In this study, glucose and lipid metabolism, perinatal outcomes and neonatal characteristics in mother with gestational diabetes mellitus were compared according to fetal sex. The insulin function and neonatal characteristics were different between two groups, whereas lipid shown no difference between two groups. These results support the concept of the bi-directional maternal–fetal metabolic interplay, showing that the mother and the fetus mutually influence the metabolism of the other, and the degree of being influence was related to fetal sex.
Previous studies in perinatal database had shown that there may be an association between fetal sex and maternal glucose metabolism. A systematic review and meta-analysis including twenty studies and 2,402,643 pregnant women, showed women carrying a male fetus had a 4% higher relative risk of GDM compared with those carrying a female fetus[21]. Retnakaran et al.[22] also found the male fetus was an individual risk factor for GDM, and β-cell function was lower in women carrying a boy. Geng et al. [13] reviewed that HOMA-β was lower in pregnant women carrying male fetus without GDM, which was similar to the present result GDM. They also found the maternal fasting glucose in male group was higher. In the present study, β-cell function was lower with significant difference, and both 50g GCT and fasting glucose were higher in women carrying the male fetus, but there was no significantly difference. These results indicated male fetus leading to maternal β-cell function declined was still in an early stage, and glucose metabolism can still be compensated without appearing worse blood glucose. On the contrary, a retrospective cohort study in Japanese population[15] did not found the difference of β cell function in pregnant women during second trimester according to fetal sex, but the HOMA-IR was higher and the insulin sensitivity index derived from the oral glucose tolerance test (IsI OGTT) was lower in women carrying female fetus. Xiao et al.[23] also found the female sex may be associated with higher maternal insulin resistance. These results may be caused by the difference in the sample size.
The mechanism of this phenomena was still unclear. Several studies had reported sex hormone binding globulin (SHGB) decreased in GDM, including maternal peripheral blood and placenta[24–28], and it increased the risk of type 2 diabetes mellitus(T2DM) [29]. The concentration of SHGB was strongly associated with markers of insulin resistance, insulin sensitivity as well as insulin and glycemic responses to oral glucose in pregnant women[30]. But androgen suppress SHGB secretion[28], which can partly explained the lower β-cell function in women carrying male fetus. Although the mechanism was unclear, the women delivered a boy should pay more attention on the glucose monitoring to decrease the risks of T2DM in the future.
Though we did not find any significant difference of lipid between two groups, women carrying a male fetus had a lower LDL-C. Rafferty et al.[14] did not find the impact of fetal sex neither on insulin resistance nor on lipid metabolism, which was similar to the present study. Previous studies showed estrogen was good for lipid metabolism whereas androgen was a risk factor under physiological state[31]. The androgen concentration was higher in women carrying a male fetus, which may lead to a higher LDL-C theoretically. However, the present study showed an inconsistent result. One of the possible reason was the pregnancy with GDM causes a complex metabolic status, including the state of placenta, which may influence the lipid metabolism. However, this changing trend of LDL-C between two groups must be interpreted with caution.
Some previous studies reported carrying male fetus was an individually risk factors for adverse perinatal outcomes[32]. They summarized the previous studies, finding male fetus responded to the adverse maternal environment by a negative approach with few gene, protein or functional changes in the placenta. This kind of strategy may lead to some adverse events during pregnancy of women carrying male fetus. But in this study, we did not find difference in premature delivery, PROM, polyhydramnios or oligohydramnios, FIUR, PIH, neonatal hypoglycemia or neonatal hypoglycemia. There was no difference in the maternal baseline characteristics between women carrying female fetus or male fetus, and all patients in this study were managed in the same endocrinology medical team after being diagnosed GDM, with the same blood glucose control criteria and diet guide. However, the male infants were larger in birth weight and length, and had a higher percentage of LGA, which was similar to the previous studies. The differences of infant birth weight and length between fetal sex can be explained by sex hormone. Male fetus [33] can get the first testosterone surge at around 8–24 weeks’ gestation, leading to a higher growth rate. SHGB[34] was a significant predictor of infant birthweight, and there were negative correlation between them, but androgen can inhibit SHGB[28]. Furthermore, a review proposed the sex differences in growth of the fetus were mediated by the sex specific function of the human placenta[35], which may also explain this result.
LGA was more likely to get metabolism disorders in the future. In consideration of the higher percentage of LGA in male fetus, we analyzed the risk factors in women carrying male fetus. In GDM, a higher amount of blood glucose passes through the placenta into the fetal circulation and as a result, extra glucose in the fetus was stored as body fat causing LGA[36]. In this study, we found the higher fasting glucose in second trimester made a great contribution to LGA. HLD-C in LGA groups was also significantly lower, but it played less important role than fasting glucose according to analysis of binary logistic regression. Although HAPO study showed the relationship between second-trimester glucose and pregnancy complications was a continuous variable[37],we suggested patients whose fasting glucose was higher than 5.25mmol/L should be more careful, and earlier diagnosis of GDM and management may be better for both mother and infant, especially in women carrying male fetus.
There are some limitations in the present study. First, maternal insulin resistance and β-cell function were not evaluated by the hyperinsulinemic–euglycemic clamp, which was the gold standard of them. Second, the study was only conducted during the second of pregnancy in a small sample size. Larger studies throughout the whole pregnancy are necessary for the validation of our findings. However, the patients in this retrospective cohort study were under the management of a specific medical team during the whole gestation period. Thus, the heterogeneity in the present study was small and the results were reliable.