Neonatal outcomes of singleton live births with vanishing twin syndrome following double embryos transfer in assisted reproductive technology: a retrospective cohort study

Assisted reproductive technology (ART) is under rapid development since the birth of the first infant through the in-vitro fertilization (IVF) technique. This marked the practice from sophisticated experimental techniques to conventional medical care. However, compared with spontaneous conceptions, ART has a low pregnancy rate, the insufficient embryos and culture techniques. Therefore, clinicians frequently transfer multiple embryos to maximize the chance of pregnancy [1, 2]. Meanwhile, ART has resulted in a dramatically increased incidence of multiple pregnancies over the past 4 decades [3]. Specifically, multiple pregnancies are indicative of an increased risk of preterm birth (PTB) and perinatal death, which are recognized as the adverse outcomes related to the interventions of ART [4, 5]. Some national policies and guidelines usually recommend selective single embryo transfer (SET) for women with favorable prognosis and those aged less than 35–38 years [6, 7]. Typically, SET can markedly reduce the rate of multiple pregnancies following ART [8]. Nowadays, successful outcomes have been increasingly defined as the healthy monocyesis and singleton live births [9, 10]. Yet, we are concerned about the outcomes of single pregnancy throughout the process of pregnancy. So, what is the difference between a single pregnancy with vanishing twin syndrome (VTS) and that without VTS? In 1945, Stoeckel had first proposed the spontaneous reduction of a fetus in a twin pregnancies, which was referred to as the phenomenon of “vanishing twins.” Dickey et al. found that 50% patients who had 3 or more gestational sacs would have spontaneous reductions before the first 12 weeks of pregnancy, and these patients were linked with higher risks of PTB and LBW [11]. It is suggested in one study that, people with spontaneous reduction of the initial multiple pregnancies to a singleton pregnancy were associated with increased risks of adverse prenatal outcomes, such as PTB and LBW, compared with those of singleton live births with SET [12]. In addition, some other studies show that the risk of fetal growth restriction (FGR) with VTS in an early twin pregnancy is elevated relative to that in the initial single pregnancy, and the later occurrence of VTS was related to a higher risk [13]. Nonetheless, no existing study has specially delineated the adverse obstetric outcomes of twin pregnancy with VTS. Therefore, the current retrospective cohort study was carried out to compare the neonatal outcomes in singleton live births between groups with and without VTS following double embryos transfer (DET).

It is discovered in this retrospective cohort study that, for both fresh and frozen cycles, the study groups have increased risks of LBW, PTB, pediatric admission and NICU admission relative to those in control groups. However, no increased risks of SGA or congenital malformation are observed in singleton live births in both the fresh and frozen ART cycles following DET.

This study has provided an important supplement to the existing literature, which confirms that VTS may result in higher risks of LBW, PTB, pediatric admission and NICU admission. Our findings are consistent with the conclusions obtained from previous studies, systematic reviews and meta-analyses. However, no study has recruited infertile couples with only tubal factors or male factor (lean and weak sperm disease). Such a study design is critical and necessary, which may avoid uncontrolled bias. For instance, polycystic ovary syndrome (PCOS) has been recognized as an endocrine disease related to the increased risk of adverse perinatal outcomes [14, 15]. Sharma et al. found that the presence of adenomyosis might contribute to the adverse effects on the IVF outcomes in terms of the clinical pregnancy rate, live birth rate and miscarriage rate [16]. Additionally, Wang LF et al. suggested that pre-pregnancy obesity might result in the high prevalence of macrosomia, which increased the mean BW in cohort analysis [17]. Therefore, it is crucial to recruit the infertile patients with tubal factors and male factors alone, to investigate the differences between the two groups in our study. Also, this study has particularly compared the perinatal outcomes in singleton live births between the groups with initial single sac and initial double sacs following DET. Our results has indicated higher risks of LBW and PTB between patients with and without VTS following DET in both the fresh and frozen cycles. According to an earlier study, compared with single births obtained from SET, PTB and LBT infants are more likely to develop spontaneous reduction in the initial multiple pregnancies to singleton fetuses following transfer of multiple embryos [12]. Almoq. B et al. held that pregnancy with VTS was linked with adverse obstetric outcomes (PTB and LBW) relative to those in the initial singleton pregnancy of IVF [18]. Furthermore, SUN et al. believed that the VTS survivors displayed a higher incidence of LBW than that in singleton fetuses from single pregnancies in IVF-ET [19]. Besides, it is also suggested in previous results that, the early death of a pair of twins may improve the pregnancy outcomes. But there may be more adverse complications when continuing the twin pregnancy [20]. Analysis by Timur H et al. indicated that VTS patients were more likely to develop LBW, very low birthweight (VLBW), intrauterine growth restriction and pre-eclampsia [21‐23]. What’s more, Zhu Y et al. revealed that VTS could affect the obstetric outcomes in survivors, but the impact of VTS was unstable. Yet it is too early to conclude that VTS will produce adverse obstetric outcomes, such a statement may also decrease their anxiety with VTS [24]. Our study shows that the rate of cesarean section is higher in the control group, because of the strong demand of women for cesarean section. Treatment of infertile couples with years of ART has brought about great panic, and these couples are more willing to choose cesarean section instead of facing the uncertainty of delivery, which is quiet common in China. Doctors will also agree with them. Fetal weight is also estimated before delivery, and there are many macrosomia and infants of normal BW, so most women are more willing to choose cesarean section to avoid the risk of huge children .

In this study, there are no statistically significant differences in SGA and congenital malformation between the two groups in both fresh and frozen ART cycles following DET, which may be affected by the strict inclusion criteria. Probably, such results may be caused by the fact that people choose to induce labor when SGA (especially in the case of abnormal chromosome) and congenital malformation are detected in middle pregnancy. Conversely, Luke suggested that the risk of moderate growth restriction in singletons was increased following transfer of multiple embryos relative to that after SET, thus demonstrating a significant adverse effect on the intrauterine growth following the multiple embryos transfer. However, it remains unclear about whether such effect can be ascribed to the compromised embryo quality, degenerated implantation sites, or other factors [25]. Typically, the higher incidence of VTS may account for the possible mechanism affecting the incidence of LBW in the study group. La Sala et al. suggested that VTS induced a deleterious effect on the ongoing pregnancy due to blood shunting from vascular anastomoses in the surviving twin placenta [26]. Besides, we found that after the dead embryo at middle or late pregnancy came out of the uterus, the surviving embryo were born in a short time, which might increase the risk of PTB, reduce the average BW, and elevate the possibilities of pediatrics admission as well as NICU admission. Nonetheless, such event is extremely rare (about 1/1000), which does not make an increase the risk of adverse outcomes. Most VTS occur in early pregnancy (7 weeks to 12 weeks), which is the real dominant factor of adverse outcomes. Additionally, chronic inflammation may account for the other speculation for the impact of VTS on the surviving twin [27]. Regrettably, no explanation is available for such speculation.

Our study finds that singleton live births with VTS have higher risks of LBW, PTB, pediatric admission and NICU admission than those without VTS in both the fresh and frozen cycles, even after adjusting for confounders. However, no increased risks of SGA or congenital malformation are observed in singleton live births in both the fresh and frozen ART cycles following DET.