Study links hypertensive disorders in pregnancy to sex-specific differences in fetal and placental growth

Study links hypertensive disorders in pregnancy to sex-specific differences in fetal and placental growth | Image Credit: © udisetiawan - stock.adobe.com.

Hypertensive disorders in pregnancy (HDPs), including chronic hypertension, gestational hypertension, and preeclampsia, are leading causes of maternal and infant morbidity and mortality. These conditions increase the risk of preterm birth, neonatal intensive care unit admission, and perinatal death, and may interfere with placental blood flow, reducing oxygen and nutrient delivery to the fetus.^1,2

While impaired circulation is thought to restrict fetal and placental growth, prior research has shown inconsistent results. One proposed explanation is that male and female fetuses may respond differently to HDPs, but few studies have directly examined this association. A new analysis led by Alexandra R. Sitarik, MS, of the Department of Public Health Sciences at Henry Ford Health, sought to clarify these sex-specific effects. The study, published in Pediatric Investigation, examined how HDPs affect fetal and placental weight in relation to fetal sex.

“According to the growth strategy hypothesis, male fetuses tend to prioritize growth and are less adaptable to prenatal stressors, while females focus more on placental development, which may help buffer adverse conditions,” Sitarik said. “Based on this, we hypothesized that males and females would respond differently to the prenatal conditions of HDPs in terms of birthweight and placental weight.”

Study design

Data were drawn from the Wayne County Health Environment Allergy and Asthma Longitudinal Study (WHEALS), a Detroit-based birth cohort of 1,258 mother-child pairs. For the primary analysis, 853 singleton pregnancies with available blood pressure and birthweight data were included. A secondary subset of 165 pregnancies, representing complicated cases with placental pathology data, was also analyzed.

HDP diagnoses were abstracted from medical records, while placental weight was obtained from pathology reports. The primary outcome was birthweight Z-score, adjusted for gestational age and sex. Secondary outcomes included placental weight and fetoplacental weight ratio. Linear regression models were used, adjusting for maternal age, body mass index, race, education, parity, gestational diabetes, smoking, and other potential confounders.

Key findings

In the primary cohort, male infants of mothers with gestational hypertension had significantly higher birthweight compared with males born to normotensive mothers (β = 0.90; 95% CI, 0.28–1.52), while no effect was observed among females (interaction P = .019). In contrast, in the complicated pregnancy subset, female infants exposed to gestational hypertension had significantly reduced birthweight (β = –1.14; 95% CI, –2.13 to –0.16), whereas males continued to demonstrate increased birthweight (β = 1.50; 95% CI, 0.15–2.86; interaction P = .013).

When evaluating placental growth, the study found that the fetoplacental weight ratio was lower in female infants exposed to any HDP (β = –0.95; 95% CI, –1.57 to –0.33; interaction P = .028). No similar association was observed among male infants. This suggests that females may adapt to maternal hypertension by prioritizing placental development over fetal growth.

“These findings help explain inconsistent results in previous research on HDPs and fetal growth,” Sitarik said. “They also show why fetal sex matters when assessing pregnancy risks.”

Interpretation

The findings align with the growth strategy hypothesis, indicating divergent adaptation strategies between sexes. Male fetuses appeared to prioritize continued growth, even in the presence of maternal hypertension, while female fetuses appeared to shift resources toward placental development, potentially to maintain survival under adverse conditions.

The authors noted that while the primary analysis was prospective and adjusted for multiple confounders, limitations included a relatively small sample size for rarer forms of HDPs, a lack of data on HDP severity, and the restriction of placental analyses to pregnancies with complications. They emphasized that replication in larger, diverse cohorts is needed to confirm the observed sex-specific associations.

Clinical implications

The results suggest that fetal sex should be considered when evaluating the risks of HDPs. Understanding sex-specific growth patterns could improve the prediction of adverse outcomes and allow for more personalized monitoring during pregnancy.

“Hopefully, these insights encourage further investigation into the biological mechanisms behind sex-specific growth patterns, helping obstetricians and gynecologists to better predict complications and provide more personalized care for mothers and babies affected by HDPs,” Sitarik said.

References:

1. Pediatric Investigation. Pediatric investigation study finds sex-based fetal responses to maternal hypertension. Eurekalert. August 14, 2025. Accessed August 18, 2025. https://www.eurekalert.org/news-releases/1094678
2. Sitarik AR, Wegienka G, Johnson CC, Khangura R, Straughen JK, Cassidy‐Bushrow AE. Sex‐specific associations between hypertensive disorders in pregnancy and fetal and placental weight. Pediatric Investigation. Published online July 11, 2025. doi:https://doi.org/10.1002/ped4.70015