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, diagnostic categories within the ART population were found to affect maternal and neonatal outcomes among all births. As summarized in Table 4 and Table 5, infertility caused by an ovulation disorder had the worst prognosis. In fact, ovulation disorders were associated with higher risks of preeclampsia (3-fold), GDM (2-fold), pPROM (2-fold), postpartum haemorrhage (2-fold), PB (2-fold), low birthweight (2-fold), macrosomia (1.5-fold), and NICU admission (2-fold), which is consistent with prior studies[12, 27, 28]. 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 pre-pregnancy 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.
Compared to spontaneous pregnancies, ART pregnancies in patients who had tubal infertility had an increased risk of GDM (1.5-fold), placenta previa (3-fold), placenta accreta (2-fold), postpartum haemorrhage (2-fold), macrosomia (2-fold), and a 5-minute Apgar score≤7 (4-fold). 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, so 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 haemorrhage, 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[32-35]. 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 remodelling of the spiral arteries. These factors may explain why endometriosis is possibly a crucial factor for increased negative outcomes in ART pregnancy. However, Benaglia L found that women with endometriosis who conceived via in vitro fertilization (IVF) do not face an increased risk of preterm birth, similar to our finding. In addition, we found that ART 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 risk of placenta previa and placenta accreta is caused by factors related to ART[38, 39]. 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, 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 ART and spontaneous conception in the male infertility subgroup. Vannuccini S found that in uncomplicated term pregnancies following ART, infants born after ART had a similar birthweight, Apgar score and arterial blood pH to those of spontaneously conceived infants. This finding 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 an increased risk 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 gemellary pregnancies, the differences in perinatal and neonatal outcomes between ART pregnancies and natural pregnancies mostly narrowed or disappeared. This may indicate that pregnancy outcomes are greatly affected by multiple pregnancies, regardless of whether they are ART pregnancies or natural pregnancies. This finding may also be the result of a small number of cases.
The major strength of our study is not only the comparison of perinatal and neonatal outcomes of ART and spontaneous conception but also the assessment of the impact of different infertility diagnosis on pregnancy characteristics and outcomes in China. China has abolished the “one child” policy, and since 2016, it 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 extremely 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 provide information for the underlying pathogenic mechanisms.
There are, however, 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 diagnosis on neonatal outcomes, nor can 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. In addition, 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.