Abstract
BACKGROUND
Recent studies have reported higher risks of adverse maternal and neonatal outcomes, such as hypertensive disorders of pregnancy, after programmed frozen embryo transfer, especially in cycles with gonadotropin-releasing hormone agonist pretreatment. It remains unclear if GnRH agonist pretreatment before programmed frozen embryo transfer further increases the risk for obstetrical complications among women with polycystic ovary syndrome.
OBJECTIVE
This study aimed to compare the obstetrical and neonatal complications of singleton and twin pregnancies after programmed frozen embryo transfer with or without gonadotropin-releasing hormone-a pretreatment among women with polycystic ovary syndrome.
STUDY DESIGN
This was a secondary analysis of a single-center, randomized controlled trial comparing the live birth rate and cost-effectiveness of programmed cycle-prepared frozen embryo transfers with or without gonadotropin-releasing hormone agonist pretreatment among women with polycystic ovary syndrome. The analysis was restricted to women with polycystic ovary syndrome, aged 24 to 40 years, who delivered live neonates after frozen-thawed blastocyst transfer. The obstetrical and neonatal outcomes were compared between programmed cycles with and those without gonadotropin-releasing hormone agonist pretreatment. The adjusted odds ratios with 95% confidence intervals were calculated and adjustments were made for relevant confounders.
RESULTS
The maternal and neonatal complications associated with 177 live single births and 38 twin births (253 newborns in total) were analyzed. There were no significant differences in the frequencies of obstetrical complications, including hypertensive disorders of pregnancy, between the gonadotropin-releasing hormone agonist pretreatment and no pretreatment group for both singleton and twin pregnancies. However, there was a significantly greater incidence of having a low birthweight neonate among singleton infants born after gonadotropin-releasing hormone agonist pretreatment when compared with no pretreatment (10.2% vs 1.3%; P=0.042), and a low birthweight among singleton infants was still more likely after adjusting for confounders (relative ratio, 3.85; 95% confidence interval, 1.13−7.11; P=.024). Other neonatal complications were all comparable between the pretreatment and no pretreatment groups for both singleton and twin pregnancies.
CONCLUSION
For women with polycystic ovary syndrome, programmed frozen embryo transfer cycles with gonadotropin-releasing hormone agonist pretreatment could lead to a greater risk of having a low birthweight singleton neonate.
Key words: endometrium preparation, frozen-thawed embryo transfer, gonadotropin-releasing hormone agonist, hormone replacement therapy, polycystic ovary syndrome
AJOG Global Reports at a Glance.
Why was this study conducted?
This study aimed to assess the potential risks and benefits of gonadotropin-releasing hormone (GnRH) agonist pretreatment before programmed frozen embryo transfer (FET) on obstetrical and neonatal complications among women with polycystic ovary syndrome (PCOS).
Key findings
Low birthweight deliveries were more likely to occur following programmed FET cycles with GnRH agonist pretreatment among women with PCOS.
What does this add to what is known?
GnRH agonist pretreatment before programmed FET for women with PCOS could further enhance the risk for neonatal complications.
Introduction
Frozen embryo transfer (FET) is widely applied as an alternative to fresh embryo transfer for assisted reproduction among women with polycystic ovary syndrome (PCOS), because FET significantly lowers the risk of ovarian hyperstimulation syndrome.1 Because oligoovulation or anovulation is observed in most women with PCOS, consecutive estrogen and progesterone with or without gonadotropin-releasing hormone agonist (GnRH-a) pretreatment is often used to prepare a suitable endometrium before FET.2 However, a few recent observational studies reported higher risks of experiencing adverse obstetrical outcomes among singleton pregnancies after programmed cycle FET because of a lack of vasoactive corpus luteal factors.3, 4, 5, 6 For example, elevated risks for hypertensive disorders of pregnancy (HDP) and preeclampsia were reported following programmed FET cycles when compared with natural cycles,4, 5, 6 and one of these recent studies also reported an even higher risk for preeclampsia among the normal ovulatory population when programmed cycles are used with GnRH-a pretreatment.6
It is widely accepted that women with PCOS are at higher risk of experiencing obstetrical and neonatal complications, including premature delivery, gestational diabetes mellitus (GDM), HDP, and both large for gestational age (LGA) and small for gestational age (SGA) neonates.7, 8, 9 Therefore, it is important to evaluate the obstetrical and neonatal outcomes using different methods of endometrial preparation in the PCOS population, such as for patients with PCOS who elected programmed cycles with and for those who elected programmed cycles without GnRH-a pretreatment. We recently completed a single-center randomized controlled trial (RCT) comparing the live birth rate and cost-effectiveness of programmed cycle-prepared FET with or without GnRH-a pretreatment for women with PCOS, during which the obstetrical and neonatal outcomes were prospectively documented.10 Therefore, we conducted a secondary analysis and compared the maternal and neonatal complications between the 2 protocol groups to help guide method selection for women with PCOS.
