Edited by: Signe Altmäe, University of Granada, Spain
Reviewed by: Julio Martín Voget, Androfert, Andrology and Human Reproduction Clinic, Brazil; Alberto Sola-Leyva, University of Granada, Spain
This article was submitted to Reproduction, a section of the journal Frontiers in Endocrinology
†These authors have contributed equally to this work
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Ectopic pregnancy (EP) accounts for ~2% of all pregnancies. It is a common life-threatening emergency and an important cause of maternal morbidity and mortality, as well as fetal loss (
With the wide application of assisted reproductive technology (ART) in the field of reproduction, it is of great clinical value to identify the risk factors of REP in infertile patients with a history of EP. If women at risk can be identified in the early stages of ART and be provided with targeted treatment to protect their reproductive ability, they may be able to avoid another occurrence of REP. However, at present, the risk factors related to REP are unclear. In this study, infertile patients with a history of EP were taken as the research objects, and their fertility outcomes were tracked. The patients with REP were taken as the experimental group, and the intrauterine pregnancy (IUP) without REP as the control group. Multivariate logistic regression was used to analyze the risk factors of REP.
This case-control study was conducted in the ART center of the First Affiliated Hospital of Zhengzhou University from January 2012 to November 2019. The data were extracted from the patients' clinical records. The selection process of the cycles is shown in
Cycles selection flowchart. *In the case of multiple cycles of clinical pregnancy after ART, bring into the first cycle.
We selected patients who completed cycles that resulted in a clinical pregnancy of either REP or IUP. We used age to match the REP women with the IUP group. We used age as a matching factor because previous studies have shown that age is an important risk factor for EP (
Biochemical pregnancy was defined as a pregnancy diagnosed only by the detection of beta hCG in the serum or urine. Clinical pregnancy was defined as in the fifth week after the embryo transfer, on ultrasound, an intrauterine gestational sac was observed with a cardiac beat. An intrauterine pregnancy was defined as a pregnancy with one or more ultrasound-confirmed gestational sacs in the uterus. Ectopic pregnancy was defined as the gestational sac outside the uterine cavity as observed by ultrasound. Heterotopic pregnancy was defined as the coexistence of an intrauterine sac and an ectopic pregnancy.
Based on previously published articles, the following risk factors were included (
Patients with fresh embryo transfer were treated with gonadotropin releasing hormone (GnRH) agonists to prevent a premature LH surge (
The FET protocols in our center were mainly divided into natural cycles and artificial cycles based on the regularity of the menstrual cycle. For natural cycles, patients were allocated to undergo ultrasonic evaluation starting from day 8–9 of the menstrual cycle. The endometrial thickness and mean diameter of the dominant follicle were examined by the same physician. When the diameter of the dominant follicle was 16–20 mm, a blood sample was obtained to determine the progesterone and LH levels.
Thawing and transferring were performed 3 days after ovulation. Intramuscular (im) progesterone (40 mg) starting on the day of ovulation and oral dydrogesterone (20 mg) starting on the embryo transfer day were used for luteal support.
For artificial cycles, patients began oral estradiol [2 mg [Progynova]; Bayer, Leverkusen, Germany] twice a day on cycle day 3. This dose was adjusted based on the endometrial thickness every 4 days. After 12–14 days, an ultrasound was performed and a serum progesterone level was determined. If no leading follicle was present, progesterone (60 mg im) and oral dydrogesterone [10 mg [this dose was changed to 20 mg 2 days later]] would be added to the regimen. Embryo transfer was performed 3 days later.
All of the patients were followed up and hCG biochemical pregnancy tests were performed 2 weeks after the embryo transfer procedure. When the serum hCG was >50 IU/L, the luteal support was continued. Transvaginal ultrasound was performed 5 weeks after embryo transfer.
SPSS21.0 software was used for the statistical analysis. The general data of the patients were primarily expressed as %; only BMI and infertility duration were expressed by mean ± standard deviation (x ± s). Differences in BMI and infertility duration were analyzed using
A total of 1,135 patients, including 227 REP patients and 908 matched IUP patients, were enrolled in this research. In the REP group, 69% had only one previous episode of EP, while 31% of patients had a history of ≥ 2 ectopic pregnancies. The basic characteristics of the two groups are shown in
Univariate analysis of risk factors related to basic characteristics of patients.
Total | 908 | 227 | ||
Age | 0.000 | 1.000 | ||
<30 | 424 (80) | 106 (20) | ||
30–35 | 380 (80) | 95 (20) | ||
>35 | 104 (80) | 26 (20) | ||
Body mass index (kg/m2) | 22.75 ± 3.06 | 22.66 ± 2.91 | 0.420 | 0.675 |
Infertility duration (years) | 2.65 ± 2.51 | 2.52 ± 2.16 | 0.756 | 0.450 |
Infertility factors | 4.747 | 0.093 | ||
Tubal factor | 645 (81.23) | 149 (18.77) | ||
Compound factors |
199 (75.38) | 65 (24.62) | ||
Others |
64 (83.12) | 13 (16.88) | ||
Gravidity | 1.780 | 0.411 | ||
1 | 323 (78.78) | 87 (21.22) | ||
2 | 304 (79.17) | 80 (20.83) | ||
≥3 | 281 (82.40) | 60 (17.60) | ||
Miscarriages | 1.704 | 0.427 | ||
0 | 511 (80.09) | 127 (19.91) | ||
1 | 242 (78.06) | 68 (21.94) | ||
≥2 | 155 (82.89) | 32 (17.11) | ||
Previous EP | 3.485 | 0.062 | ||
1 | 618 (78.53) | 169 (21.47) | ||
≥2 | 290 (83.33) | 58 (16.67) | ||
Treatment of last EP | 6.883 | 0.032 | ||
Salpingectomy | 443 (83.27) | 89 (16.73) | ||
Conservative operation | 391 (77.43) | 114 (22.57) | ||
Methotrexate | 74 (75.51) | 24 (24.49) |
A total of 661 fresh embryo transfer cycles and 474 frozen-thawed embryo transfer (FET) cycles were included as shown in
Univariate analysis of risk factors associated with fresh and frozen cycles.
