Newborn boys have higher morbidity and mortality than girls. Several studies have shown that male newborn sex is an independent risk factor for adverse outcome. The specific mechanisms leading to the increased risks for newborn boys are not known. However, several sex-specific reactions and physiologic responses have been described in both the fetus and newborn infants. Some of these differences persist during childhood; although later other sex and gender-specific differences become more important. Recently, the research aiming at explaining the vulnerability in male infants has been intensified. Experimental data from newborn animals have shown that many sex differences can be explained by differences in hormonal function and stress responses. However, if these findings apply to humans as well is not yet known. The aim of this paper is to review literature on very early sex-specific differences and shed some light on the increased risks for male fetuses and newborn boys.

Background. Male fetal gender is associated with an overall increased risk of pre-eclampsia. However, it was recently shown that the male: female birth ratio was decreased in pre-eclampsia associated with preterm delivery. The reason for this discrepancy is not known. Objective. To investigate whether the fetal and newborn gender is associated with the incidence of antenatal maternal pregnancy complications, and to investigate if gender-associated risk changes with gestational age at delivery. Methods. Population-based study including 1,158,276 infants born in Sweden 1990–2001. Five maternal diagnosis groups (pre-eclampsia, infection, preterm premature rupture of membranes, abruptio placentae, and polyhydramnios) were explored in relation to newborn infant gender and gestational age at delivery. Results. When all gestational ages were evaluated, male newborn gender was associated with increased odds ratios for all five diagnosis groups, and for preterm birth before 37 weeks gestation, M/F ratio 1.17. In very preterm births (gestational age below 32 weeks), male newborn gender was associated with a significantly lower risk for pre-eclampsia (OR 0.88, 95%CI 0.80–0.97), and a marginally lower risk for polyhydramnios (OR 0.74, 95%CI 0.54–1.01). Conclusion. The fetal gender seems to affect the occurrence of pre-eclampsia, and possibly also polyhydramnios. The finding could be due to an increased risk for spontaneous abortions in pregnancies with male fetuses, but could also be associated with the etiology of these conditions. Evaluation of antenatal pregnancy complications from a fetal/newborn gender perspective may contribute to new insights regarding their pathophysiological mechanisms.

BACKGROUND:Male fetal gender is associated with an overall increased risk of pre-eclampsia. However, it was recently shown that the male: female birth ratio was decreased in pre-eclampsia associated with preterm delivery. The reason for this discrepancy is not known.OBJECTIVE:To investigate whether the fetal and newborn gender is associated with the incidence of antenatal maternal pregnancy complications, and to investigate if gender-associated risk changes with gestational age at delivery.METHODS:Population-based study including 1,158,276 infants born in Sweden 1990-2001. Five maternal diagnosis groups (pre-eclampsia, infection, preterm premature rupture of membranes, abruptio placentae, and polyhydramnios) were explored in relation to newborn infant gender and gestational age at delivery.RESULTS:When all gestational ages were evaluated, male newborn gender was associated with increased odds ratios for all five diagnosis groups, and for preterm birth before 37 weeks gestation, M/F ratio 1.17. In very preterm births (gestational age below 32 weeks), male newborn gender was associated with a significantly lower risk for pre-eclampsia (OR 0.88, 95%CI 0.80-0.97), and a marginally lower risk for polyhydramnios (OR 0.74, 95%CI 0.54-1.01).CONCLUSION:The fetal gender seems to affect the occurrence of pre-eclampsia, and possibly also polyhydramnios. The finding could be due to an increased risk for spontaneous abortions in pregnancies with male fetuses, but could also be associated with the etiology of these conditions. Evaluation of antenatal pregnancy complications from a fetal/newborn gender perspective may contribute to new insights regarding their pathophysiological mechanisms.