Materials and Methods
Study design and study population
This RCT was conducted from April 2017 to October 2019 at a single reproductive center. The original study was registered with the Chinese trial registry (under identifier ChiCTR-IOR-17010729) and approved by the Medical Ethics Committee of the First Affiliated Hospital, Sun Yat-sen University. The design and main outcomes of this trial have been reported previously.10 Briefly, participants were patients with PCOS, aged 24 to 40 years, who underwent FET cycles and who received no more than 2 blastocysts from the first in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle and no more than 2 total FET cycles.
PCOS was diagnosed according to the modified Rotterdam criteria validated in the Chinese population.11 Patients with congenital or acquired anatomic uterine anomalies, intrauterine adhesion, endometriosis, adenomyosis, recurrent implantation failure, recurrent pregnancy loss, or abnormal results on parental karyotyping were excluded.
In this study, 177 patients who delivered a single live neonate and 38 who delivered live twins were included in the analyses (Figure). Live birth was defined as delivery of any neonate at ≥28 weeks of gestation with signs of life.
Figure.
Flow chart of study
ET, embryo transfer; GnRH-a, gonadotropin-releasing hormone agonist.
Jie. Obstetrical outcomes of programmed frozen embryo transfer with or without gonadotropin-releasing hormone agonist pretreatment for polycystic ovary syndrome. Am J Obstet Gynecol Glob Rep 2023.
Endometrial preparation protocols for FET
Endometrial preparation protocols were described in our previous report.10 Briefly, the GnRH-a pretreatment group received a depot of long-acting GnRH agonist (1.0 mg Triptorelin, Ferring GmbH, Kiel, Germany). Both the GnRH-a pretreatment and no pretreatment groups received sequentially increasing doses of oral estradiol valerate (Progynova, Schering AG, Berlin, Germany). Progesterone treatment was started when the endometrial thickness reached a minimum of 8 mm and the blood estradiol level surpassed 100 pg/mL; the criteria were met after 10 to 20 days of oral estrogen supplementation in all patients who were included in the analysis. Intramuscular injections of progesterone in oil (20 mg per ampoule; Shanghai General Pharmaceutical Factory, Shanghai, China) was started at 40 mg daily for 2 days and increased to 60 mg daily for the following 15 days. In cases of a successful pregnancy, progesterone was continued until 10 weeks of gestation. If endometrial thickness remained <8 mm after 20 days of oral estrogen supplementation, the embryo transfer was cancelled. Blastocysts were thawed on day 6 of progesterone initiation and embryo transfer was performed on the day of thawing.
Follow-up and data collection
Only the results from live births were included in the present analysis. A follow-up to obtain information on the pregnancy outcomes was conducted prospectively by phone interview. To further increase the reporting accuracy, maternal and neonatal outcomes were confirmed through medical record review after the completion of the RCT.
