Hypertensive disorders of pregnancy and neuroimaging markers of dementia risk: A pilot study

Abstract

Background and objectives: Hypertensive disorders of pregnancy (HDP) are associated with a long-term risk of maternal cognitive decline. Limited data exist regarding maternal brain structure in midlife after HDP. We examined the association between prior HDP and neuroimaging markers associated with microvascular brain injury, detected on high-resolution brain MRI.

Methods: We conducted a pilot study embedded within the nuMoM2b Heart Health Study, a multicenter prospective cohort of nulliparous US individuals recruited between 2010 and 2013 in the first trimester of pregnancy. Participants with no history of HDP, preterm birth, small-for-gestational age infant, or stillbirth in any pregnancy, and participants with HDP in the index or any subsequent pregnancy were invited to undergo brain MRI at two study sites between December 21, 2021 and September 30, 2023, using a standardized protocol on identical scanners. Imaging outcomes of interest included white matter hyperintensity (WMH) volume, regional cerebral blood flow (CBF), fractional anisotropy (FA), radial diffusivity (RD), regional grey matter volume (GMV), and cortical thinning.

Results: A total of 81 participants (mean age 39 years; 27% White, 9% non-Hispanic Black, 52% Hispanic, 10% Asian) had brain MRI, of whom 27 (33%) had a history of HDP. The median time from index delivery to MRI was 11 years. Participants with HDP had lower CBF in the left medial orbitofrontal, left inferior temporal, and right superior temporal lobes (Cohen's d = 0.3, cluster-wise corrected p = 0.0002 for all subregions); lower FA in the left superior frontal lobe, right lateral occipital lobe, and right precuneus (d = 0.2-0.3, p ≤ 0.01 for all regions); and higher RD in the bilateral medial orbitofrontal lobes (d = 0.2-0.3, p < 0.001). Cortical thickness, regional GMV, and total WMH volume did not differ between groups. A subgroup analysis including only participants with preeclampsia in the exposed group showed similar results.

Discussion: Midlife individuals who experienced HDP had lower regional CBF and reduced white matter microstructural integrity, compared with those with no adverse pregnancy outcomes. Our results suggest that HDP are associated with long-term impairment of white matter structure and cerebrovascular function, potentially suggesting a mechanism underlying the association of HDP with risk of cognitive decline, and requiring further study.

Keywords: Alzheimer’s disease; dementia; hypertensive disorders of pregnancy; neuroimaging; pregnancy.

FIGURE 1

Flow diagram of the study sample selection. Participants were recruited between December 2021, and September 2023 from eligible nuMoM2b Heart Health Study participants at two study sites (Northwestern University and Columbia University).

FIGURE 2

White matter hyperintensity volume comparison between individuals with and without a history of hypertensive disorders of pregnancy. Panel (A) shows overlapping histograms created using kernel density estimation, detailing the distribution of WMH volumes (cm³) across the frontal, parietal, occipital, and temporal lobes for all participants. Panels (B) through (F) show kernel density estimation–derived violin plots illustrating the data distribution for regional (lobar) and total WMH volume by exposure group. Mean values are indicated by a bold horizontal line, median with red dot, and quartiles by dashed lines. p values calculated using the Mann–Whitney U test are displayed at the top of each plot. APO, adverse pregnancy outcome; HDP; hypertensive disorders of pregnancy; WMH, white matter hyperintensity.

FIGURE 3

Effect size of differences between individuals with and without a history of hypertensive disorders of pregnancy. This figure illustrates the magnitude of effect size (Cohen’s d) differences in MRI-derived metrics between individuals with and without a history of HDP. Variations in cerebral blood flow (A), fractional anisotropy (B), cortical thickness (C), and cortical grey matter volume (D) are visualized on the brain surface to highlight the effect estimates, regardless of statistical significance. The color scale represents effect size and ranges from −0.5 to 0, where positive values indicate an increase and negative values a decrease in the measured metric in individuals with a history of HDP, compared to those with a history of healthy pregnancies. HDP, hypertensive disorders of pregnancy.

FIGURE 4

Surface-based analyses of differences in MRI-derived metrics between individuals with and without a history of hypertensive disorders of pregnancy. Surface-based analysis was conducted on the pial surface to evaluate differences in cerebral blood flow (A), fractional anisotropy (B), radial diffusivity (C), gray matter volume (D), and cortical thickness (E). Analyses were carried out using FreeSurfer and were corrected for multiple comparisons (p < 0.05). The figures are aggregate anatomical representations of the brain, with regional color coding to indicate an increase (red) or decrease (blue) in the respective metrics in the group with a history of HDP, compared to the group with a history of healthy pregnancies. HDP, hypertensive disorders of pregnancy.