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.

Keywords: Birthweight; Cognition; Cognitive function; Externalizing problems; Gender; Internalizing problems; Prematurity; Sex differences; Systematic review.

Fig. 1

Flow diagram showing study selection. Reasons for exclusion at assessment of full-text articles included outcomes that were not of interest, results that not presented in a way that allowed assessment of sex dependence, or the absence of term/normal birthweight controls

Fig. 2

Qualitative synthesis of effects of prematurity/low birthweight on measures of cognitive function. Numbers indicate studies that found measures of cognitive function to be affected in both sexes, to be affected more in females, to be affected more in males, or to be affected in neither sex in childhood (1–10 years), adolescence (11–18 years), and adulthood (over 19 years). In each age group, the y-axis indicates the logarithm (base 10) of the sample size. A single study could show different results for different traits and so may appear in more than one cell. Study numbering is the same as in text. Circles indicate studies that examined sex-dependence using statistical interaction terms, whereas squares indicate studies that analyzed the sexes separately

Fig. 3

Qualitative synthesis of effects of prematurity/low birthweight on internalizing traits

Fig. 4

Qualitative synthesis of effects of prematurity/low birthweight on externalizing traits

Fig. 5

Qualitative synthesis of effects of prematurity/low birthweight on language traits

Fig. 6

Meta-analysis of the effects of severe prematurity/low birthweight on cognitive function. Squares represent estimates (with confidence intervals) and marker size indicates weight. Diamonds represent estimates for each sex and for the difference between sexes, with the width of the diamond indicating the confidence interval. SMD standardized mean difference

Fig. 7

Meta-analysis of the effects of moderate prematurity/low birthweight on cognitive function

Fig. 8

Meta-analysis of the effects of severe prematurity/low birthweight on internalizing problems

Fig. 9

Meta-analysis of the effects of moderate prematurity/low birthweight on externalizing problems

Fig. 10

Meta-analysis of the effects of severe prematurity/low birthweight on externalizing problems