Abstract
High maternal serum estradiol (E2) levels in the first trimester of pregnancy are associated with a high incidence of low birth weight (LBW) and small for gestational age (SGA). This study aimed to investigate the effect of first-trimester high maternal serum E2 levels on fetal growth and the underlying mechanisms in multiple pregnancies. Maternal serum E2 levels of women at 8 weeks of gestation were measured. The expression levels of imprinted genes and DNMT1 were determined by RT-qPCR, and KvDMR1 methylation in embryo tissue, placenta, and newborn cord blood samples was examined by bisulfite sequencing PCR. The effect of E2 on CDKN1C expression was investigated in HTR8 cells. The incidence of SGA was significantly higher in multiple pregnancies reduced to singleton than that in primary singleton pregnancies (11.4% vs. 2.9%) (P < 0.01) and multiple pregnancies reduced to twins than primary twins (38.5% vs. 27.3%) (P < 0.01). The maternal serum E2 level at 8 weeks of gestation increased with the number of fetuses and was negatively correlated with offspring birth weight. CDKN1C and DNMT1 expression was significantly upregulated in embryo tissue, placenta, and cord blood from multiple pregnancies. Furthermore, there was a positive correlation between CDKN1C mRNA expression and KvDMR1 methylation levels. In HTR8 cells, DNMT1 mediated the estrogen-induced upregulation of CDKN1C, which might contribute to SGA. To minimize the risks of LBW and SGA, our findings suggest that abnormally high maternal serum E2 levels should be avoided during the first trimester of multiple pregnancies from assisted reproductive technology (ART).
Highlights
Studies from diverse human cohorts and animal models have demonstrated that low birth weight (LBW) is a great risk for developing future adult chronic diseases [1, 2]
Our study showed that multiple pregnancies reduced to twins after assisted reproductive technology (ART) treatment were still associated with a higher incidence of LBW and small for gestational age (SGA) than primary twin pregnancies
The incidence of SGA in multiple pregnancies reduced to singletons (11.4%, 12/105) was significantly higher than that to primary singleton pregnancies (2.9%, 6/210) (P < 0.01)
Summary
Studies from diverse human cohorts and animal models have demonstrated that low birth weight (LBW) is a great risk for developing future adult chronic diseases [1, 2]. The maternal intrauterine environment plays a critical role in fetal development and growth. The mechanisms by which an adverse intrauterine environment affects fetal growth are still largely unknown. A multiple gestation pregnancy is a common iatrogenic outcome of assisted reproductive technology (ART) mainly due to ovarian hyperstimulation. Multiple gestation pregnancies have an increased risk of LBW, especially when more than two fetuses are present [4,5,6]. It has been proposed that the reduced intrauterine growth of fetuses results from the constraints imposed by uterine size and a restricted ability of the placenta to support
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