In recent years, more researchers suggested a freeze-all strategy [14–16]. Compared with fresh embryo transfer, the hormone levels in FET cycle were more comparable to those in natural cycle, and thus was supposed to establish a better intrauterine environment. Yet, it was well accepted that the long-term safety of FET was still to be elucidated due to the additional unphysical exposures to the embryo. Our sibling study indicated that the “frozen babies” show vigorous growth in both the neonatal period and early childhood. The neonates born from FET suffered higher odds of LGA, and still had higher z-score of length several years after.
The adverse perinatal outcomes caused by abnormal peri-implantation environment following superovulation can be minimized by transferring frozen embryos[1, 12, 17, 18]. Two previous studies have evaluated the association between frozen embryo transfer and birthweight in siblings. One large cohort study from Danish found that birthweight of children born after FET were 167 g (95% confidence interval 95% CI, 90–244] higher than siblings born after fresh embryo transfer [12]. Another Danish study found the adjusted ORs of LGA and macrosomia in singletons conceived after FET were 1.34 [95% (95% CI) 0.98–1.80] and 1.91 (95% CI 1.40–2.62) compared with singletons conceived after Fresh embryo transfer [6]. Our data showed consisted results in birth weight and LGA risk.
The reason of increased risk of LGA after frozen embryo transfer are not fully understood. Possible reasons include supraphysiological hormone levels during fresh embryo transfer, adverse stress reactions caused by temperature or chemical stimulation during frozen process. A retrospective cohort study conducted in siblings born after women undergoing oocyte donation found that there was no difference in birthweights between fetus obtained after fresh embryo or frozen embryo transfers [19]. The result indicated that supraphysiological hormone levels during fresh embryo transfer may affect fetus growth in uterine. Besides, animal studies showed that freezing and thawing procedures may affect methylation of the early embryo, which may alter intrauterine growth of FET offspring [20, 21].
Several studies reported that there were no differences in child anthropometrics between children born after fertility treatment and spontaneously conceived children [22–24]. In contrast, other studies found that differences in birthweight persisted into childhood. One cohort study conducted in Finland showed that weight was lower in children born after IVF compared with general population at 1, 2 and 3 years of age [25]. Another study reported that children born after fresh embryo transfer were taller than children conceived after frozen embryo transfer and conceived spontaneously at 6 years of age [9]. Studies focusing on the childhood growth of children born after frozen IVF cycles were rare. Still, it remains unknown whether higher birthweight in children born after frozen embryo transfer persists later in childhood.
Consistent with our findings, one study showed that an increased height at 12 months of postnatal life was observed in singletons born after FET compared to those born after fresh embryo transfer [26]. Previous studies found that high birth weight was associated with increased risks of childhood obesity [27, 28] and metabolic diseases [29, 30]. Obesity of children was a predictor of metabolic disease in adults[31]. Increased metabolic risk in children born after frozen embryo transfer is of importance for individuals as well as for the whole society.
The major strength of our study is the ability to identify sibling pairs to evaluate the effect of frozen embryo transfer on the growth of offspring within families. There are also some limitations. First, we had no information on the difference of parental BMI before pregnancy. We could not account for the impact of a potential change in parental BMI in the second birth. Second, the percentage of male was significantly higher in singleton born from frozen cycles. This was caused by China culture background and government policy. Thus, we did sensitive analysis in women conceived children with same sex in two groups. The results showed the prevalence of LGA was also higher in FET group. Third, more women transferred blastocyst in FET group than fresh embryo group. The sensitive analysis was conducted in women transferred same stage of embryos in two groups. The results were consistent. Forth, considering maternal age, parity may be associated with the prevalence of LGA, we divided our population into two groups (Fresh/FET group and FET/Fresh group). The prevalence of LGA was also higher in newborns conceived by FET in two groups. Last, the prevalence of LGA was significantly higher in FET group in women undergoing natural ovulation cycle or ovarian stimulation cycle, while not in women undergoing programmed cycle. Previous studies reported that uterine artery Doppler studies in pregnancies from frozen-thawed blastocysts with absent corpus luteum present lower uterine artery pulsatility index as compared to fresh group [32]. Considering the limited sample size, this result needed to be confirmed in future studies.