Hypertensive disorders in pregnancy (HDPs) represent a complex and critical area of maternal-fetal medicine, marked by elevated blood pressure conditions that arise either before or during pregnancy. These disorders, encompassing chronic hypertension present prior to pregnancy or before 20 weeks of gestation and gestational hypertension which emerges later, profoundly affect maternal and fetal health outcomes worldwide. The physiological perturbations induced by HDPs not only escalate the risk of maternal complications and fetal mortality but also predispose neonates to premature birth and admission to intensive care units. The multifaceted nature of these disorders demands an in-depth understanding of their mechanism and impact, particularly concerning how male and female fetuses respond to the prenatal environment shaped by maternal hypertension.
The pathophysiology of HDPs centers on aberrant vascular resistance and impaired placental perfusion, resulting in compromised oxygen and nutrient delivery critical for fetal development. Despite extensive investigation, the literature reveals inconsistent findings regarding the influence of HDPs on fetal and placental growth. A plausible explanation for this inconsistency lies in potential sex-specific differences in fetal adaptive responses. Male and female fetuses may employ divergent biological strategies to navigate the intrauterine milieu altered by maternal hypertension, yet scientific inquiry into these sex-dependent effects remains limited. As global incidence rates of HDPs continue to rise, elucidating sex-specific fetal responses becomes an urgent research priority with significant implications for prenatal care.
In a pioneering study led by Ms. Alexandra R. Sitarik of Henry Ford Health, USA, the nuanced interplay between hypertensive disorders during pregnancy and fetal-placental growth metrics was examined with particular emphasis on fetal sex differences. Published in July 2025 in the journal Pediatric Investigation, the research leveraged data from the Wayne County Health Environment Allergy and Asthma Longitudinal Study (WHEALS), a profound birth cohort study based in Detroit. WHEALS longitudinally tracks mother-child dyads, providing a rich dataset for exploring developmental origins of health, an investigative domain central to Ms. Sitarik’s expertise encompassing asthma, allergy, obesity, and biostatistical methodologies.
Ms. Sitarik’s analytical approach hinged on the growth strategy hypothesis, a theoretical framework positing that male fetuses inherently maximize somatic growth potentially at the expense of adaptability, whereas female fetuses exhibit preferential investment in placental development, conferring resilience against prenatal stressors. This conceptual model guided the hypothesis that hypertensive insults during gestation would elicit differential birthweight and placental weight outcomes depending on fetal sex, reflecting divergent evolutionary survival strategies. To rigorously test this, the researchers utilized advanced linear regression models adjusted for confounding variables and incorporated correction for selection bias to infer robust associations.
The primary analysis involved 853 singleton pregnancies identified within the cohort, selected based on comprehensive availability of blood pressure records and other clinical parameters. A subset of 165 pregnancies exhibiting placental pathology data constituted a secondary analytic group, focusing on more severe or complicated hypertensive contexts. Birthweight and placental weight were quantified from delivery and pathology records respectively, enabling calculation of fetoplacental weight ratios—a critical metric contrasting fetal mass relative to placental mass, thereby reflecting allocation of growth resources.
Remarkably, findings revealed that male offspring of mothers with gestational hypertension displayed significantly elevated birthweight Z-scores compared with male peers from normotensive pregnancies. This suggests a potential growth prioritization in males despite hypertensive stress. Conversely, female fetuses in this primary cohort did not manifest increased birthweight, indicating sex-specific growth modulation. Intriguingly, in the secondary subset, a contrasting pattern emerged whereby females exposed to gestational hypertension exhibited reduced birthweight, while males continued to demonstrate upward birthweight trends. This divergent response pattern underscores the complexity of fetal adaptation in the context of placental pathology and maternal hypertension.
Analysis of the fetoplacental weight ratio further illuminated these sex-specific dynamics. Only female fetuses showed a marked decrease in this ratio in relation to hypertensive disorders, indicative of increased placental investment relative to fetal mass. This supports the notion that females might mitigate adverse prenatal environments by bolstering placental function rather than fetal growth per se. The differential allocation strategies emphasized here provide a mechanistic rationale for observed variations in clinical outcomes and help reconcile contradictions in earlier research where fetal sex was often overlooked as a modifier.
Beyond the immediate clinical relevance, these insights have profound implications for obstetric management and risk stratification. Recognizing fetal sex as a determinant of growth trajectories in HDP-affected pregnancies could refine predictive models and enable tailored surveillance strategies that anticipate sex-specific vulnerabilities. Personalized approaches to antenatal care informed by such data could enhance the detection of fetuses at risk and potentially guide interventions to improve both perinatal and long-term health outcomes.
Furthermore, this study emphasizes the broader importance of integrating biological sex into research design and analysis within perinatal epidemiology. The differential fetal responses to environmental stresses encapsulated by maternal hypertension likely extend to other prenatal insults, heralding a paradigm shift toward sex-conscious research frameworks. Unraveling the molecular and epigenetic pathways underpinning these distinctions remains a fertile ground for future investigation, promising to deepen our understanding of the developmental origins of health and disease.
Ms. Sitarik’s research also showcases the critical role of sophisticated biostatistical techniques in disentangling complex data patterns within longitudinal cohort studies. The rigorous methodology, encompassing causal inference and mediation analysis, ensures that observed associations are not spurious but instead reflect underlying biological phenomena. This methodological robustness strengthens the validity of the conclusions and serves as a model for subsequent studies seeking to explore fetal-maternal interactions under pathological conditions.
In conclusion, this landmark study highlights the necessity of considering fetal sex in the context of hypertensive disorders during pregnancy. The dichotomous growth strategies revealed—males favoring fetal size increase, females emphasizing placental development—reflect evolutionary adaptations that influence prenatal resilience. These findings not only advance scientific understanding but also bear potential to inform clinical practice, ultimately contributing to improved maternal-fetal health worldwide as HDPs remain an enduring challenge in obstetrics.
Subject of Research: People
Article Title: Sex-specific associations between hypertensive disorders in pregnancy and fetal and placental weight
News Publication Date: 11-Jul-2025
Web References:
https://doi.org/10.1002/ped4.70015
References:
Sitarik, A. R., Wegienka, G., Johnson, C. C., Khangura, R., Straughen, J. K., & Cassidy-Bushrow, A. E. (2025). Sex-specific associations between hypertensive disorders in pregnancy and fetal and placental weight. Pediatric Investigation. https://doi.org/10.1002/ped4.70015
Image Credits:
Ms. Alexandra R. Sitarik from Henry Ford Health, USA
Keywords:
Pregnancy, Hypertension, Placenta, Reproductive biology, Human health, Neonatology, Pediatrics, Obstetrics, Gynecology, Pregnancy complications
