Although we did not find any association between the fetal sex and the prevalence of GDM in the mothers in this retrospective study, we demonstrated that—during mid- and late pregnancy—women carrying a female fetus had higher insulin resistance, after adjustment for the considerable confounders.
Di Renzo et al. [2] reviewed the association between fetal sex and pregnancy outcomes and described that maternal GDM and fetal macrosomia more frequently occurred as complications in women carrying a male fetus than those carrying a female fetus. In a systematic review and meta-analysis of observation studies to investigate whether the maternal risk of GDM was associated with fetal sex differences [11], the authors concluded that pregnant women carrying a boy have a 4% higher relative risk of GDM than those carrying a girl. In contrast, Xiao et al. [5] found no association between the risk of GDM and fetal sex, which is similar to the findings of the present study. Indeed, in the meta-analysis by Jaskolka et al. [11], only 6 of 21 studies showed a significant difference according to the fetal sex. These inconsistent results may be caused by the difference in the sample size. Indeed, In the six studies, with the exception of one study with a small sample size (n = 439), the populations of all of the studies were > 25,000. Racial diversity may also have affected the results in the studies with a small sample size. In our study, despite the small sample size, the study population was homogeneous, because we only included women of Japanese ethnicity. Thus, our study might have had sufficient power to detect statistical significance.
A few studies have reported an association between fetal sex and maternal insulin dynamics. Retnakaran et al. [3] reported that in pregnant women, although the surrogate indices of insulin sensitivity, including HOMA-IR and IsOGTT, did not differ according to the sex of the fetus, the β-cell function, as measured by the insulinogenic index/HOMA-IR, was lower in women carrying a male fetus. More recently, Geng et al. [12] reported that the presence of a male fetus was an independent risk factor for elevated FPG and lower HOMA-β in Chinese mothers with normal glucose tolerance at 24–28 weeks of gestation. However, they did not find any difference in the FIRI and HOMA-IR values of the groups. These two studies [3, 12] concluded that women carrying a male fetus are at risk for abnormal insulin dynamics during pregnancy. On the contrary, similarly to our study, Xiao et al. [5] found that women carrying a female fetus had higher insulin resistance than those carrying a male fetus, and the difference remained significant after adjusting for confounders. Retnakaran et al. [4] investigated the association between fetal sex in women with GDM in their first pregnancy and the risk of recurrence of GDM in their subsequent pregnancy. They found that fetal sex in the first pregnancy did not affect the risk of recurrence in the second pregnancy. Interestingly, however, a female in the first pregnancy was associated with the development of T2DM before the subsequent pregnancy [4].
The mechanism underlying the effects of sex difference in fetus on the maternal glucose and insulin metabolism remains unexplained. The increase in maternal insulin resistance during late mid-pregnancy is a physiological change that reflects normal fetal growth acceleration during the period [13]. Pregnancy-associated hormones and adipokines, including placental lactogen, estrogen, leptin and tumor necrosis factor-α—which are mainly produced by placenta—increase with advancing gestation, especially during mid-pregnancy. These placental products are considered to cause enhanced maternal insulin resistance during mid-pregnancy [14], although the mechanism is not completely understood. Regarding the association between placental products and fetal sex, controversial results have been reported in the literature. It has been reported that mothers carrying a female fetus have higher levels of placental lactogen and estrogen [15, 16], which promote insulin resistance [17–19]. Another study [20] reported that maternal leptin levels were higher in women carrying a female fetus. On the other hand, Retnakaran et al. [3] failed to demonstrate an association between fetal sex and maternal adipokines (including leptin and adiponectin levels) or lipid concentrations (including total cholesterol and triglyceride). From the aspect of genetics, some studies have suggested an association between fetal sex and the maternal glycemic status during pregnancy [21–23]. These studies suggested that interaction between fetal sex and maternal polymorphism in progesterone receptor [21], angiotensin converting enzyme [22], and peroxisome proliferator-activated receptor gamma2 [23] may affect the maternal glycemic status during pregnancy.
The present study was associated with some limitations. First, in addition to the small sample size in the study, we evaluated maternal insulin resistance using surrogate indices, including HOMA-IR, IsOGTT and QUICKI, because of the retrospective study design. Although the euglycemic glucose clamp method is gold standard for the assessment of insulin resistance, HOMA-IR and IsOGTT are considered to be crucially associated with the clamp method results [24]. The application of the clamp method in the clinical setting was impractical in the present study, which included 600 pregnant women. For the same reason, previous investigations [3, 5, 12] also used these surrogate indices. In addition, because of the retrospective study design and the limited sample size, it could not be concluded whether or not fetal sex was associated with maternal β-cell function. Finally, as we excluded women with a negative GCT result from this study, our results may not have reflected those of the whole population of Japanese pregnant women.