Objective: To elucidate whether the risk of macrosomia, large for gestational age (LGA) and small for gestational age (SGA) is influenced by maternal body mass index and glucose tolerance differently in male and female fetuses.
Methods: A population study was conducted in 16 general hospitals from the Spanish National Health Service that included 9270 consecutive women with singleton pregnancies and without a former diagnosis of diabetes mellitus who delivered 4793 male and 4477 female newborns. Logistic regression analyses were performed to predict the effect of body mass index (BMI) category and glucose tolerance on macrosomia, large for gestational age newborns (LGA) and small for gestational age newborns (SGA) Separate analyses according to foetal sex were carried out for each outcome. The results were adjusted for maternal age, gestational age and pregnancy-induced hypertension.
Results: There were significant differences between males and females in the percentage of infants who had macrosomia, LGA or SGA. Maternal BMI category was positively associated with the risk of macrosomia and LGA in both male and female newborns. In addition, there was a negative association between maternal BMI and SGA that only reached significance in males. In contrast, gestational diabetes was only a predictor of macrosomia exclusively in male fetuses (OR 1.67, 95% CI 1.12 to 2.49)
Conclusions: There is sexual dimorphism in the risk of abnormal birth weight attributed to maternal glucose tolerance status. A closer surveillance of foetal growth might be warranted in pregnant women with abnormal glucose tolerance carrying a male fetus.
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Sex differences in perinatal outcome and neonatal mortality have been described in the literature. Male sex has been associated with an increased risk of preterm and post-term birth, labour dystocia, cord problems, foetal distress related to a delayed lung maturation lower Apgar scores, instrumental or Caesarean deliveries, perinatal mortality, birth defects and worse outcome in intrauterine growth restriction.1–14 In recent reports, male sex persists as an independent risk factor for adverse pregnancy outcome even after controlling for possible confounding factors.6 15 For example, the increased risk of Caesarean section in male fetuses is attributable to higher birth weight, but this is not the case for foetal distress.11 As to diabetes-related morbidity, the contribution of foetal sex has only been considered on few occasions: Bracero described a poorer foetal outcome in male fetuses of diabetic pregnancies, mainly due to a higher rate of hypoglycaemia.16 Birth weight is clearly affected by sex, so that growth charts are both sex- and gestational age-specific. However, it is noticeable that when searching for predictors of large for gestational age (LGA) (sex- and gestational age-adjusted), male sex has been consistently reported as a positive predictor.15 17
Foetal growth is influenced by foetal genes and a wide range of factors that act on the maternal uterine environment. These inherited and environmental factors have a complex interrelation, contributing to both foetal and early childhood growth as well as to neonatal morbidity and long-term disease risk.18 Although maternal glucose tolerance and maternal obesity raise the risk of increased foetal growth,19–21 it has not been elucidated whether or not foetal sex modifies this risk.
The present study aimed to determine whether the risk of macrosomia, LGA and small for gestational age (SGA), attributed to maternal body mass index and altered glucose tolerance status, is different in male and female fetuses.
This prospective study was conducted in 16 general hospitals from the Spanish National Health Service across the country (Spain) and the general research design and methods have been already reported elsewhere.15 22 In brief, all women with singleton pregnancies and without a former diagnosis of diabetes mellitus were included. Pregnancies delivering at a gestational age lower than 28 weeks and the second pregnancy of women with two pregnancies in the same year were excluded from the analysis. The study recruited 9513 consecutive women aged 14–45 years. Two hundred and six women (2.2%) who did not undergo screening and 37 with non-available anthropometric data were excluded. The final study group was therefore made up of the remaining 9270 (97.4%) pregnant women. There were 4793 (51.7%) deliveries of male and 4477 (48.3%) deliveries of female neonates. The research was performed in accordance with the Declaration of Helsinki as revised in 2000 and informed consent was obtained from pregnant women.
Macrosomia was defined as a birth weight at or above 4 kg. Newborns were defined as LGA when sex-specific birth weight for gestational age was above the ninetieth percentile of Spanish foetal growth curves23 and SGA when under the tenth percentile. Weight adjusted to fiftieth percentile (WA50pct) was calculated as birth weight*100/50th percentile for the corresponding sex and gestational age.
Information was gathered from a specific electronic record on maternal age, pregestational height and weight, pregestational body mass index (BMI), chronic arterial hypertension, pregnancy-induced hypertension (PIH) (including pre-eclampsia), gestational age at delivery, delivery (vaginal/caesarean section), and newborn characteristics (birth weight, sex, Apgar score, perinatal mortality, major congenital malformations). Gestational age was defined as completed weeks, based on the last menstrual period or on the earliest ultrasound assessment if discordant. Pregestational weight was self-reported and trained nurses measured height at the first prenatal visit. Chronic hypertension was defined as treated hypertension before pregnancy or arterial blood pressure ⩾ 140/90 mmHg in the first 20 weeks of pregnancy.
