and averaging 5% based on a review published in 2012. Several factors confer risk for the development of PPT. Typically, the clinical course of PPT is characterized by three phases: thyrotoxic, hypothyroid, and euthyroid phase. Approximately half of PPT women will have permanent hypothyroidism. The best humoral marker for predictivity, already during the first trimester of gestation, is considered positivity for thyroperoxidase autoantibodies (TPOAb), though only one-third to half of such TPOAb-positive pregnant women will develop PPT. Nutraceuticals (such as selenium) or omega-3-fatty acid supplements seem to have a role in prevention of PPT. In a recent study on pregnant women with stable dietary habits, we found that the fish consumers had lower rates of positivity (and lower serum levels) of both TPOAb and thyroglobulin Ab compared to meat eaters. Finally, we remind the reader of other diseases that can be observed in the postpartum period, either autoimmune or non-autoimmune, thyroid or non-thyroid.

The year following parturition is a critical time for the de novo appearance or exacerbation of autoimmune diseases, including autoimmune thyroid disease. The vast majority of postpartum thyroid disease consists of postpartum thyroiditis (PPT) and the minority by Graves' disease and non-autoimmune thyroiditis. PPT has a worldwide prevalence ranging from 1 to 22% and averaging 5% based on a review published in 2012. Several factors confer risk for the development of PPT. Typically, the clinical course of PPT is characterized by three phases: thyrotoxic, hypothyroid, and euthyroid phase. Approximately half of PPT women will have permanent hypothyroidism. The best humoral marker for predictivity, already during the first trimester of gestation, is considered positivity for thyroperoxidase autoantibodies (TPOAb), though only one-third to half of such TPOAbpositive pregnant women will develop PPT. Nutraceuticals (such as selenium) or omega-3-fatty acid supplements seem to have a role in prevention of PPT. In a recent study on pregnant women with stable dietary habits, we found that the fish consumers had lower rates of positivity (and lower serum levels) of both TPOAb and thyroglobulin Ab compared to meat eaters. Finally, we remind the reader of other diseases that can be observed in the postpartum period, either autoimmune or non-autoimmune, thyroid or non-thyroid.
It is important to emphasize that in some cases inflammatory changes seen in subacute thyroiditis can obscure sonographic evidence of underlying papillary thyroid cancer. Also, a clinical picture of painful thyroid enlargement, even with fever, and local mechanical complications can be due to intrathyroid hemorrhages Studies indicate that new-onset autoimmune thyroid disease (AITD) "occurs in up to 10% of all women in the postpartum period and that up to 60% of GD patients in the reproductive years give a history of postpartum onset" (28).
Two contemporary Canadian studies in the same province (Ontario) but in different areas and on different categories of women found different frequencies of PPT and postpartum GD (29,30). The Toronto area study on 1,372 unselected women found that 78 (5.7%) had PPT and 3 (0.22%) GD; in addition, 1 other woman (0.07%) had postpartum thyrotoxicosis due to toxic nodular goiter (29). Thus, the PPT to postpartum GD ratio was 78:3 (26:1). Instead, in 40 Canadian women with type 1 diabetes mellitus (DM1) residing in the Hamilton area, the ratio was 9:1, since PPTD consisted of PPT in 9 patients (22.5%) and postpartum GD in 1 patient (2.5%) (30). The ratio between PPT and postpartum GD can be inferred from additional studies. In one Iranian investigation on 1,040 pregnant women (31), 119 had PPT (11.4%) and only 1 GD (1%), with a ratio of 119:1. Instead, a Spanish study on 641 pregnant women (32), not all of whom sampled at all-time points throughout 12 months postpartum, found that 45 developed PPT [incidence rate 7.8%; confidence interval (CI) 5.6-10%], 8 developed GD (incidence rate 1.5%; CI 0.5-2.5%) and 3 developed non-palpable toxic thyroid adenoma-associated hyperthyroidism (incidence rate 0.5%; CI 0-1.5%). Thus, the ratio between PPT and postpartum GD was 6:1. Incidentally, this 8:3 (2.7:1) ratio between postpartum GD and postpartum toxic adenoma matches the 3:1 ratio of the aforementioned Canadian study (29). According to Japanese authors (33), the frequency of postpartum GD in the general population is estimated at around 0.5%, that is, 1 in 200 postpartum women.
