As the use of IVF increases and newer technologies continue to push the boundaries of science, it is important to consider the clinical safety of these approaches. Through this retrospective, hospital-based cohort study of pregnant Chinese women, we verified that infertility etiologies within the IVF population were found to affect maternal and neonatal outcomes among all births. Among singleton pregnancies, compared with spontaneous pregnancies, IVF pregnancies with ovulation disorders have higher risks of adverse pregnancy and perinatal outcomes. The rates of the following were significantly increased: GDM (1.8-fold), preeclampsia (4.5-fold), postpartum hemorrhage (1.6-fold), pPROM (2.1-fold), and preterm birth (2-fold), while IVF pregnancies with male infertility have lower risks of adverse pregnancy and perinatal outcomes.
Our study shows that ovulation disorders were associated with higher risks of many pregnancy and neonatal complications. The results are consistent with prior studies[13, 28, 29]. One possible explanation is that a high proportion of women with ovulation disorders have polycystic ovarian syndrome (PCOS), and many of them have multiple metabolic abnormalities. Growing evidence demonstrates that PCOS has a negative impact on fertility and pregnancy outcomes, such as GDM, gestational hypertensive disorders, and PB. GDM is evidently related to the delivery of an infant with macrosomia, so the incidence of macrosomia is significantly higher for pregnant women with PCOS. In addition, neonates of women with PCOS are at greater risk of neonatal complications, including perinatal mortality, prematurity, SGA, lower birth weight and higher NICU admission. Current evidence also suggests that prepregnancy hormonal dysfunction, including hyperandrogenism, progesterone resistance and hyperinsulinism, impairs uterine placentation mechanisms, which may lead to a greater risk of adverse obstetric and neonatal outcomes.
In our study, compared with spontaneous pregnancies, IVF pregnancies in patients who had tubal infertility had increased risks of GDM, placenta previa, placenta accreta, postpartum hemorrhage, macrosomia, and a 5-minute Apgar score ≤7. One study reported that infertility, particularly due to an ovulatory disorder or tubal blockage, was associated with an increased GDM risk; specifically, women with a history of infertility due to tubal blockage had an 83% greater risk, consistent with our results. GDM is closely related to the birth of an infant with macrosomia; therefore, the rate of macrosomia in tubal infertility is also significantly increased. Tubal-factor infertility is always associated with reproductive inflammation, which may lead to an imbalance in immune-endocrine crosstalk among the endometrium, myometrium and cervix and between the decidua and trophoblasts, predisposing patients to pregnancy complications, such as placenta previa, placenta accreta and postpartum hemorrhage, which could affect neonatal outcomes.
Our data showed that endometriosis was significantly associated with placenta previa, SGA, and NICU admission, similar to the findings of previous studies[33-36]. Endometriosis is a common reason for infertility and may cause chronic inflammation and adhesions in the pelvis of reproductive-aged women. Moreover, women with endometriosis exhibit defective deep placentation because of defective remodeling of the spiral arteries. These factors may explain why endometriosis is possibly a crucial factor for increased negative outcomes in IVF pregnancy. However, Benaglia L found that women with endometriosis who conceived via IVF do not face an increased risk of preterm birth, similar to our findings. In addition, we found that IVF pregnancies in patients with endometriosis had a higher rate of macrosomia (2-fold) than those who conceived naturally. Regrettably, we have not found any literature on the relationship between endometriosis and macrosomia. This controversial result still needs to be further studied by expanding the sample size.
In the male infertility subgroup, the rates of placenta previa and placenta accreta were also increased, but this has not been universally reported. One possible explanation is that the increased risks of placenta previa and placenta accreta are caused by factors related to IVF[39, 40]. Indeed, the intrauterine operation and manipulation of embryonic cells in IVF might induce uterine contraction, leading to higher frequencies of implantation in the lower uterine segment, which may increase the risk of placenta previa. The changes to the endometrium wrought by IVF treatment protocols, and the use of hormone therapy to promote embryo implantation, may increase the risk of placenta accreta. In this research, the risk of placenta previa increased in all subgroups except for the ovarian disorder subgroup, which was similar to previous research. Interestingly, there were no significant differences in neonatal outcomes between IVF and spontaneous conception in the male infertility subgroup. Vannuccini S found that in uncomplicated term pregnancies following ART, infants born after ART had similar birthweights, Apgar scores and arterial blood pH values as those of spontaneously conceived infants. These findings might indicate that the factors associated with infertility are more likely to be associated with adverse neonatal complications rather than the ART procedure itself, which is consistent with a previous study. Overall, the results require further analysis in larger cohorts, adjustments for as many confounders as possible and further preclinical studies.
Our study also showed increased risks for GDM, placenta previa, chorioamnionitis, PB, and a 1-minute Apgar score ≤7 in the mixed infertility subgroup compared with corresponding controls. When there are mixed reasons for parental infertility, pregnancy complications and parental and neonatal outcomes might differ, but perinatal morbidities will always increase. In addition, in twins, the differences in perinatal and neonatal outcomes between IVF pregnancies and natural pregnancies mostly narrowed or disappeared, which may indicate that pregnancy outcomes are greatly affected by multiple pregnancies, regardless of whether they are IVF or natural pregnancies. This finding may also be the result of the small number of cases.
The major strength of our study is the assessment of different infertility etiology on maternal characteristics and pregnancy outcomes in China. China has abolished the “one child” policy, and, since 2016, it has entered into the two-child policy era. As a result, the number of infants is expected to increase greatly, which may promote the demand for IVF. Our findings have extremely important clinical implications and may provide guidance for couples and obstetricians in determining whether IVF is useful as a first-line treatment or as a last resort. Moreover, these findings may help in identifying likely perinatal and neonatal complications relating to different infertility etiologies and provide information for the underlying pathogenic mechanisms.
However, there are a few limitations of this study. First, the numbers of stillbirths and neonatal deaths were few; hence, these figures were not included in the main analysis, which may have given rise to the possibility of residual confounding in our results. Therefore, we could not accurately determine the severity of the effects of different infertility diagnoses on neonatal outcomes, nor could we identify the high-risk factors related to the long-term prognosis of the newborn. Another gap in the data that were available was the severity and treatment process of infertility. For example, data on the stage of endometriosis, baseline endocrine level, body mass index, duration of infertility, and ovarian stimulation protocol were incomplete. Although the IVF-ET method in our research was only frozen-embryo transfer, the data include both blastocyst and cleavage-stage embryo transfer. Additionally, each number of blastocysts and cleavage-stage embryos transferred was unknown, which would introduce bias in our results. Additionally, since the perinatal period starts at 28 complete weeks in China, the records of infants born before 28 weeks of gestational age are relatively incomplete. Therefore, only gestational ages above 28 weeks are included in this research. As a result, the exclusion of preterm birth between 24 and 28 weeks may lead to a reduction in the prevalence of PTB. In addition, we excluded unknown infertility diagnosis in the methods. Because of the substantial number of excluded cycles, those excluded due to unknown cause of infertility may introduce bias in the results. Moreover, we lack specific BMI data and have only data on prepregnancy obesity (BMI ≥28 kg/m2), which means higher BMI. Therefore, we could not add BMI as a continuous variable in the study groups. Finally, some information about environmental exposure (educational level, income level) was not included in this study, which may lead to bias. Further studies, particularly systematic reviews of observational studies such as the current study and prospective studies with adjustments for important confounders, will be required to confirm these initial findings.