Sex-Specific Growth and Development Mechanisms in Human Pregnancy

Sex-specific differences in foetal growth and developmental trajectories emerge early in human gestation and are largely mediated by the placenta. Male and female foetuses exhibit distinct patterns of placental structure, nutrient transport and hormone signalling that influence in utero growth rates, susceptibility to adverse events and long-term health outcomes. Male foetuses tend to prioritise rapid growth via enhanced anabolic pathways, rendering them more vulnerable to environmental challenges, whereas female foetuses often adopt a conservative growth strategy that confers resilience at the expense of maximal size. Underpinning these differences are genetic and epigenetic mechanisms—including sex-biased DNA methylation, histone modifications and X-chromosome gene dosage—as well as discrete transcriptional programmes in trophoblast subtypes. These processes modulate placental adaptation to maternal stressors such as infection, inflammation or nutrient imbalance, leading to divergent risks of complications such as intrauterine growth restriction, pre-eclampsia and preterm birth. Understanding these sex-specific pathways is key to developing tailored antenatal interventions and improving lifelong health trajectories.

Research from Nature Portfolio

Recent studies have uncovered sex-dependent regulation of the placental methylome and transcriptome, revealing extensive differential methylation of autosomal loci between male and female placentae and limited divergence in gene expression. These findings highlight imprinted clusters such as KCNQ1OT1/CDKN1C as key mediators of birthweight and lifelong disease risk, linking early epigenetic variation to adult health trajectories. Complementary work has shown that female placentae exhibit elevated levels of the repressive histone mark H3K27me3 in trophoblast cells, conferring resilience to prenatal stressors by shaping gene expression programmes that protect developing hypothalamic circuits. Together, these studies elucidate molecular mechanisms by which foetal sex modulates placental function and developmental programming.

Sex-Specific Growth and Development Mechanisms in Human Pregnancy publication trend

The graph below shows the total number of articles in sex-specific growth and development mechanisms in human pregnancy across all publications each year (not limited to Nature Index journals).

Technical terms

Placenta: Transient foetal organ facilitating nutrient, gas and waste exchange between mother and fetus.

Trophoblast: Outer layer of placental cells responsible for implantation and maternal–foetal interface functions.

DNA methylation: Addition of methyl groups to DNA that modulates gene expression.

Transcriptome: Complete set of RNA transcripts produced by a tissue or cell population.

Epigenetic modification: Heritable regulation of gene activity without changes to DNA sequence.

Imprinted genes: Genes expressed in a parent-of-origin-specific manner due to epigenetic marks.

H3K27me3: Tri-methylation of histone H3 lysine 27, an epigenetic mark associated with gene repression.

X-chromosome inactivation (XCI): Silencing of one X chromosome in female cells to equalise gene dosage with males.

References

1. Sex-differentiated placental methylation and gene expression regulation has implications for neonatal traits and adult diseases. Nature Communications (2025).
2. Regulation of sexually dimorphic placental adaptation in LPS exposure-induced intrauterine growth restriction. Molecular Medicine (2023).
3. Placental H3K27me3 establishes female resilience to prenatal insults. Nature Communications (2018).
4. Let’s Talk about Placental Sex, Baby: Understanding Mechanisms That Drive Female- and Male-Specific Fetal Growth and Developmental Outcomes. International Journal of Molecular Sciences (2021).
5. Placental polyamine metabolism differs by fetal sex, fetal growth restriction, and preeclampsia. JCI Insight (2018).