In two retrospective Italian studies (34,35), the postpartum period was a risk factor for relapse(s) of GD, not for the onset. Instead, an earlier Swedish study concluded for a risky role of the postpartum period in the onset of GD (36). In this study (36), 93 consecutive women with GD aged 20-40 years were examined for a possible relation between onset of GD and previous pregnancy.
An increased relative risk of developing GD within 1 year following delivery was found (RR = 6.5, CI 3.8-11.0). After excluding the nulliparous women, almost two out of three women who developed GD in the childbearing age of 20-35 years had a postpartum onset, suggesting an important role of immunomodulatory events following delivery for the development of this disease in young women. A similar relative risk (that is, RR = 5.6) was reported for American women aged 35-39 years (37). This is retrospective study on 152 consecutive women, aged 18-39 years when diagnosed with GD (37). The authors found that, in parous women, 45% were diagnosed with GD in the postpartum period and 55% had an onset in subsequent years. The risk of developing post-pregnancy GD was the greatest in the age band 35-39 years, with 56% of them developing GD compared to 42% of nulliparous women (37). In a Japanese retrospective study on 289 consecutive women with GD, 92 were of childbearing age (20-39 years) and had one or more deliveries (38). At least 37 patients had evident postpartum onset of the disease. Thus, at least 40% of GD women aged 20-39 years developed their disease during the postpartum period (38). In another study, in women diagnosed with GD during the ages of 20-35 years, 66% had a postpartum onset, and women with a previous history of GD relapsed frequently in the postpartum period (39).
In a French study (40), 98 patients with GD were compared to 95 patients with Hashimoto's thyroiditis (HT) and to 97 patients with benign thyroid nodules (control group) in order to evaluate the triggering role of pregnancy and other major stressors in the occurrence of AITDs. A stress factor was encountered in 11% of GD women and 6% of HT or thyroid nodularity women, an insignificant difference. Instead, in women of childbearing age, GD after a pregnancy occurred more frequently than HT or benign thyroid nodules (25 vs. 10 or 13%, p < 0.05). The author concluded that the role of stressors, if any, in triggering GD seems to be weak and dubious compared to the role of pregnancy and postpartum.
Concerning possible prevention of GD relapse in the postpartum, continuing antithyroid drugs therapy throughout pregnancy prevents recurrence of GD without neonatal hypothyroidism or malformations (41). However, the use of methimazole is related to its potential teratogenic effects, especially in the first trimester of pregnancy (42).
Concerning medical therapy of GD and in view of the reference made to the omega-3 fatty acids-rich fish in the next heading, it is noteworthy mentioning the following case (43). A professor of physiology self-reported her GD developed 4 months postpartum with a TSH normalization, within 8 weeks of beginning flaxseed oil supplement (5-1,000 mg tablets twice a day). Flaxseed oil is over 50% omega-3 fatty acids (mainly alpha-linolenic acid), but it also contains about 15% omega-6 fatty acids (mainly linoleic acid) (43).
It is noteworthy that GD and PPT may affect the same woman, at different times. A clear case of PPT (in the form of transient thyrotoxicosis) in a young woman in whom GD had appeared 6 years earlier was reported (44). Shortly prior to becoming pregnant, an increase in thyroperoxidase autoantibodies (TPOAb) was observed in this woman. In another Japanese woman with thyroid hemiagenesis, GD was present in the pregnancy that preceded the postpartum period during which PPT appeared (45). Other case reports of PPT following GD have appeared in the literature (46,47), one being noteworthy because of the sequence onset of GD → PPT → relapse of GD (47). The chronological sequence of PPT preceding GD was described in three young Caucasian women (48,49). Based on the different pattern of radioiodine thyroid uptake, rate of positivity and mean levels of TSH-binding inhibiting antibodies, and evolution of hyperthyroidism in almost 100 women with GD followed up in the postpartum period, it was concluded that PPTD develops frequently in the postpartum period of patients with GD (50).
Finally, concurrent Sheehan's syndrome and GD in the postpartum has been reported (51). In this case report, GD appeared first and Sheehan's syndrome later.

