Higher maternal socioeconomics offer little protection against toxic prenatal stress

Summary: Maternal stress and anxiety alter the structure and biochemistry of the developing fetal brain.

Source: Children’s National Hospital

When pregnant women experience elevated anxiety, stress or depression, these prenatal stressors can alter the structure of the developing fetal brain and disrupt its biochemistry – even if these women have uncomplicated pregnancies and high socioeconomic status, according to Children’s National Hospital research published online Jan. 29, 2020, in JAMA Network Open.

“Previously we found that 65% of pregnant women who received a diagnosis of fetal congenital heart disease had elevated levels of stress. It’s concerning but not surprising that pregnant women who wonder if their baby will need open heart surgery would feel stress,” says Catherine Limperopoulos, Ph.D., director of the Center for the Developing Brain at Children’s National and the study’s senior author. “In this latest study, we ran the same panel of questionnaires and were surprised to find a high proportion of otherwise healthy pregnant women whose unborn babies are doing well also report high levels of stress.”

Anxiety and depression are the most common mental health problems during pregnancy. To learn more about the implications for the developing fetal brain, the Children’s National research team recruited 119 healthy volunteers with low-risk pregnancies from obstetric clinics in Washington, D.C., from Jan. 1, 2016, to April 17, 2019. The women’s mean age was 34.4 years old. All were high school graduates, 83% were college graduates, and 84% reported professional employment.

The team performed 193 fetal brain magnetic resonance imaging (MRI) sessions between 24-40 weeks gestation and measured the volume of the total fetal brain as well as the cortical gray matter, white matter, deep gray matter, cerebellum, brainstem and hippocampus volumes. On the same day as their MRI visit, the pregnant women completed validated questionnaires to measure maternal stress, anxiety and depression, answering questions such as “how do you feel right now,” “how do you generally feel” as well as the degree of stressful feelings they experienced the month prior.

Of the pregnant women in the study:

  • 27% tested positive for stress
  • 26% tested positive for anxiety
  • 11% tested positive for depression
  • Maternal anxiety and stress were associated with increased fetal cortical gyrification
  • Elevated maternal depression was associated with decreased creatine and choline levels in the fetal brain
  • Maternal stress scores decreased with increasing gestational age, while anxiety and depression did not

“We report for the first time that maternal psychological distress may be associated with increased fetal local gyrification index in the frontal and temporal lobes,” says Yao Wu, Ph.D., a research associate working with Limperopoulos at Children’s National and the study’s lead author. “We also found an association with left fetal hippocampal volume, with maternal psychological distress selectively stunting the left hippocampal volumetric growth more than the right. And elevated maternal depression was associated with decreased creatine and choline levels in the fetal brain,” Wu adds.

Late in pregnancy – at the time these women were recruited into the cohort study – the fetal brain grows exponentially and key metabolite levels also rise. Creatine facilitates recycling of adenosine triphosphate, the cell’s energy currency. Typically, levels of this metabolite rise, denoting rapid changes and higher cellular maturation; creatine also is known to support cognitive function. Choline levels also typically rise, marking cell membrane turnover as new cells are generated and support memory, mental focus and concentration.

This shows brain scans from the study
T2-Weighted Magnetic Resonance (MR) Imaging Brain Segmentation. Segmentation results of total brain (orange), cortical gray matter (green), white matter (blue), deep gray matter (brown), brainstem (yellow), cerebellum (light blue), left hippocampus (purple) and right hippocampus (red) on a 3-Dimensional reconstructed T2-weighted MR image of a fetus at 26.4 gestational weeks. The hippocampus plays a central role in memory and behavioral inhibition and contains high concentrations of corticosteroid receptors and, thus, this brain region is sensitive to stress. Image is credited to JAMA Network Open.

“These women were healthy, and of high socioeconomic status and educational level, leading us to conclude that the prevalence of prenatal maternal psychological distress may be underestimated,” Limperopoulos adds. “While stress is an everyday reality for most of us, this is different because elevated stress during pregnancy can alter fetal brain programming. Our findings underscore the critical need to universally screen all pregnant women for prenatal psychological distress, even young mothers whose pregnancies wouldn’t otherwise raise red flags.”

In addition to Drs. Limperopoulos and Wu, Children’s National study co-authors include Yuan-Chiao Lu, Ph.D., research associate; Marni Jacobs, Ph.D., biostatistician; Subechhya Pradhan, Ph.D., research faculty; Kushal Kapse, MS, staff engineer; Li Zhao, Ph.D., research faculty; Nickie Niforatos-Andescavage, M.D., neonatologist; Gilbert Vezina, M.D., director of the neuroradiology program; and Adré J. du Plessis, M.B.Ch.B., director, Fetal Medicine Institute. Research coordinators Catherine Lopez, MS, Kathryn Lee Bannantine, BSN, and Jessica Lynn Quistorff, MPH, assisted with subject recruitment.

Funding: Financial support for the research described in this post was provided by the National Institutes of Health under grant No. RO1 HL116585-01 and the Thrasher Research Fund under Early Career award No. 14764.

About this neuroscience research article

Children’s National Hospital
Media Contacts:
Diedtra Henderson – Children’s National Hospital
Image Source:
The image is credited to JAMA Network Open.

Original Research: Open access
“Association of Prenatal Maternal Psychological Distress With Fetal Brain Growth, Metabolism, and Cortical Maturation”. Catherine Limperopoulos et al.
JAMA Network Open doi:10.1001/jamanetworkopen.2019.19940.


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

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.


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.

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).

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 cm3; 95% CI, –0.003 to –0.0008 cm3; P = .004). Maternal anxiety and stress were associated with increased fetal cortical gyrification in the frontal lobe (β for SSAI score: 0.004 [95% CI, 0.001-0.006; P = .002]; β for STAI score: 0.004 [95% CI, 0.002-0.006; P < .001]; β for PSS score: 0.005 [95% CI, 0.001-0.008; P = .005]) and temporal lobe (β for SSAI score: 0.004 [95% CI, 0.001-0.007; P = .004]; β 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.

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