Association of Prenatal Maternal Psychological Distress With Fetal Brain Growth, Metabolism, and Cortical Maturation

Importance Prenatal maternal stress is increasingly associated with adverse outcomes in pregnant women and their offspring. However, the association between maternal stress and human fetal brain growth and metabolism is unknown. Objective To identify the association between prenatal maternal psychological distress and fetal brain growth, cortical maturation, and biochemical development using advanced 3-dimensional volumetric magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H-MRS). Design, Setting, and Participants This cohort study prospectively recruited pregnant women from low-risk obstetric clinics in Washington, DC, from January 1, 2016, to April 17, 2019. Participants were healthy volunteers with a normal prenatal medical history, no chronic or pregnancy-induced physical or mental illnesses, and normal results on fetal ultrasonography and biometry studies. Fetal brain MRI studies were performed at 2 time points between 24 and 40 weeks' gestation. Exposures Prenatal maternal stress, anxiety, and depression. Main Outcomes and Measures Volumes of fetal total brain, cortical gray matter, white matter, deep gray matter, cerebellum, brainstem, and hippocampus were measured from 3-dimensional reconstructed T2-weighted MRI scans. Cortical folding measurements included local gyrification index, sulcal depth, and curvedness. Fetal brain N-acetylaspartate, creatine, and choline levels were quantified using 1H-MRS. Maternal stress, depression, and anxiety were measured with the Perceived Stress Scale (PSS), Edinburgh Postnatal Depression Scale (EPDS), Spielberger State Anxiety Inventory (SSAI), and Spielberger Trait Anxiety Inventory (STAI). Results A total of 193 MRI studies were performed in 119 pregnant women (67 [56%] carrying male fetuses and 52 [44%], female fetuses; maternal mean [SD] age, 34.46 [5.95] years) between 24 and 40 gestational weeks. All women were high school graduates, 99 (83%) were college graduates, and 100 (84%) reported professional employment. Thirty-two women (27%) had positive scores for stress, 31 (26%) for anxiety, and 13 (11%) for depression. Maternal trait anxiety was associated with smaller fetal left hippocampal volume (STAI score: -0.002 cm(3); 95% CI, -0.003 to -0.0008 cm(3); P = .004). Maternal anxiety and stress were associated with increased fetal cortical gyrification in the frontal lobe (beta for SSAI score: 0.004 [95% CI, 0.001-0.006; P = .002]; beta for STAI score: 0.004 [95% CI, 0.002-0.006; P < .001]; beta for PSS score: 0.005 [95% CI, 0.001-0.008; P = .005]) and temporal lobe (beta for SSAI score: 0.004 [95% CI, 0.001-0.007; P = .004]; beta for STAI score: 0.004 [95% CI, 0.0008-0.006; P = .01]). Elevated maternal depression was associated with decreased creatine (EPDS score: -0.04; 95% CI, -0.06 to -0.02; P = .005) and choline (EPDS score: -0.03; 95% CI, -0.05 to -0.01; P = .02) levels in the fetal brain. Conclusions and Relevance This study found that the prevalence of maternal psychological distress in healthy, well-educated, and employed pregnant women was high, underappreciated, and associated with impaired fetal brain biochemistry and hippocampal growth as well as accelerated cortical folding. These findings appear to support the need for routine mental health surveillance for all pregnant women and targeted interventions in women with elevated psychological distress. This cohort study examines the association between prenatal maternal psychological distress and fetal brain growth, cortical maturation, and biochemical development by using magnetic resonance imaging and proton magnetic resonance spectroscopy. Question What is the association between maternal stress, anxiety, and depression and in vivo fetal brain growth, metabolism, and cerebral cortical maturation? Findings In this cohort study of 119 pregnant women, prenatal maternal psychological distress was associated with impaired fetal hippocampal development during the late second and third trimesters of gestation and altered fetal cortical gyrification in the frontal and temporal lobes. Maternal depression was also associated with decreased choline and creatine levels in the fetal brain. Meaning Findings from this study suggest that prenatal maternal psychological distress may have an adverse association with brain structure and biochemistry in utero in the human fetus.