Sex differences in the effects of prematurity and/or low birthweight on neurodevelopmental outcomes: systematic review and meta-analyses

Abstract

Background Premature birth and/or low birthweight have long-lasting effects on cognition. The purpose of the present systematic review is to examine whether the effects of prematurity and/or low birth weight on neurodevelopmental outcomes differ between males and females. Methods Web of Science, Scopus, and Ovid MEDLINE were searched for studies of humans born premature and/or of low birthweight, where neurodevelopmental phenotypes were measured at 1 year of age or older. Studies must have reported outcomes in such a way that it was possible to assess whether effects were greater in one sex than the other. Risk of bias was assessed using both the Newcastle–Ottawa scale and the National Institutes of Health Quality assessment tool for observational cohort and cross-sectional studies. Results Seventy-five studies were included for descriptive synthesis, although only 24 presented data in a way that could be extracted for meta-analyses. Meta-analyses found that severe and moderate prematurity/low birthweight impaired cognitive function, and severe prematurity/low birthweight also increased internalizing problem scores. Moderate, but not severe, prematurity/low birthweight significantly increased externalizing problem scores. In no case did effects of prematurity/low birthweight differ between males and females. Heterogeneity among studies was generally high and significant, although age at assessment was not a significant moderator of effect. Descriptive synthesis did not identify an obvious excess or deficiency of male-biased or female-biased effects for any trait category. Individual study quality was generally good, and we found no evidence of publication bias. Conclusions We found no evidence that the sexes differ in their susceptibility to the effects of severe or moderate prematurity/low birthweight on cognitive function, internalizing traits or externalizing traits. Result heterogeneity tended to be high, but this reflects that one sex is not consistently more affected than the other. Frequently stated generalizations that one sex is more susceptible to prenatal adversity should be re-evaluated.

Sex-based disparities in DNA methylation and gene expression in late-gestation mouse placentas

“…These findings align with existing evidence-primarily based on meta-analyses of human pregnanciesconsistently indicating that male fetuses have higher susceptibility to pregnancy complications such as gestational diabetes, premature membrane rupture, preterm birth, and macrosomia (8)(9)(10)(11)(12)(13)(14). Males also exhibit a higher prevalence of neurodevelopmental disorders, including dyslexia and attention deficit hyperactivity disorder.…”

Influence of environmental and biological factors on functional connectivity of the superior temporal sulcus in neonates scanned at term age

“…The effect of sex on brain development and notably language is often discussed with mixed results (Christians et al, 2023; Etchell et al, 2018; Hirnstein et al, 2019). First, there are anatomical differences between male and female brain even when the sizes of the brain and the body are taken into account (Williams et al, 2021b).…”

“…Second, girls have in average better language and social abilities than boys (Frank et al, 2017) and are less subjects to oral and written language pathologies (Altarelli et al, 2013). Finally, considering the effect of prematurity, it is classically estimated that girls present less negative consequences (Etchell et al, 2018;Hirnstein et al, 2019 but see the recent metanalysis of Christians et al, 2023) Although it is intrinsically difficult to disentangle cultural from biological factors, some studies report early biological differences in brain maturation and response to stress in males and females (Bale, 2016). STS depth asymmetry was shallower in female than in male neonates, a feature already reported in adults.…”

Sex-Specific DNA Methylation and Gene Expression Changes in Mouse Placentas After Early Preimplantation Alcohol Exposure

“…It is possible that some female embryos with growth delays at mid-gestation may catch up later in development, eventually achieving a similar embryo weight to control. Several studies have demonstrated that female embryos generally exhibit greater adaptability to adverse in utero environments than male embryos, facilitating their development even in the presence of altered resource availability (Bale, 2016;Christians et al, 2023;Meakin et al, 2021). Male ethanolexposed placentas displayed altered methylation and/or expression patterns in several genes that are directly linked to embryonic growth restriction.…”