Postpartum Thyroiditis
In this minireview, we will focus on the endocrine and autoimmune side of PPT, with no reference to the neuropsychological disturbances, particularly the association with postpartum depression (52,53). Neuropsychological disturbances, such as acute psychosis, can also occur in association with postpartum GD (54). Very recently, we have reviewed the postpartum mood disorders (55).
Postpartum thyroiditis is a thyroid dysfunction, characterized by lymphocytic infiltration of the gland, which appears in the first postpartum year in women who were euthyroid prior to pregnancy (42,53). The just released guidelines of the American Thyroid Association (42) endorse the original definition by Amino et al. (56), namely PPT is "the occurrence of thyroid dysfunction, excluding GD, in the first postpartum year in women who were euthyroid prior to pregnancy. "

Epidemiology and Risk Factors
Based on a review published in 2012 (53), PPT has a worldwide prevalence of approximately 5%, but ranging from 1 to 22%. Because of its autoimmune nature, other autoimmune disorders may appear years after PPT. In one study, 40 women (mean age 36 years) with documented PPT 5 years earlier and 30 agematched healthy women who all had undergone normal delivery an average of 5 years previously, were investigated (57). Women with previous PPT had symptoms of dry eyes, caries, arthralgias, swollen joints, and fatigue significantly more often than control group (p < 0.05). One-third (34%) of the women were anti-SSB positive and 46% were anti-SSA positive at follow-up. Furthermore, 15/35 women with a history of PPT had objectively reduced tear and/or saliva secretion; 5/24 investigated women had keratoconjunctivitis sicca, and 2/7 salivary gland biopsies showed chronic lymphocytic sialadenitis. Three women (8.6%) had both xerophthalmia and xerostomia. The authors concluded that features of Sjögren's syndrome are frequent in young women with previous PPT (57).
Several factors confer risk for the development of PPT, a major one being serum positivity for thyroid autoantibodies (TAb) during gestation (53). Furthermore, based on a systematic review (58), the risk for PPT conferred by positivity for TAb during gestation is much greater than the risk for other outcomes. Indeed, compared with women who are TAb negative, odds ratio (OR) for maternal PPT was 11.5, greater than the OR for miscarriage (3.73), recurrent miscarriage (2.3), preterm birth (1.9), or unexplained subfertility (1.5) (58). Paralleling GD, parturition can be a risk factor for autoimmune thyroiditis (AIT) (59). Women with at least one pregnancy had increased likelihood for AIT (OR 4.6, p < 0.05) compared to women who have never been pregnant. Similar results were observed using hypoechogenic thyroid pattern (OR 1.7, p < 0.05) and positive TPOAb levels (OR 1.8, p = 0.05) as separate dependent variables or using number of births as alternate independent variable. Furthermore, immune rebound after parturition may cause not only AITD, including PPT, but other autoimmune diseases: postpartum renal failure or postdelivery hemolytic-uremic syndrome, postpartum idiopathic polymyositis, postpartum syndrome with antiphospholipid antibodies, and postpartum autoimmune myocarditis (60).
Considering the relative rarity of the thyroid hormone resistance (RTH) syndrome, a non-autoimmune genetic disorder in which elevated circulating levels of thyroid hormones fail to suppress serum TSH, it is worthwhile mentioning two cases of association between RTH and PPT (70, 71) ( Table 2). This association has been reported also outside of the postpartum setting (72). Concerning the role of cigarette smoking as a risk factor for PPT, data are controversial (73-75) ( Table 2).

Postpartum Thyroid Hormone Autoantibodies
Positivity for TPOAb, already during the first trimester of gestation, is the best humoral marker for predictivity of PPT; nonetheless, only 33-50% of these women will develop PPT, whereas TAb-negative women have a very low incidence of PPT (53). Some studies have reported the appearance of thyroid hormones autoantibodies (THAb) in postpartum period that can interfere with the evaluation of thyroid function. Jansson and Forberg described the presence of Ab against T3 in a woman who developed biphasic PPT, namely thyrotoxicosis followed by transient hypothyroidism after childbirth (76). In another study, three women with PPT had spuriously increased concentrations of free thyroid hormones because of antibody binding of radiolabeled T4 and T3 analogs. The antibody binding of radiolabeled analogs disappeared by 48 weeks postpartum. Postpartum women who develop THAb have about 2% prevalence of increased binding of radiolabeled analogs, which can Postpartum Thyroid Disorders Frontiers in Endocrinology | www.frontiersin.org July 2017 | Volume 8 | Article 166 result in an interference in thyroid hormone assays (77). Thus, it was suggested that women with PPT should receive full thyroidfunction testing and be checked for possible antibody binding of analog tracers if free thyroid hormone levels are inappropriately increased (77).
Recently, the first case of transient appearance of THAb in pregnancy was reported (78). A 35-year-old pregnant woman, with a known diagnosis of HT, and under levothyroxine (L-T4) replacement therapy, was clinically euthyroid with normal TSH but elevated free triiodothyronine (FT3) and free thyroxine (FT4). Serum FT4 and FT3 returned progressively normal postpartum. The presence of circulating THAb was confirmed by demonstrating THAb against the two hormones (78).
In a Welsh larger study, THAb were searched, from week 4 through week 48 postpartum, in 148 thyroid antibody-positive women and 261 thyroid antibody-negative women (77). The study started with selecting, in the 409 women, those showing interference in the FT4 and/or FT3 assays using the corresponding free thyroid hormone Amerlex assay (77). Only 3 of the 148 women thyroid antibody-positive women (2.0%) had THAb, particularly T3-analog Ab (n = 1), T3-analog and T4-analog Ab (n = 2). Only two of the three women had PPT. Previously, the same group (79) found that the rate of THAb, as estimated by the interference (overestimation) of FT4 and/or FT3 by the Amerlex analog method, was 0.04% (1/2460), 50-fold less than the above 2.0%.
In these three women (77), THAb measured by non-specific precipitation of serum enriched with radiolabeled Amerlex-T4 analog or Amerlex T3-analog immunoglobulin classes, could not be identified. In the same three women (77), antibody binding of radiolabeled analogs and its effect (overestimation) on free T4 and free T3 assays disappeared by 48 weeks postpartum. However, there is the extreme variability of the THAb in causing interference.
In brief, one cannot predict the presence of THAb based simply on the interference (overestimation) in the assay of free thyroid hormones, since this interference is frequently absent. Furthermore, the greater the frequency of sampling and associated THAb search over a given time course, the greater the chances to detect THAb. Until now, there is no study that has evaluated their role as predictors for future development of PPT. However, it is noteworthy that THAb (at least one among T3IgM, T3IgG, T4IgM, and T4IgG) are highly prevalent in patients with DM1 (80), an autoimmune endocrine disorder that confers high risk for PPT ( Table 2).