Background: Previous studies indicate that there may be infant gender differences in cytokine expression associated with differences in neonatal morbidity. Objective: We tested the hypothesis that umbilical cord interleukin-1 receptor antagonist (IL-1ra) correlates with infant gender and neonatal outcome in preterm infants. Study Design: IL-1ra was measured in cord blood taken from 58 preterm infants (33 males, 25 females) with gestational age less than 32 weeks. Receiver operating characteristics (ROC) curve were used for identifying IL-1ra values with high sensitivity and specificity for neonatal morbidity and adverse outcome, i.e., death or survival with severe intraventricular hemorrhage or periventricular leukomalacia. Results: In the female infants, but not the male infants, cord IL-1ra values correlated with postnatal depression, expressed as Apgar scores at 1 min (correlation coefficient, rs; p value: –0.542; 0.005), 5 min (–0.571; 0.018), and 10 min (–0.442; 0.035); and postnatal age at intubation (–0.799; 0.001). The ROC area under the curve (AUC) was 0.735 for adverse outcome (p = 0.013), and 0.683 for bronchopulmonary dysplasia (p = 0.021) when all infants were included. However, there was a significant gender difference in the ROC curve for adverse outcome (p = 0.026), with AUC 0.640 (p = 0.240) in males and AUC 0.929 (p = 0.008) in females. Above a chosen cutoff at 13,500 ng/l for IL-1ra cord the sensitivity and specificity for predicting adverse outcome was 100 and 81%, respectively in females versus 50 and 84% in males. Conclusion: Increased levels of cord IL-1ra levels are associated with neonatal morbidity and adverse outcome in preterm infants. Comparable levels of IL-1ra have different predictive value depending on infant gender.

Aim: The aim of this study was to investigate possible gender-related differences in clinical parameters during the first week of life that could explain the higher morbidity and mortality of preterm male infants. Methods: In total, 130 clinical variables were collected from 236 inborn infants (130 male and 106 female infants) with gestational age (GA) <29 wk. A subgroup of 175 extremely low birthweight infants (ELBW) <1000 g (n = 86 males; n = 89 females) was analysed separately. Results: At 6 postnatal h, 60.8% of the male infants needed mechanical ventilation versus 46.2% of the females (p = 0.026). Chronic lung disease (CLD) developed in 36.2% of males versus 9.8% of female infants (p = 0.004). Inotrope support with dopamine was used in more than 50% of the infants; additional inotrope support to dopamine was needed by 19.4% of male and 9.7% of female infants (p = 0.041). The gender-related difference in need for inotrope support was more evident among the ELBW infants; 67.1% of male infants needed inotrope support versus 50.6% of females (p = 0.028). At 12-24 h, male ELBW infants had lower minimum mean arterial blood pressure ( mean (SD) 25(4) mmHg vs 28(6) mmHg, p = 0.004)) and lower minimum PaCO2 than females infants (4.3 (1.1) kPa vs 4.7 (0.9) kPa, p = 0.043).Conclusions: There are early gender-related differences in need for ventilatory and circulatory support that may contribute to the worse long-term outcome in prematurely born male infants.

Background: Increased levels of umbilical cord proinflammatory cytokines are associated with early and late neonatal morbidity. Extremely preterm male infants need more circulatory and ventilatory support than female infants, and have worse outcome. Experimental interventions which include administration of interleukin-1 receptor antagonist (IL1-ra) improves cerebral outcome after neonatal brain injury, and stabilise arterial blood pressure after experimental sepsis. Furthermore, IL-1ra is increased in amniotic fluid and neonatal urine from female fetuses/newborns. We tested the hypothesis that umbilical cord IL-1ra is related to infant gender, postnatal blood pressure and neonatal morbidity.Method: Blood from the umbilical cord of 58 infants (33 male, 25 female) with gestational age <32 weeks was sampled at birth. Receiver operating characteristics (ROC-curve) were used for identifying IL-1ra values with high sensitivity and specificity for “poor outcome”. “Poor outcome” was defined as either death (n=3), grade 3–4 IVH or cystic PVL (n= 9). A cut-off for IL-1ra at 13500 pg/ml rendered an area under the curve (AUC) = 0.735, p-value= 0.013, with 67% sensitivity and 85% specificity for “poor outcome”.Results: There was no correlation between IL-1ra and newborn gender, blood pressure during the first 72 hours or need for inotrope support. There were significant correlations (p-value; rs) between IL-1ra and a) depression at birth, including Apgar at 1 minute (0.020; −0.305) and 10 minutes (0.020; − 0.313) and, b) age at intubation during the first 12 hours (0.011; −0.330). Besides the association with “poor outcome”, IL-1ra values above 13500 pg/ml were associated with other parameters of neonatal morbidity such as development of NEC (p= 0.015), sepsis with positive blood culture (p= 0.027), and need for extra oxygen at 36 weeks (p= 0.033). There were no significant correlations between IL1-ra >13500 pg/ml and development of ROP (p= 0.096), days with mechanical ventilation (p= 0.098), or clinical seizures (p= 0.220).Conclusion: IL-1ra levels above 13500 pg/ml in umbilical cord blood are associated with depression at birth, need for early intubation and severe neonatal morbidity.