After a 50-g glucose challenge test (GCT), women who had a venous plasma glucose ⩾ 7.8 mmol/l were scheduled for a diagnostic 100-g, 3-h oral glucose tolerance test (OGTT). National Diabetes Data Group (NDDG) (fasting: 5.8 mmol/l; 1-h: 10.6 mmol/l; 2-h: 9.2 mmol/l; 3-h: 8.1 mmol/l) criteria was considered.24 Gestational diabetes mellitus (GDM) was defined when more than two plasma glucose measurements were equal to or higher than cut-off points. Three glucose tolerance groups were defined: women with GDM according to NDDG criteria receiving usual care (NDDG-GDM) and two untreated groups, representing a gradient of carbohydrate tolerance. Negative screens had a glucose value below 7.8 mmol/l after a 50-g GCT. False-positive screens (non-diabetic positive screens) had a positive GCT but a negative oral glucose tolerance test (OGTT) by NDDG criteria and did not receive specific treatment. Carpenter and Coustan criteria for GDM were not considered as it has been previously reported that they are not associated with significant morbidity in this population.15 Body mass index was categorized according to World Health Organization (underweight < 18.5 kg/m2, normal weight 18.5–24.9 kg/m2, overweight 25–29.9 kg/m2 and obese ⩾ 30 kg/m2).25
Statistical analysis was performed with the SPSS package (SPSS Chicago, IL, USA). In order to test the statistical significance of the results, χ2 square test or Fisher exact test were used as appropriate. For continuous variables the T-test or Mann–Whitney were used when appropriate. Multivariate logistic regression models were constructed to predict macrosomia, LGA and SGA. Afterwards, separate multivariate logistic regression models with multiple predictors with a enter method were used in boys and girls to find independent associations between foetal sex and macrosomia, LGA and SGA. All potentially predictive variables (glucose tolerance category, prepregnancy BMI categories, maternal age, gestational age at delivery and pregnancy-induced hypertension) were introduced in the model. Odds ratios (OR) and 95% confidence intervals (CI) were computed; p value < 0.05 was considered statistically significant.
Table 1 compares the maternal and newborn characteristics according to sex. No significant differences were observed in maternal age, prepregnancy BMI, glucose tolerance status, or hypertensive disorders.
Female and male newborns were not different in gestational age and, as expected, male newborns were heavier and displayed a higher rate of macrosomia than female ones (7.3 vs 3.5%). Male fetuses had also significant higher rates of both LGA (15.4 vs 13.8%) and SGA (7.3 vs 6.4%) (table 1).
Crude univariate analyses showed that both pregestational BMI and maternal glucose tolerance status were associated with macrosomia and LGA in both male and female fetuses. However, multiple regression models adjusted by confounding factors showed important differences depending on the sex of the newborn. In table 2, the multivariate prediction of the three outcomes studied according to sex is shown. In male newborns, macrosomia was strikingly directly predicted by gestational age, prepregnancy BMI category and maternal glucose tolerance. In contrast, in females, maternal glucose tolerance was not a predictor of macrosomia (table 2). The multivariate prediction of LGA (table 2) did not show differences according to sex, except for glucose tolerance. Overall, glucose tolerance test was not a predictor of abnormal birth weight in both males and females. However, from non-treated women with altered glucose challenge test but not fulfilling criteria for GDM, the risk for LGA was increased among male but not female newborns.
In the prediction of SGA (table 2), maternal obesity was associated with a lower risk in male but not in female fetuses.
In the current study, maternal glucose tolerance status and maternal BMI modify the risk of macrosomia, LGA and SGA according to foetal sex. Maternal glucose tolerance status was consistently associated to these three outcomes in male but not in female fetuses. The lack of association of glucose tolerance with birth weight outcomes in female newborns could not be attributed to an insufficient statistical power of the sample, as this study had enough statistical power to detect increases in risk of as low as 25% for some outcomes. In fact, most of the null association in female newborns showed odds ratios close to one. All associations went in the expected direction, with the exception of GDM being non-significantly associated with SGA in male infants. This can be reconciled with the fact that although GDM is a risk factor for increased BW, too tight maternal metabolic control has also been reported to induce restriction of foetal growth.26
All other predictors had the expected influence on the rate of macrosomia, LGA and SGA, and the influence was similar for male and female fetuses, with the single exception of maternal BMI not reaching significance for SGA prediction in females.
