Maternal Hypertension and Adverse Neurodevelopment in a Cohort of Preterm Infants

Abstract

Importance: Whether maternal hypertensive disorders of pregnancy (HDP) confer independent neurodevelopmental deficit risks in premature infants is controversial. Previous studies are limited by inadequate confounding variable control and other biases.

Objective: To evaluate the associations between maternal HDP, especially preeclampsia, and neurodevelopmental outcomes of preterm infants at 2 years' corrected age.

Design, setting, and participants: Regional prospective cohort study of 395 preterm infants (≤32 weeks' gestation) from 5 level III and IV southeast Ohio neonatal intensive care units from September 2016 to November 2019. Data analysis was conducted in August 2022.

Exposure: HDP, defined by maternal diagnosis of chronic or gestational hypertension or preeclampsia during pregnancy.

Main outcomes and measures: Structural brain magnetic resonance imaging was performed at term-equivalent age. Neurodevelopment was assessed by Bayley Scales of Infant and Toddler Development (BSID), Third Edition, between 22 and 26 months' corrected age. Multivariable regression was used to identify the independent association of HDP and preeclampsia on cognitive (primary outcome), language, and motor development, controlling for several confounders. Mediation analyses were performed to understand if the association with HDP was mediated by its association with birth weight or brain abnormalities.

Results: In a cohort of 395 infants, the median (IQR) gestational age was 29.6 (27.6-31.4) weeks, birth weight was 1230 (950-1628) g, and 210 (53.2%) were male. Of these, 170 (43%) were HDP-exposed, of which 104 of 170 (61%) were exposed to preeclampsia. A total of 341 children (87%) completed the BSID. In adjusted analyses, HDP exposure was negatively associated with BSID cognitive scores (-3.69; 95% CI, -6.69 to -0.68; P = .02) and language scores (-4.07; 95% CI, -8.03 to -0.11; P = .04). Preeclampsia exposure showed similarly negative but greater associations for BSID scores (-4.85; 95% CI, -8.63 to -1.07; P = .01 for cognitive and -6.30; 95% CI, -11.49 to -1.09; P = .02 for language scores). Mediation analysis revealed that the association between HDP and cognitive scores was partially mediated by its adverse association with brain abnormalities at term-equivalent age (24% of the total effect; -0.82; 95% CI, -1.72 to -0.13; P = .02).

Conclusions and relevance: In this preterm cohort study, maternal HDP was independently associated with adverse cognitive and language development, with accentuated associations observed in preeclampsia-exposed preterm infants, emphasizing the clinical importance of recognizing HDP as a risk, enabling targeted risk management strategies for closer monitoring and aggressive early intervention in affected populations.

Figure 1.. Directed Acyclic Graph Representing Potential Causal Pathways Between Maternal Hypertensive Disorders of Pregnancy, Brain Abnormalities, Confounders, and Neurodevelopmental Outcomes in Preterm Infants

This directed acyclic graph represents the causal pathways between maternal hypertensive disorders of pregnancy and preterm infant neurodevelopment at 2 years’ corrected age in preterm infants, illustrating confounders and mediators. BSID-III indicates Bayley Scales of Infant and Toddler Development, Third Edition.

Figure 2.. Mediation Model Evaluating the Indirect Effects of Global Brain Abnormality Scores on Magnetic Resonance Imaging (MRI) at Term-Equivalent Age as a Mediator of the Adverse Effects of Hypertensive Disorders of Pregnancy on Cognitive Scores in Preterm Infants

This model demonstrates that hypertensive disorders of pregnancy-induced early brain abnormalities are a significant mediator (dashed blue lines) in the pathway between maternal hypertension and lower cognitive scores on the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at 2 years’ corrected age in preterm infants.