Study variables and outcome measures
The baseline patient characteristics included in the analysis were age, body max index (BMI), years of infertility, type of infertility, cause of infertility, and fertilization method (IVF or ICSI). The primary outcome measures were the obstetrical and neonatal complications. In detail, obstetrical complications included HDP (gestational hypertension [International Classification of Diseases, 10th Revision, {ICD-10} code O13] and preeclampsia and eclampsia [ICD-10 code O14–O150]), GDM (diagnosed on the basis of recommendations by the International Association of Diabetes and Pregnancy Study Groups [International Association of Diabetes and Pregnancy Study Groups Consensus Panel, 2010]12), placenta previa (ICD-10 code O44), placenta abruption (ICD-10 code O45), oligohydramnios (ICD-10 code O41), premature rupture of membranes (PROM) (ICD-10 code O42), and intrahepatic cholestasis of pregnancy (ICP) (ICD-10 code O71). Neonatal complications included preterm birth (PTB) (delivery between 28 and 37 weeks of gestation), very preterm birth (VPTB) (delivery between 28 and 32 weeks of gestation), low birthweight (LBW) (birthweight of <2500 g), macrosomia (birthweight of >4000 g), SGA (birthweight below the 10th percentile for the gestational age of the same sex), and LGA (birthweight more than the 90th percentile for the gestational age of the same sex). The references for SGA and LGA were based on the latest nationwide neonatal birthweight curve for Chinese singletons and twin respectively.13
Statistical analysis
Continuous variables are expressed as mean (standard deviation) if normally distributed according to the Shapiro–Wilk test or as median (interquartile range) if deemed to be non-normally distributed by the same test. Categorical variables are expressed as numbers (percentages). For univariable analyses, normally distributed continuous variables were compared using independent samples t tests and non-normally distributed continuous variables were compared using Wilcoxon rank-sum tests. Categorical variables with more than 5 cases were compared using Pearson's chi-square tests and categorical variables with <5 cases were compared using Fisher's exact tests. A multivariable logistic regression was also performed to adjust for confounders. For comparison of the obstetrical complications between the GnRH-a pretreatment and no pretreatment groups, confounders included maternal age, BMI, years of infertility, type of infertility, cause of infertility, and fertilization method. For comparison of the neonatal complications between the groups, gestational age, delivery of singleton or twins, PROM, and HDP were also included in addition to the aforementioned factors. Results of the multivariable analyses are expressed as adjusted odds ratios (aORs) with 95% confidence intervals (CIs). A P <.05 was considered statistically significant for all tests. All statistical analyses were performed using SPSS Statistics (version 22.0) (SPSS Inc, Chicago, IL).
Results
The baseline clinical and demographic characteristics of the study participants are summarized in Table 1. Maternal age, BMI, duration of infertility, proportion of primary infertility, cause of infertility, and insemination method did not differ significantly between the pretreatment group (GnRH-a group) and no pretreatment group (HRT groups) of patients with PCOS who delivered singleton neonates or the corresponding GnRH-a and HRT groups with twin deliveries. Estrodial level at the time of progesterone initiation was significantly lower in the GnRH-a group than in the HRT group for singleton pregnancies (P=.033), but the day of estrodial exposure before progesterone initiation were comparable between groups.