These findings would be in line with a higher frailty of male fetuses to external influences. In humans, as in mammals, the sex ratio is biased towards females in unfavourable circumstances such as increased parental age, reduced maternal energy stores and seasons unfavourable for reproduction.27–30 Along the same lines, it has recently been reported that in human pregnancy, there is a selective loss of male fetuses in situations of acute stress.31
Overall, these findings indicate that male fetuses are more sensitive to maternal environment with maternal pregestational BMI influencing the risk of macrosomia, LGA and SGA, and maternal glucose tolerance status influencing their rates of macrosomia, LGA and SGA. On the other hand, female fetuses appear to be less sensitive (or more resilient) to these well-known predictors of foetal growth, especially to maternal glucose tolerance.
In clinical terms, there is strong evidence that the incidence and prevalence of obesity is increasing in most of the countries where nutritional status is being monitored. It is well known that increased BMI also conveys a higher risk of diabetes.32 It is described here that, once GDM was diagnosed and treated in women carrying female fetuses, no increased risk of abnormal foetal weight was observed. However, in those carrying male fetuses, we observed an increased risk of both macrosomia and LGA. It is not known what would happen in untreated GDM patients, although it is speculated that the risk would have been even higher in male than female fetuses. If these findings are confirmed in other prospective studies, a differential approach in the treatment and/or surveillance of GDM according to foetal sex is warranted.
What this study adds
The study shows that there is sexual dimorphism in the influence of maternal glucose tolerance status on abnormal birth weight.
The results have implications in terms of actions to improve surveillance of foetal growth in pregnant women with abnormal glucose tolerance carrying a male foetus. Furthermore, these results can contribute to a better understanding of some pathways that link maternal conditions with birth weight and health outcomes in adulthood.
Sexual dimorphism for insulin sensitivity, growth hormone–insulin growth factor 1 axis and cytokines is well known and could play a role in these findings. Maternal insulin sensitivity has been proposed as a major environmental factor in foetal size.21 In an analysis of factors affecting foetal growth in women with normal glucose tolerance or gestational diabetes, late pregnancy insulin sensitivity index had the strongest correlation with fat accretion in male fetuses.19 20 It has been suggested that an increased metabolic rate might cause an increased vulnerability of male infants during critical stages of development.10 In addition, a prolongation of pregnancy could increase the exposure of the fetus to higher levels of glucose, insulin and different metabolic alterations if gestational diabetes is present. Interestingly, pregnancies of male fetuses are associated with prolongation of pregnancy.3 The potential implications for foetal growth are obvious. However, in the present study, no differences in gestational age according to foetal sex were observed. Furthermore, all regression analysis models were adjusted for gestational age. Other physiological mechanisms have been related to different foetal size according to foetal sex and glucose tolerance status. The growth hormone (GH), insulin-like growth factors (IGF) and their proteins (IGFBP) are essential for foetal growth and development. Birth weight has been reported to correlate with serum GH, IGF-1 and IGF-2 concentrations.33 34 A sexual dimorphism has been described in the GH–IGF axis, related to foetal size.33–36 There exists the possibility that the influence of the GH–IGF system on foetal growth may be the result of the interaction between maternal physical constrains, placental function, several foetal regulatory systems and genotype.36–39 A strong relationship between maternal factors and postnatal serum IGF-1 and IGFBP-3 has been revealed. On the other hand, obesity and diabetes mellitus have been recognized as chronic inflammatory conditions strongly related to innate immune response.40 Inflammatory reactions have been reported to reduce GH–IGF-1 axis in preterm infants.41 Defective placentation has been related to alterations in innate immune system, and activation of chronic inflammation.42 There is some evidence that prenatal cytokine exposure results in obesity and gender-specific programming. In experimental studies, cytokines led to increased insulin sensitivity of female fetuses but to insulin resistance in male fetuses. Interestingly, tissues from patients with gestational diabetes released greater amounts of TNF-α in response to high glucose.43 It is hypothesised that this maternal cytokine might lead to different effects in male and female fetuses.
In conclusion, a sexual dimorphism is reported in the influence of maternal glucose tolerance status on abnormal birth weight while other predictors seem to exert a similar influence. A closer surveillance of foetal growth might be warranted in pregnant women with abnormal glucose tolerance carrying a male fetus.
Funding: CIBER (Instituto de Salud Carlos III, Spain).
Competing interests: None declared.
Ethics approval: Doctor Josep Trueta Hospital Clinical Investigation and Ethics Committee (CEIC Hospital Josep Trueta).
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