Clinical Picture
The clinical course of PPT is similar to subacute thyroiditis but in absence of anterior neck pain or tenderness of the thyroid (53). The classic form is characterized by transient hyperthyroidism (8-24 weeks postpartum), followed by a phase of transient hypothyroidism (3-12 months postpartum), and then by return to euthyroidism at the end of the initial postpartum year. However, the clinical course of PPT is variable because about 25% of women presenting the classical form, 25% isolated thyrotoxicosis, and one-half presenting isolated hypothyroidism (53). In the thyrotoxic phase, asthenia and irritability are the most frequent symptoms; instead, lack of energy, aches and pains, poor memory, dry skin, paresthesias, and cold intolerance are the most frequent hypothyroid features (81).
Approximately half of PPT women will have permanent hypothyroidism (53). Unless evolved into permanent hypothyroidism, PPT tends to recur after subsequent deliveries. A Welsh study (82) reported a 70% chance of developing recurrent PPT after the first PPT attack, and a 25% risk even in women who were only TPOAb positive without thyroid dysfunction during the first postpartum period.

Diagnosis
The diagnostic procedures depend on the phases of the disease. In the thyrotoxic phase (TSH suppressed with increased serum FT3 and FT4), it may be necessary to differentiate PPT from GD. In GD, radioactive iodine uptake is high, while it is low in PPT, but this test is contraindicated during breastfeeding. Therefore, in these cases, the dosage of thyroid receptor antibodies is useful: in PPT, they are absent in almost all cases. Also, the thyroid echography can to show an increased hypoechogenicity in many cases of PPT. In the hypothyroid phase, TSH levels are increased with low or normal FT4 concentrations (81). However, during postpartum, the susceptible period to develop GD and PPT is different: around 3 months for PPT vs later than 6 months for GD (83).

Nutraceuticals, Food, and Prevention Strategy of PPT
Selenium, through selenoproteins, has a key action on thyroid function by protecting thyrocytes from oxidative damage (84). Moreover, selenium supplementation can ameliorate thyroid autoimmunity in patients with mild-form or early-stage HT (85). Also, when given to pregnant women, selenium reduced serum levels of TPOAb and prevalence of PPTD and permanent hypothyroidism (85,86).
Omega-3-fatty acid supplements can diminish the inflammation associated with certain autoimmune disorders, so that they could be used to treat AIT (43).
Concerning food, small oily fish consumption was reported to cure and/or prevent autoimmune disorders, and improve certain maternal and neonatal outcomes (87,88). Small oily fish are a source of long-chain polyunsaturated n-3 fatty acids, while large predator fish contain a number of pollutants (87). Recently, in a study on pregnant women with stable dietary habits who were sampled throughout gestation and day 4 postpartum, fish consumers had lower rates of positivity of both TPOAb and thyroglobulin Ab compared to meat eaters. Furthermore, within the fish-eater women, those consuming small oily fish had lower rates of either Ab compared to those consuming large fish. Hence, pregnant women should avoid consuming swordfish and increase consumption of oily fish (87,88).

Therapy and Follow-up of PPT
As appropriately underscore (53), "treatment of PPT is based on clinical experience because there have been no trials comparing therapeutic alternatives. " In the thyrotoxic phase, if necessary, can be administered betablocker drugs, while antithyroid drugs are not recommended.
During the hypothyroid phase, symptomatic women could be treated with L-T4 at replacement doses and L-T4 therapy is recommended in hypothyroid women who are attempting pregnancy or who are breastfeeding. If treatment is not initiated, TSH dosage should be repeated every 4-8 weeks until thyroid function normalizes. L-T4 therapy should be continued for 12 months (42).

AUTHOR COnTRibUTiOnS
FDB, RG, MLD, RV, and SB designed the study and reviewed the literature on postpartum and thyroid autoimmunity. SB and FDB wrote the manuscript. All the authors have revised the paper and approved the final edition.