Table 1.
Demographic and baseline in vitro fertilization characteristics of the study cohort
| Demographics | Singleton birth |
Twin birth |
||||
|---|---|---|---|---|---|---|
| Pretreatment (n=59) |
Control (n=80) |
P value | Pretreatment (n=26) |
Control (n=12) |
P value | |
| Maternal age (y) | 31 (29–34) | 31 (28–34) | .49 | 28 (24–30) | 27 (24–32) | .84 |
| BMI (kg/m2) | 21.9 (19.7–25.4) | 21.8 (20.2–24.2) | .26 | 20.8 (19.2–23.4) | 20.8 (19.3–23.4) | .27 |
| Type of infertility (primary infertility %) | 32 (55.1) | 46 (57.5) | .91 | 18 (66.6) | 9 (69.2) | .87 |
| Duration of infertility (y) | 3 (2–5) | 3 (2–5) | .67 | 3 (2–5) | 3 (2–4.5) | .36 |
| Cause of infertility, n (%) | ||||||
| Tubal factor | 34 (58.6) | 44 (55.0) | .20 | 13 (48.1) | 4 (30.7) | .51 |
| Male factor | 17 (29.3) | 32 (40.0) | 12 (44.4) | 7 (53.8) | ||
| Combined factors or unknown reasons | 7 (12.0) | 4 (5.0) | 2 (7.4) | 2 (15.3) | ||
| Insemination method (ICSI %) | 19 (32.7) | 32 (40) | .39 | 12 (44.4) | 7 (53.8) | .49 |
| Vanishing twin, n(%) | 1 (1.69) | 1 (1.25) | .94 | — | — | — |
| Hormonal status in FET cycle | ||||||
| Total testosterone at baseline (ng/mL) | 0.6 (0.3–0.9) | 0.6 (0.2–0.9) | .77 | 0.6 (0.2–0.9) | 0.7 (0.2–0.8) | .47 |
| Fasting blood glucose at baseline (ng/mL) | 5.2 (4.1–5.9) | 5.3 (4.4–5.9) | .82 | 5.4 (4.2–5.7) | 5.3 (4.1–5.8) | .92 |
| Fasting blood insulin at baseline (ng/mL) | 15.5 (5.4–18.8) | 15.2 (6.5–19.6) | .51 | 14.7 (5.3–19.1) | 15.0 (6.2–18.2) | .65 |
| HOMA index | 3.9 (1.3–5.7) | 4.0 (1.4–5.9) | .40 | 4.0 (1.5–5.6) | 4.0 (1.4–5.8) | .78 |
| LH level at the time of E2 initiation (IU/L) | 0.5 (0.1–1.2) | 6.5 (3.4–8.9) | <.01 | 0.6 (0.2–1.2) | 6.3 (3.2–8.8) | .032 |
| E2 level at the time of E2 initiation (ng/mL) | 12.8 (10.4–18.5) | 47.7 (26.5–68.7) | <.01 | 12.3 (10.4–17.7) | 48.9 (23.2–66.4) | .028 |
| E2 level at the time of P4 initiation (ng/mL) | 132.3 (101.3–195.8) | 165.5 (119.6–260.4) | .033 | 128.8 (103.6–200.1) | 168.9 (113.1–288.0) | .060 |
| Length of E2 exposure before P4 initiation (d) | 15 (13–17) | 14 (12–17) | .25 | 15 (12–17) | 14 (12–17) | .67 |
Data are presented as median (interquartile range) or number (percentage) unless otherwise indicated.
BMI, body mass index; FET, frozen embryo transfer; HOMA, homeostasismodel assessment; ICSI, intracytoplasmic sperm injection; E2, estrodial; P4, progestersterone.
Jie. Obstetrical outcomes of programmed frozen embryo transfer with or without gonadotropin-releasing hormone agonist pretreatment for polycystic ovary syndrome. Am J Obstet Gynecol Glob Rep 2023.
Furthermore, the rates of PROM, GDM, HDP, placental abruption, placenta previa, oligohydramnios, ICP, and cesarean delivery did not differ significantly between the groups that delivered singleton or twin neonates (Table 2). However, the prevalence of singleton neonates with LBW was significantly higher in the GnRH-a group than in the HRT group (10.2% vs 1.3%; P=0.042) (Table 3). LBW prevalence was comparable between the GnRH-a and HRT group patients who delivered twins. Other neonatal complications, including PTB, VPTB, macrosomia, SGA, and LGA, did not differ between the groups for either singleton or twin births. According to the multivariable logistic regression analyses, GnRH-a pretreatment before programmed FET was a significant independent risk factor for LBW singleton births (RR, 3.85; 95% CI, 1.13−7.11; P=.024). Alternatively, other obstetrical and neonatal complications were not related to GnRH-a pretreatment.
Table 2.
