The impact of gender medicine on neonatology: the disadvantage of being male: a narrative review

Higher incidence of congenital diseases, preterm birth, and premature rupture of membranes have been observed in pregnancies with male newborns [4]. Women carrying male foetuses had higher rates of gestational diabetes mellitus, foetal macrosomia, failure to progress during the first and second stages of labor, cord prolapse, nuchal cord, and true umbilical cord knots. Higher incidence of caesarean sections (CS) and preterm births [5] with a higher overall mortality rate [6] have been found in male neonates [7]. The reasons are various and not fully understood yet.

A study on women undergoing elective CS without complications showed a higher pro-inflammatory response in the plasma of male infants subjected to lipopolysaccharide stimulation [8]. Such a result could be a reason for premature membranes’ rupture and might explain the different reaction to neonatal infections.

The rate of free beta-hCG is, in the first trimester, significantly higher in the female foetuses, while the contrary is for the pregnancy-associated plasma protein-A levels. That may explain an increased risk for Down syndrome reported in pregnancies with female foetuses, but without statistical significance [9]. Knippel et al. [10] found higher levels of ^{alphafetoprotein} (AFP) in male foetuses and, due to the higher incidence of malformations AFP-related in females, hypothesized a protective role for this protein.

A possible additional reason justifying the disadvantage of male birth is the increased metabolic request due to the acceleration of growth, which causes greater vulnerability to minimal reductions in fetal oxygenation and blood flow, during both pregnancy and labor. Such differences, albeit small in oxygenation and lactacidemia, could increase susceptibility to early neonatal infections [11], explaining the worst outcome in case of an adverse event.

Antenatal drugs exposure causes different effects depending on sex. Neonatal abstinence syndrome secondary to prenatal opioid exposure is significantly more frequent and severe in the male population [12], while females show more benzodiazepine deficiency symptoms, either alone or combined with opioid [13].

Among opioid-exposed infants, antidepressant medication co-exposure is common. Some studies, addressed to investigate its long-term effects, reported a worse influence on male neonates, mainly resulted in an increasing length of hospitalization, but without statistical significance [14].

Infant gut microbiota, without differences between the sexes at birth but with small variations due to the type of delivery, can be influenced by maternal drugs assumption. In a group of newborns with mothers requiring anti-asthma treatments during pregnancy, the amount of Lactobacilli in faeces resulted significantly lower in males [15], while a higher value of Bacteroidacæ has been recorded in females.

postnatal adaptation is sex-related, due to both the higher prevalence of associated complications [16] and the ability to recover from an adverse event [17]. A neurobehavioral follow-up study on premature babies born at less than 28 weeks of gestational age found a lower incidence of complications such as cerebral palsy, deafness, blindness, and mental or psychomotor retardation in females [18].

Recently, a meta-analysis involving 41 studies and 625,680 neonates confirmed this theory and demonstrated greater clinical instability and need for invasive interventions in preterm males. Additionally, it reported higher rates of bronchopulmonary dysplasia (BPD), retinopathy of prematurity, necrotizing enterocolitis, intraventricular haemorrhage, and periventricular leukomalacia [19]. Although geographic factors, proper perinatal care and gestational age can reduce the gap between sexes, the feeling of generic “weakness” remains in males. Of note is its persistence even after hospital discharge, and especially for respiratory infections [20], until the first year of life [21].

Gender differences in the pulmonary develop are noticeable as early as 16–20 weeks of gestation. Mouth movements, related to both swallowing and intrauterine “respiratory function”, are more frequent in female fetuses [22]. Conversely, animal studies reported lower lung tissue stability [23], reduced gas exchange with no improvement in respiratory mechanics after steroid treatment [24], and an increased risk of lung injury due to hyperoxia [25] in males. A possible reason for this might be connected with the sex hormones levels circulating in the prenatal period. The amount of estrogen and progesterone is comparable between genders, as they both result from transplacental passage, but testosterone levels are higher in males [26]. Another hypothesis focuses on the alveolar epithelial transport of Na⁺ as a determinant of the perinatal pulmonary transition [27], with differences among the sexes. Finally, a study carried out by measuring the diversity in the expression of microRNA during fetal lung development hypothesized its role as a cofactor in lung diseases, both in neonatal and adulthood [28].

Furthermore, it is possible to hypothesize that delayed lung development observed in male newborns causes a gap between the development of the airways and the lung parenchyma, thereby increasing airway resistance. Overall, female fetuses produce surfactant earlier, move their mouths more, develop larger airways that are less reactive to insult, and develop more mature parenchyma. Therefore, males have a higher incidence and severity of respiratory distress syndrome, BPD, wheezing, asthma, and chronic diffuse interstitial lung disease, while cystic fibrosis is more severe in girls, who have a higher risk of complications and worse outcomes [29].

Recently a large and comprehensive systematic review and meta-analysis of preterm babies with persistent patent ductus arteriosus (PDA) showed no difference between boys and girls in both the incidence and the response rate to pharmacological treatment [30]. A common conception among neonatologists is the interaction between PDA and the respiratory evolution of the premature babies. The presence of a hemodynamically significant PDA is frequently suspected based on respiratory findings, such as increased oxygen or mechanical ventilation requirements. Although male gender is associated with an increased risk of RDS, higher rates of birth intubation, surfactant treatment, mechanical ventilation, and pneumothorax, the actual results suggest that the presence of PDA is unlikely to play a role in these sex differences in respiratory courses.

