Is There an Association Between Fetal Sex and Common Pregnancy-Induced Pathologies?

  

    
Diagnosis
    
Male    Infant
    
Female    Infant
    
P- Value
  
  

    
Cardiac    anomaly
    
0.76 %
    
1.4 %
    
0.658
  
  

    
Hyperbilirubinemia
    
5.7 %
    
3.8 %
    
0.36
  
  

    
IUGR
    
1.5 %
    
1.9 %
    
0.735
  
  

    
Meconium    aspiration
    
4.5 %
    
5.8 %
    
0.544
  
  

    
Preterm    delivery
    
13.7 %
    
17.4 %
    
0.266
  
  

    
Respiratory    distress Syndrome
    
27.0 %
    
20.3 %
    
0.092
  
  

    
Diabetes
    
12.9 %
    
17.9 %
    
0.14
  
  

    
Sepsis
    
46.9 %
    
46.6 %
    
0.941
  

Table 3:  NICU Admission Diagnosis.

Discussion

While our study did not reflect any predilection for maternal illness in women carrying male fetuses, the literature had previously indicated a higher incidence of preeclampsia in this population [1,11- 13]. However, not all the studies are supportive of the association between pregnancies with a male fetus and preeclampsia. Japanese's group had reported preeclampsia to be more associated with lower fetal sex ratio (female preponderance) compared to normotensive pregnant women [8,9], but Makhseed's study did not confirm fetal gender association with preeclampsia [14]. Furthermore, another study reported a significantly lower rate of preeclampsia among women with male offspring in a cohort of singleton pregnancies delivered at <32 weeks gestation [15]. Evidence for this controversy can also be seen at the molecular level: Meta-analysis profiling of placental gene expression in preeclampsia indicates that up-regulation of the LHB cluster gene contributes to the gene expression signature of preeclampsia [16] and LHB is up-regulated in placental interface among pregnancies with a female fetus [17]. In contrast, other studies suggest that in pregnancies complicated by preeclampsia, micro vascular vasodilatation is reduced in women pregnant with a male fetus relative to normotensive women pregnant with a male fetus, with no difference observed in women pregnant with females [12]. These findings attribute the higher placental release of circulating anti-angiogenic products in the male fetus [18]. What if fetal sex association is a biased observation and the maternal pathology happens randomly regardless of fetal gender? It is plausible that other confounding factors such as birth sex ratio, ethnicity, obesity and environmental factors might play roles resulting in the perceived discrepancy of fetal gender preponderance in preeclampsia. In all studies, risk factors for preeclampsia such as maternal diabetes, obesity, weight gain, advanced maternal age, etc. are simply ignored and were not adjusted when calculating the correlation between fetal gender and preeclampsia. Thus, the observed gender association might be casual and this might account for the conflicting findings among different studies. In our study, almost 60% of the study population is Hispanic in origin, with a relatively higher body mass index (BMI) and prevalence of preeclampsia when compared to other patient populations. These factors might account for the lack of gender preponderance in our study. The sex ratio at birth (SRB) alone may be another plausible explanation of the discrepancy of fetal gender predilection in different ethnic groups. The sex ratio of males to females at birth is, on average, 1.03:1, favoring male preponderance. Asian/Pacific Islander newborns, as a group, have the highest male to- female ratio, 1.06:1. SRB of 1.04:1 for Hispanic newborns was intermediate between non-Hispanic white newborns, 1.05:1, and non-Hispanic black newborns, 1.03:1 [19-21]. SRB can be further influenced by sex selection abortion practice, environmental and socioeconomic factors [1]. The underlying reason behind the conflicting data reported in the published studies remains elusive, further studies are needed to gain better understanding.