Comparisons of obstetrical and neonatal outcomes between the pretreatment and control groups
| Demographics |
Singleton birth |
Twin birth |
||||
|---|---|---|---|---|---|---|
| Obstetrical outcomes | Pretreatment (n=59) |
Control (n=80) |
P value | Pretreatment (n=26) |
Control (n=12) |
P value |
| PROM | 10 (16.9%) | 8 (10.0%) | .23 | 2 (7.7%) | 2 (16.67%) | .58 |
| PPROM | 3 (5.1%) | 3 (3.8%) | .70 | 2 (7.7%) | 2 (16.67%) | .58 |
| GDM | 8 (13.6%) | 12 (15.0%) | .81 | 5 (19.2%) | 4 (33.3%) | .42 |
| HDP | 9 (15.3%) | 6 (7.5%) | .15 | 2 (7.7%) | 0 | .46 |
| Placenta abruption | 1(1.7%) | 0 | .42 | 0 | 0 | — |
| Placenta previa | 0 | 2 (2.5%) | .22 | 1 (3.85%) | 0 | .68 |
| Oligohydramnios | 2 (3.4%) | 4 (5.0%) | .64 | 0 | 0 | — |
| ICP | 1 (1.7%) | 0 | .42 | 1 (3.85%) | 0 | .68 |
| Cesarean delivery | 41 (69.5%) | 61 (76.2%) | .37 | 26 (100%) | 11 (91.6%) | .32 |
| Total obstetrical complications | 24 (40.6%) | 27 (33.7%) | .40 | 11 (42.3%) | 6 (50.0%) | .66 |
| Singleton birth newborn |
Twin birth newborn |
|||||
|---|---|---|---|---|---|---|
| Neonatal outcomes | Pretreatment (n=59) |
Control (n=80) |
P value | Pretreatment (n=52) |
Control (n=24) |
P value |
| Gestational week of delivery | 38 (38–40) | 39 (38–39) | .98 | 36 (34–37) | 36 (34–37) | .65 |
| Birthweight (g) | 3200 (2950–3500) | 3350 (3000–3570) |
.091 | 2480 (2120–2800) |
2500 (2025–2960) |
.98 |
| PTB, n (%) | 4 (6.78) | 9 (11.3) | .37 | 38 (73.1) | 16 (66.7) | .57 |
| VPTB, n (%) | 0 | 0 | — | 2 (3.9) | 0 | .33 |
| LBW, n (%) | 6 (10.2) | 1 (1.3) | 0.042 | 26 (50.0) | 13 (54.2) | .74 |
| VLBW, n (%) | 0 | 0 | — | 2 (3.9) | 0 | .33 |
| Macrosomia, n (%) | 3 (5.1) | 4 (5.0) | .98 | 0 | 0 | — |
| SGA, n (%) | 3 (5.1) | 1 (1.3) | .18 | 8 (15.4) | 3 (12.5) | .52 |
| LGA, n (%) | 4 (6.8) | 14 (17.5) | .063 | 14 (26.9) | 3 (12.5) | .24 |
| Birth defect, n (%) | 0 | 1 (1.3) | .39 | 1 (1.9) | 0 | .49 |
| Total neonatal complications, n (%) | 12 (20.6) | 22 (27.5) | .33 | 42 (80.7) | 17 (70.8) | .33 |
Data are presented as median (interquartile range) or number (percentage) unless otherwise indicated.
GDM, gestational diabetes mellitus; HDP, hypertensive disorders of pregnancy; ICP, intrahepatic cholestasis of pregnancy; PTB, preterm birth; VPTB, very preterm birth; LBW, low birthweight; VLBW, very low birthweight; LGA, large for gestational age; SGA, small for gestational age.
Table 3.
Relative ratios of obstetrical and neonatal outcomes for the gonadotropin-releasing hormone agonist pretreatment group in comparison with the control group
| Outcome | Singleton birth |
Twin birth |
||||
|---|---|---|---|---|---|---|
| Relative ratio | 95% CI | P value | Relative ratio | 95% CI | P value | |
| Total obstetrical complications | 1.21 | 0.56–2.62 | .57 | 0.70 | 0.14–3.58 | .67 |
| HDP | 1.53 | 0.31–7.56 | .60 | 0.99 | 0.78–1.33 | .91 |
| Total neonatal complications | 0.60 | 0.20–1.26 | .14 | 1.56 | 0.36–6.72 | .55 |
| LBW | 3.85 | 1.31–7.11 | .024 | 1.74 | 0.43–7.07 | .44 |
| LGA | 0.38 | 0.11–1.32 | .13 | 2.07 | 0.42–10.11 | .37 |
| Total obstetrical and/or neonatal complications | 1.13 | 0.53–2.39 | .75 | 2.17 | 0.17–25.4 | .54 |
Data are presented as median (interquartile range) or number (percentage) unless otherwise indicated.
