As the use of ART 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 ART pregnancies are related to increased risks of pregnancy complications, perinatal complications and poor neonatal outcomes. Furthermore, diagnosis categories within the ART population were found to affect maternal and neonatal outcomes among all births. As summarized in Table 2, infertility caused by ovulation disorder had the worst prognosis. In fact, ovulation disorder was associated with higher risks of preeclampsia (2-fold), GDM (2.06-fold), pPROM (2.10-fold), postpartum hemorrhage (1.48-fold) and chorioamnionitis (2.11-fold), which is consistent with prior studies[5, 8]. One possible explanation is that a high proportion of the women with ovulation disorder 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. Current evidence also suggests that pre-pregnancy hormonal dysfunction, including hyperandrogenism, progesterone resistance and hyperinsulinism, impairs uterine placentation mechanisms, which may lead to a greater risk of adverse obstetric outcomes.
Compared to spontaneous pregnancies, ART pregnancies in patients having tubal infertility had an increased risk of GDM (1.35-fold), placenta previa (2.75-fold), and postpartum hemorrhage (1.57-fold). One study reported that infertility, particularly due to ovulatory disorder and 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. Tubal factor infertility is always associated with reproductive inflammation, which may lead to imbalance in immune-endocrine crosstalk among the endometrium, myometrium and cervix and between the decidua and trophoblast, predisposing toward pregnancy complications, such as placenta previa and postpartum hemorrhage.
Our data showed that endometriosis was significantly associated with placenta previa, similar to the findings of previous studies[12-14]. 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 ART pregnancy.
Interestingly, in the male factor subgroup, the rate of placenta previa was also increased, but this has not been universally reported. One possible explanation is that the increased risk of placenta previa is caused by factors related to ART. Indeed, the intrauterine operation and manipulation of embryonic cells in ART might induce uterine contraction, leading to higher frequencies of implantation in the lower uterine segment and thereby increasing the risk of placenta previa. Therefore, the risk of placenta previa would increase in all subgroups except for ovarian disorder, similar to previous research.
In this retrospective study, we found that PB, LBW and SGA risks were significantly higher in all subgroups of ART. Regarding ART with female factor infertility, the risk of macrosomia increased. This finding might indicate that ART with female abnormality is more likely to be associated with adverse neonatal complications rather than the ART procedure itself, similar to a previous study. Nonetheless, Galit Levi Dunietz et al. assert that preterm birth among ART singletons is increased within each treatment type and all underlying infertility diagnoses, including male infertility, but Benaglia L found that women with endometriosis who conceived via in vitro fertilization(IVF) do not face an increased risk of preterm birth. Overall, the results require further analysis in larger cohorts and control for as many confounders as possible and also further pre-clinical studies.
Our study also showed an increased risk for GDM, placenta previa, chorioamnionitis, and PB in the multiple infertility-related diagnosis sub-group compared with corresponding controls. When there are multiple infertility-related diagnoses for parental infertility, pregnancy complications, parental and neonatal outcomes might differ, but they will always increase perinatal morbidities.
The major strength of our study is not only the comparison of perinatal and neonatal outcomes of ART and spontaneous conception, but also assessment of the impact of different infertility diagnoses on pregnancy characteristics and outcomes in China. China has abolished the “one child ”policy and since 2016 has entered into an era of the two-child policy. As a result, the number of infants is expected to increase greatly, which may promote the demand for ART. Our findings have significantly important clinical implications and may provide guidance for couples and obstetricians in determining whether ART is useful as a first-line treatment or as a last resort. Moreover, these findings may help in identifying likely perinatal and neonatal complications and providing information for the underlying pathogenic mechanisms.
There are, however, a few limitations of this study. First, information about environmental exposure and risk behaviors (alcohol, tobacco use, educational level, income level) were not be included in this study, which may lead to bias. Another gap in the data that were available was the severity and treatment process of infertility. For example, the stage of endometriosis, baseline endocrine level and ovarian stimulation protocol were incomplete. Finally, this study represents results from a high-level specialty hospital in China, which may not be representative for other countries.