Mid-pregnancy uterine artery Dopplers and child neurodevelopment

Resistance to blood flow in the maternal uterine artery (UtA) has been associated with both preeclampsia (PE) and small-for-gestational age (SGA). Our objective was to assess the association of increased maternal UtA resistance with child neurodevelopmental and behavioral outcomes in low-risk pregnancies.

Serial ultrasound exams were prospectively performed in 2334 racial and ethnically diverse, healthy patients with low-risk singleton pregnancies (July 2009 to Jan 2013) as part of the NICHD-Fetal Growth Studies. Maternal UtA Dopplers were performed between 18w0d and 25w6d and pregnancy outcomes were collected at delivery including the occurrence of PE and SGA birthweight. Mother-child pairs from the original study were re-recruited to the NIH-Environmental Influences on Child Health Outcomes (ECHO) Study (May 2017 to April 2019). Analysis of neurodevelopment was performed using age-appropriate versions of the NIH Toolbox for children including executive (inhibitory control/attention, cognitive flexibility, and working memory) and motor domains (dexterity, grip strength, and standing balance). Assessment of behavioral problems was obtained by parent report using the Child Behavioral Checklist. Multivariable adjusted general linear and logistic regression models were used to determine the mean difference in standardized test scores of observed child executive and motor functions and parent-reported child behaviors associated with a 1-standard deviation (SD) increment in UtA pulsatility index (PI).

A total of 675 patients had both interrogation of mid-pregnancy UtA Dopplers and at least one measure of executive or motor domain function or parent-reported behavior between the ages of 4 and 8 years. Each 1-SD increase in UtA PI was associated with a significant reduction in cognitive flexibility in children aged 4-7 years (n = 457; adjusted mean difference[aMD] -0.97; 95% CI -1.8, -0.14). There were no associations between motor function and increased UtA resistance. A 1-SD increase in UtA PI was not associated with any increased parent report of child behavioral problems. A 1-SD increase in UtA PI was associated with a 1.5-fold increased risk of PE. In mediation analyses, differences in executive function domains associated with increased UtA PI Doppler findings were not explained by either maternal PE, SGA, or birthweight z-scores.

Increased maternal mid-pregnancy UtA resistance appears to be associated with small decreases in executive domain function (cognitive flexibility) but not motor domain function. In this exploratory study, the observed effect sizes were modest and the clinical implications are uncertain, but they suggest the possibility of long-term neurodevelopmental effects of subclinical placental dysfunction in low-risk pregnancies. The findings, however, are biologically plausible and contribute to a growing body of literature exploring antenatal predictors of child neurodevelopment. Larger confirmatory studies will be needed to determine if maternal UtA resistance can contribute to the early identification of at-risk children.

Clinicaltrials.gov identifiers: NCT00912132, NCT03266198.