CI, confidence interval; HDP, hypertensive disorders of pregnancy; LBW, low birthweight; LGA, large for gestational age.
Jie. Obstetrical outcomes of programmed frozen embryo transfer with or without gonadotropin-releasing hormone agonist pretreatment for polycystic ovary syndrome. Am J Obstet Gynecol Glob Rep 2023.
Comment
Principal findings
This prospective study compared the obstetrical and neonatal outcomes of women with PCOS following programmed FET with or without GnRH-a pretreatment. Obstetrical outcomes following these 2 endometrial preparation methods were comparable for both singleton and twin pregnancies. However, programmed FET with GnRH-a pretreatment was associated with a significantly higher risk of delivering LBW singleton neonates than FET cycles without GnRH-a pretreatment.
Meaning of the findings related to other studies
Assisted reproductive medicine technologies must not only increase the chance of live births for infertile women but must do so with minimal risk of obstetrical and neonatal complications, and recent studies have suggested that the endometrial preparation method can influence these risks. For instance, a large-scale analysis of a national database by Ernstad and colleagues4 reported that programmed cycles increased the risks of HDP and macrosomia when compared with natural cycles, and these findings have since been verified by several retrospective studies and meta-analyses.3, 4, 5, 6 It is speculated that programmed cycles do not generate sufficient levels of vasoactive corpus luteal factors, such as relaxin, which could impair maternal cardiovascular adaptation during pregnancy and lead to the development of hypertension.3, 4, 5, 6 Gu et al,6 for example, compared both programmed cycles with and cycles without GnRH-a pretreatment with natural cycles in the Chinese population and found a higher incidence of preeclampsia following GnRH-a pretreatment.
PCOS is a strong independent risk factor for several maternal and neonatal complications, including HDP, GDM, preterm birth, LBW, and LGA.7,8 However, most previous studies that evaluated the effect of different endometrium preparation methods on maternal and neonatal outcomes have excluded anovulatory patients (eg, women with PCOS). Because HRT cycles may not induce sufficient production of vasoactive corpus luteal factors and thus further exacerbate the risk of adverse outcomes among women with PCOS, stimulated cycles could be an alternative method to FET cycles. Two retrospective studies14,15 compared the obstetrical outcomes after stimulated FET and HRT FET among women with PCOS and found a lower HDP risk following stimulated cycles but similar risks of neonatal complications among singletons. Thus, stimulation protocols are a reasonable choice to simulate natural cycles in anovulatory females such as patients with PCOS. However, HRT programmed cycles are still used more frequently for anovulatory patients because of the convenient scheduling and significantly lower risk for cycle cancellation. Therefore, the impacts of GnRH-a pretreatment before HRT programmed cycles on maternal and neonatal complications require further investigation. In a retrospective study, Liu et al16 reported a higher risk for PTB after programmed FET with GnRH-a pretreatment among women with PCOS, but other important complications were not reported. A retrospective study using propensity score matching by Wang and colleagues17 found a higher risk for SGA singleton birth following GnRH-a pretreatment cycles when compared with cycles without pretreatment for women with PCOS. In addition, all previous studies on the obstetrical and neonatal complications among women with PCOS have been retrospective and observational and included only singleton pregnancies. Thus, prospective studies including twin pregnancies are still required.
Our data confirmed the results of previous retrospective studies showing that maternal complications were comparable between stimulation methods for both singleton and twin pregnancies. However, GnRH-a pretreatment for programmed FET cycles increased the chances of LBW singleton deliveries, even after adjusting for maternal age, gestational age, neonate sex, and other important variables related to infertility. This result is in accordance with the findings of Wang et al17 who showed an increased risk for SGA in the GnRH-a pretreatment group. Twin pregnancies were associated with significantly higher risks of both maternal and neonatal complications, but the total prevalence was similar between the groups for twin pregnancies.