Similarly, we were not able to replicate previous reports which described both increased incidence of gestational diabetes in pregnancies with a male fetus [1,11]. It is well know that glucose tolerance deteriorates in human pregnancy, but about 97-98% of all pregnant women retain a normal glucose tolerance and only 2-3% develop gestational diabetes [22]. Diabetes develops during pregnancy in women whose pancreatic function is insufficient to overcome the insulin resistance mediated by the placental secretion of diabetogenic hormones including growth hormone, corticotrophin-releasing hormone, placental lactogen, and progesterone [23]. Recent studies postulate an alternative theory linking a male fetus to maternal gestational diabetes with a significantly higher level of testosterone detected in cord blood in male infants compared to female infants [24- 26]. Higher levels of testosterone in maternal and fetal circulations were positively associated with insulin resistance in pregnant women resulting in gestational diabetes [24,27]. One interesting observation of Morriset et al., study implied that maternal BMI, rather than the fetal sex, might be the culprit. When considering only male offspring, there was a trend for a positive association between maternal and fetal testosterone levels. When adjusting for maternal BMI, those associations were attenuated to near significant trends, suggesting that maternal BMI may explain in part these associations, confirming that maternal factors, rather than fetal gender, was responsible for the occurrence of gestational diabetes [24]. Our patient population in this study had a significantly higher BMI and incidence of gestational diabetes. We do believe that maternal obesity contributed significantly to the insulin resistance regardless of fetal gender. In addition, we found no fetal sex predilection to intra hepatic cholestasis and gestational hypertension in our study. The result is in concordance with previously published studies [9,14,28].

Although our study did not reveal any particular male vulnerability to preterm labor, previous investigations have reported a higher incidence of preterm birth and preterm premature rupture of membranes in women carrying males. Shorter intrauterine gestations in male fetuses may be a correlate of their greater weight at earlier gestational ages [3]. Another theory links the increased infection rate (in women with male fetuses) to increased incidence of preterm labor and preterm premature rupture of membranes. A third theory implicates the higher androgen levels in males as the mechanism of preterm labor [29]. Our study confirmed a statistically higher number of male neonates required NICU admission. Upon further data stratification based on infant gender, no statistically significant differences were seen based on admission diagnosis (Table 3). For instance, we were not able to draw any definite conclusions based on increased susceptibility to infection or meconium aspiration for male neonates; but as a group, male neonates had a predisposition for critical care referral. Although male infants were larger in size and more likely to be admitted to NICU, we were not able to observe a correlation between male infant weight and NICU admission.

The results of our research support our hypothesis that male sex may be an independent risk factor for adverse neonatal outcomes. Although the exact mechanisms have not been defined, several studies have suggested that differences in metabolism may play a significant role in intrauterine growth, development, and response to stress. Bovine studies show that total glucose metabolism was doubled in male embryos, in comparison to female embryos at the same gestational age [30]. The higher metabolic rate may contribute to accelerated growth and development with a correspondent increase in birth weight. This might explain why the male infants in our study are significantly larger than the female infants. Human studies have demonstrated elevated glucose levels at birth in male neonates [31]. In the same study sample, umbilical cord arterial blood was analyzed in term deliveries, immediately after birth and the majority of male newborns had serum glucose levels above the 95th percentile. Additionally, metabolic variation may account for adaptive response to stress. The same study also measured sex differences in response to labor stress via differences in cord blood pH values. In the group of neonates exposed to labor, there were significantly more male than female neonates with academia (pH < 7.10). Additionally, 7 of 9 cases in the severe acidemia subgroup were males. There were no differences in cord artery blood pH in neonates who underwent planned Cesarean section. The sexual dimorphism of perinatal outcome can be related to the sex-biased gene expression in the placental interface [17]. Female fetuses invest more in extra-embryonic tissue development than males. Since mothers can allocate limited resources to a fetus in utero, male fetuses invest more resources in body growth and development (embryonic tissue) at the expense of investing less in the development of extra-embryonic tissues [32,33]. This may account for a male bias in the incidence of placental dysfunction [34] and in pregnancy complications where placental pathology is implicated [1,16 19].

We recognize the limitations of our study--a retrospective chart review with a relatively low number of pregnancies enrolled could account for the lack of statistical significance between gender difference and pregnancy-induced maternal pathology. Other reports on the same topic have examined similar sample sizes but the current subject number should nevertheless be taken into account. Despite these limitations, we were able to observe a significant association between male fetal sex and poorer perinatal outcome and higher NICU admission. The strength of this study is that it is one of few studies to investigate the correlation of fetal gender and pregnancy-induced pathologies other than preeclampsia and diabetes. Further studies are needed using different ethnic populations and controlling for confounding factors for maternal pathologies to validate the fetal gender association.

Conclusion

Our study found no association between fetal sex and maternal preeclampsia, gestational hypertension, diabetes, or intra hepatic cholestasis. Male infants are at significantly increased risk of higher birth weight and perinatal complication except preterm birth. One particularly significant finding of this study was the predisposition of males with regard to neonatal intensive care unit admissions.

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