On the other hand, congenital heart disease (CHD) is significantly influenced by gender, not only in terms of incidence and severity, but also in postnatal evolution and long-term outcomes. However, this influence is not universal, and varies depending on the type of anomaly considered [31]. Females have a higher incidence of less serious CHD, such as interventricular and interatrial defects, pulmonary stenosis, and aortic coarctation, while major pathologies like Fallot tetralogy or left hypoplastic heart are more prevalent in males [32]. After surgical treatment, the volume index and ventricular masses are larger in males, as in the normal healthy population. Right ventricular hypertrophy and dilatation correlate with loading conditions in a similar way for both sexes. However, under comparable loading conditions, males show more severe functional impairment [33]. Although the clinical history of infants with CHD is related to gender, there is no significant prevalence for either sex. A higher mortality rate has been reported in older males with CHD, while sudden cardiac death is more prevalent in young males. However, mortality for CHD after surgery is higher among girls compared to boys, probably due to their smaller body size. Women are at higher risk of developing pulmonary arterial hypertension but at lower risk of adverse aortic outcomes, even though the possibility of them undergoing aortic surgery remains minimal. Moreover, females have a lower risk of infective endocarditis [34].

Observations from clinical research in humans have suggested a difference in brain and neuronal physiology based on sex differences that begin in the fetal and newborn period, and extend throughout the human lifespan into adulthood. In premature infants, girls have significantly lower cerebral blood flow (CBF) than boys of similar gestational and postnatal age [35]; however, adult females have higher CBF than males. The mechanism regulating these differences are not well-understood, but the relative immaturity of CBF auto-regulation in premature infants may be the reason why females with relatively lower cerebral blood flow have a lesser incidence of germinal matrix or intraventricular haemorrhage.

Pain sensitivity is another issue significantly connected with gender. Newborns and preterm male tolerate fewer painful stimuli [36, 37], although there is a difference in which side of the body is involved [38]. This is probably due to bilateral somatosensory cortical activation, which is less evident in females [39] and persists until adolescence [40]. Conversely, a study conducted on an ex-preterm cohort in adulthood showed a lower capacity to modulate pain in females with a consequent increased risk of developing persistent pathological pain, although the reason for this is still unclear [41].

Differences between sexes exist in cellular and molecular development [42], which affect both normal neuronal function and the effectiveness of various therapies [43] in cases of brain damage. However, the correlation with the behavioural and psychological aspects is still a matter of discussion [44].

Sexual dimorphism of the fetus manifests during pregnancy. Intrauterine and postnatal growth nomograms are sex-specific. There is increasing evidence showing that from fetal life, boys and girls have different responses to maternal nutrition, and that maternal breastmilk composition differs based on fetal sex [45]. Furthermore, early neonatal nutritional interventions affect boys and girls differently, and early nutrition has sex-specific effects on both body composition and neurodevelopmental outcomes [46, 47]. However, no studies have investigated whether nutritional requirements differ between the sexes. Thus, the current nutrition guidelines for preterm infants are unisex and could be sub-optimal. More information is needed to determine sex differences in infants’ macronutrient requirements, such as whether preterm females require higher fat intake and preterm males require higher protein intake for optimal growth and neurodevelopmental outcomes [48].

Pharmacological treatments have varying efficacy and side effects depending on a patient’s sex, especially in preterm population [49]. Unfortunately, scientific literature seldom covers gender differences in infant pharmacology, whether in randomized controlled studies or meta-analyses.

The pharmacological inhibition of prostaglandin synthesis has been shown to promote the stability of germinal matrix vessels and prevent intraventricular haemorrhage (IVH) in preterm rabbit pups. A similar effect has been reported in humans. Two large North American trials investigated the early use of intravenous indomethacin in preterm infants at high risk for IVH, and the results showed a significant reduction in severe intraventricular haemorrhage in only the male papulation [50]. On the other hand, less positive long-term cognitive outcomes and a higher mortality rate were observed in female infants [51]. Therefore, this prophylaxis appears to be as beneficial for males as potentially harmful for females. Conversely, hydrocortisone for BPD prophylaxis is more effective in females, increasing bronchopulmonary dysplasia-free survival rate [52].

Experimental studies carried out by administering caffeine (an adenosine receptor antagonist) to rats have shown several positive effects on respiratory pattern, such as an increase in respiratory frequency in the early phase of response to hypoxia and in tidal volume in the late phase of response. This effect has been observed exclusively in male rats [53], probably due to the long-term effects on the nucleoside receptor system. In addition, the increased expression of the Adenosine (2 A) receptor, which is specific to male rats, may have affected adenosine-dopamine interactions that regulate chemosensory activity.

Therapeutic hypothermia is a widely used procedure to protect neonates from hypoxic–ischaemic brain injury [54], which was found to be more effective in the female population, particularly in medium and long-term outcomes [55]. For the same purpose, experimental treatment with the infusion of stem cells did not show differences between genders [56].