Clinical and research implications
In our previous RCT, no significant difference in the live birth rate was reported following endometrium preparation with or without GnRH-a pretreatment but significantly increased costs per live birth was associated with GnRH-a pretreatment.10 As an important supplement, the present data provided multiple final outcomes, including maternal and neonatal complications, and revealed a significantly increased risk for LBW singleton births following GnRH-a pretreatment. Therefore, our findings provide further information to guide method selection for patients with PCOS. As one of the most convenient and promising methods of programmed endometrium preparation, HRT cycles with GnRH-a pretreatment is still a feasible approach. However, because the live birth rate is not increased but the risks of neonatal complications and costs are higher, GnRH-a pretreatment before HRT cycles seems to be unnecessary and unwarranted for patients with PCOS.
Consistent with previous studies comparing HRT cycles with or without GnRH-a pretreatment in both PCOS populations and ovulatory patients, the risk of complications seemed to be higher after pituitary down-regulation by GnRH-a.3, 4, 5, 6,16,17 The underlying mechanism cannot be explained by a deficiency in vasoactive corpus luteal factors. The most important difference between endometrial preparation with or without GnRH-a pretreatment could be the lower level of estrogen caused by pituitary down-regulation following GnRH-a administration. Indeed, estradiol exposure duration was comparable but peak estradiol was lower before progesterone administration in the GnRH-a pretreatment group. However, the direct relationship between estradiol exposure during FET cycles and the subsequent neonatal outcomes remains uncertain. It has been reported that estrogen deficiency may slow angiogenesis and vasculogenesis.18 Estrogen may also participate in trophoblast development and placental vascular cell proliferation, which are critical for expansion of the maternofetal contact surface and promotion of uterine myocyte proliferation.19,20 Studies on fresh IVF cycles have reported that supraphysiological estradiol level during ovarian stimulation can increase LBW risk.21,22 However, the estradiol level reported to affect neonate birthweight is much higher during ovarian hyperstimulation cycles than HRT cycles and the differences in estradiol level between cycles with and without pituitary down-regulation are not that remarkable. Therefore, the underlying mechanisms require further study.
Strengths and limitations
The greatest strength of this study was the design. Randomization ensured comparability between the GnRH-a pretreatment and no pretreatment groups. Moreover, obstetrical and neonatal outcomes were prospectively collected and retrospectively confirmed through the patients’ medical records after completion of the RCT. Outcomes of twin pregnancies were also provided. However, the study design also presented limitations. Because the original study was designed to compare the live birth rate as the primary endpoint, the sample size was limited in comparison of individual obstetrical and neonatal complications. There were also absolute differences in some outcome measurements, such as HDP, preterm birth, and LGA among singletons, but statistical analysis failed to reach significant levels because of the limited case numbers. Furthermore, some differences may have been missed, especially for twin pregnancies, because of the limited case numbers. However, the results of this study can be included in a future meta-analysis to obtain further validation. Finally, the study was conducted at a single center in China, which may limit the generalizability of our findings to other ethnic groups.
Conclusion
This RCT expands our current knowledge on the benefits and risks of programmed FET cycles for women with PCOS by revealing that programmed FET with GnRH-a pretreatment may increase the risk of LBW singleton neonates. Further prospective randomized studies with larger sample sizes are needed to verify our results. We conclude that careful protocol selection is critical for successful assisted reproduction among women with PCOS and other populations more vulnerable to pregnancy-related complications.
Acknowledgments
We thank all the investigators and women who participated in this study.
Footnotes
H.J. and R.H. contributed equally and share first authorship.
The authors report no conflict of interest.
This study received funding from the National Natural Science Foundation of China under grant numbers 81871159 and 81701403.
All the participants gave their written informed consent.
Cite this as: Jie H, Hu R, Zhang L, et al. Obstetrical and neonatal outcomes after programmed frozen embryo transfer with or without gonadotropin-releasing hormone agonist for polycystic ovary syndrome: secondary analysis results from a randomized controlled trial. Am J Obstet Gynecol Glob Rep 2023;XX:x.ex–x.ex.
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