Our findings are consistent with the pre-existing meta-analysis[3, 29] and retrospective studies[30, 31] published until 2018 showing that singletons born after FET have higher birth weight and higher gestational age at birth but a higher risk of hypertensive disorders of pregnancy, while singletons born after fresh ET tend to have a higher risk of preterm birth and low birthweight. However, our single-center singleton study showed that compared to those born after fresh ET, singletons born after FET had higher birth weight but not increased LGA. The birthweight difference was also not associated with maternal BW and BMI before pregnancy or during labor, maternal BW gained after the second trimester, and total BW gained during pregnancy. Furthermore, the birth weight increase in our FET subgroup seems favorable due to a lower frequency of preterm birth and no increase in the proportion of births with LGA or macrosomia. When the second- and third-trimester gestational ages by ultrasound measurement were compared with EDD and estimated fetal weight, there were also no significant differences. Thus, the difference in birthweight among singletons born after FET and fresh ET becomes significant in the late third trimester. The main reason is that singletons conceived from FET were at a lower relative risk of preterm delivery and had greater gestational age at birth.
The absolute sequence of events that trigger and sustain human parturition has not yet been fully clarified. However, there are several factors involved in the initiation of human parturition. Placental corticotropin-releasing hormone production seems to serve as a placental clock that might be set to ring earlier or later, determining the duration of pregnancy and timing of labor. In addition, infection and microbe invasion resulting in chorioamnionitis also represents a common cause of early preterm labor.
In a mouse model, ART treatment can disturb mouse placental and fetal development during late gestation; ART can result in the own regulation of a majority of placental nutrient transporters and reduce placental efficiency during mid- to late gestation. After humans receive ART, is it possible that fetal weight growth or initiation parturition will only start to make a difference from the second to the third trimester?
A single-center retrospective cohort study compared crown-rump length (CRL) at the first trimester (T1: 11–13 weeks of gestation [WG] + 6 days) and estimated fetal weight (EFW) at the second (T2: 21–23 WG + 6 days) and third (T3: 31–33 WG + 6 days) trimesters in singleton pregnancies conceived after ICSI, IVF, FET, and IUI. It was found that for all ART fetuses, growth kinetics differed from T2 but became significant at T3. For all ART fetuses, the ultrasounds of CRL at T1 and EFW at T2 were significantly higher than the reference curves. However, only FET singletons remained to have a greater EFW above the reference curve at T3. The EFW of ICSI, IVF, and IUI dropped below the reference curves at T3, indicating a higher proportion of decelerated growth from the second trimester than among those in the FET group. Our study did not find a difference in T3. Besharati et al. also examined fetal growth trajectories following infertility treatment and suggested no significant differences in fetal growth of fresh ET and FET conception.
It is possible that imprinted genes may also play a role in the regulation of placental development and the control of nutrient transporter expression, and, in this way, they may also indirectly control fetal growth, development or parturition. Some studies claim that both ovulation induction and embryo vitrification may disrupt genomic imprinting by interfering with imprinting maintenance during preimplantation[37, 38]. Loss of imprinting caused by embryo manipulations was also found in mid-gestation extraembryonic tissues in mice[39, 40].
In our singleton study, the mean birth weight was 134 g heavier in the FET group than in the fresh ET group. A similar result was also observed for the different delivery methods: 133 g heavier in the FET/NSD group and 128 g heavier in the FET/CS group. These findings were consistent with those previously published in the literature. Multiple studies[41, 42] have found that newborns born after FET have higher birthweight than do newborns born in controlled groups or their siblings born after fresh ET. The differences in birthweight were reported to be 50 ~ 250 g greater among those born after FET than among those born after fresh ET: 50 g in China , 91 ~ 100 g in Japan[16, 43], 133 g in a Nordic cohort study, 145 g in Australia and New Zealand, 162 g in France, 166 g in the United States , 191 g in Spain and 167 ~ 250 g in Denmark[11, 47, 48]. Interestingly, the reports of weight differences in Asia are lower than those in European and American countries.
Judging from our research, the increase in the birth weight of fetuses in FET cycles should not be viewed as negative, but the risk of the main complication, namely, preeclampsia, is still high, and this issue cannot be ignored because it is reflected in our data. Multiple studies have reported an increased risk of pregnancy-induced hypertension or preeclampsia in women conceiving by IVF with frozen embryo transfer (FET) [3, 4, 49–51]. A possible explanation for the increased risk of preeclampsia is related to the absence of the corpus luteum and the use of endometrial priming with estrogens performed during artificial FET cycles [50, 52].
One strength of our study is the large sample size (784 live singleton births) in comparison to that of other single-center studies. Most of the included cases received prenatal care and were delivered at our hospital. Thus, the data for second- and third-trimester ultrasound, perinatal maternal body weight and BMI, and maternal and neonatal outcomes were well recorded. We also took into account factors that are known to influence fetal weight, such as fetal sex, maternal age, weight, and GDM, although no significant differences in these factors were observed between the FET and fresh ET groups. To our knowledge, only one study has analyzed fetal growth by reproductive method in the second and third trimesters using ultrasound measurements. The limitations include the fact that this study uses retrospective data, which are not as rigorously controlled as data collected for a prospective research study. Although the study was conducted in a single center, the embryo transfer was performed by different operators, the stimulation protocols were slightly different, some data were missing, and some patients did not return for follow-up after embryo transfer, so we could contact participants only by telephone for outcomes and associated information. Additionally, the patients in this study were Taiwanese women, so it is necessary to exercise caution when applying our results to other ethnic and racial groups.