Total | 908 | 227 | ||
Type of ART | 0.063 | 0.802 | ||
IVF | 821 (80.10) | 204 (19.90) | ||
ICSI | 87 (79.09) | 23 (20.91) | ||
Type of transfer | 3.370 | 0.066 | ||
Fresh embryo | 541 (81.85) | 120 (18.15) | ||
Thawed embryo | 367 (77.43) | 107 (22.57) | ||
Stage of embryo | 29.013 | 0.000 | ||
Cleavage stage | 641 (76.22) | 200 (23.78) | ||
Blastocyst stage | 267 (90.82) | 27 (9.18) | ||
FET protocols | 0.026 | 0.872 | ||
Natural cycle | 130 (77.84) | 37 (22.16) | ||
Artificial cycle | 237 (77.20) | 70 (22.80) | ||
No. of embryos transferred | 16.933 | 0.000 | ||
1 | 200 (89.29) | 24 (10.71) | ||
2 | 640 (78.34) | 177 (21.66) | ||
3 | 68 (72.34) | 26 (27.66) |
To evaluate the effect of these risk factors on the occurrence of REP after IVF, we included infertility factors, previous EP, previous treatment of EP, type of embryo transferred, stage of the embryo and the number of embryos transferred for multivariate logistic regression analysis, as shown in
Risk factors associated with REP by logistic regression analysis.
Infertility factors | ||
Tubal factor | REF | |
Compound factors | 1.320 (0.936–1.861) | 0.113 |
Others | 0.730 (0.378–1.412) | 0.350 |
Previous EP | ||
1 | REF | |
≥2 | 0.738 (0.525–1.037) | 0.080 |
Treatment of last EP | ||
Salpingectomy | REF | |
Conservative operation | 1.484 (1.078–2.042) | 0.015 |
Methotrexate | 1.729 (1.007–2.967) | 0.047 |
Type of transfer | ||
Fresh embryo | REF | |
Thawed embryo | 1.651 (1.203–2.265) | 0.002 |
Stage of embryo | ||
Cleavage stage | REF | |
Blastocyst stage | 0.275 (0.158–0.479) | 0.000 |
No. of embryos transferred | ||
1 | REF | |
2 | 0.981 (0.551–1.746) | 0.947 |
3 | 1.115 (0.527–2.360) | 0.775 |
Ectopic pregnancy (EP) is a common cause of acute abdomen in obstetrics and gynecology, and it is also one of the important causes of maternal death. While ART meets people's fertility needs, it has a risk of EP, which can easily increase the incidence of REP (
According to the statistics, the recurrence rate of EP ranges from 10 to 27% in the general population (
The management of EP includes expectant behavior, conservative drug treatment (methotrexate) and surgical treatment. Surgical treatment could be divided into conservative operations and radical resection. No matter what kind of treatment is used in patients with EP, the pathological changes of the fallopian tubes might persist, or the fallopian tubes on the affected side might adhere again, resulting in secondary infertility.
When applying general drug conservative treatment, drugs are used to interfere with the synthesis of DNA and RNA of the embryonic cells, making it difficult for them to grow and stopping the development of the embryo, but the damage the pregnancy products inflict on the fallopian tubes and any subsequent tubal inflammation cannot be effectively removed. Zhang Anhong (
The surgical treatment of tubal pregnancy includes tubal sparing focus clearance (conservative operation) and salpingectomy on the affected side. Some studies have suggested that previous treatment of EP with a conservative operation had a comparable risk of REP as salpingectomy (
Many previous studies have evaluated the incidence of EP after ART, but there have been few reports on a specific population with a history of EP. Additionally, it was not clear whether there was a difference in the recurrence rate of EP between fresh and frozen cycles. The subjects of this research were all patients with a history of EP. The results showed that the risk of REP in fresh cycles was lower than that in frozen cycles. Pan Le Le's research results showed that the recurrence rate of EP in fresh cycles was 4.99%, which was lower than that of frozen cycles (11.03%), and the difference was statistically significant (
Although the effects of blastocyst embryo vs. cleavage embryo transfer on the incidence of EP remain controversial, most studies have shown that blastocyst embryo transfer is beneficial for reducing the incidence of EP (
As for the number of embryos transferred, theoretically, the incidence of EP would increase with an increased number of transferred embryos, and some studies such as Perkins et al. (
The main strength of our study was that we are the first to investigate the risk factors of REP after ART in patients with a history of EP. In addition, this was an original study. However, our study also had several limitations due to its retrospective design and a single medical center. In addition, this research is only a preliminary discussion, due to the small sample size and collection time, and there is an inevitable bias. It is necessary to expand the sample size for further research. Therefore, the conclusions needed to be interpreted carefully.
In summary, conservative treatment, FET and cleavage embryo transfer were independent risk factors for REP after ART treatment. Patients with conservative treatment should be on guard against the occurrence of REP. This suggests that salpingectomy on the affected side should be selected when there is a surgical indication for an EP. In addition, during the course of ART treatment, fresh cycles or blastocyst embryo transfer should be selectively performed for populations at high risk of REP.
All datasets generated for this study are included in the article.
All study methods were approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (Scientific Research-2020-KY-256). All participants provided written informed consent. All studies were conducted in accordance with the relevant guidelines and regulations.
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.
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.
We would like to acknowledge the professional manuscript services of American Journal Experts.