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.
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.
An individual’s neurodevelopmental trajectory is not only determined by their genetic heritage, but also by interaction with the environment, in particular during sensitive periods of rapid cell division throughout fetal and early postnatal life. An adverse early environment may lead to neurodevelopmental changes that have lasting negative effects on health over the lifespan. During the last decades, there has been increasing scientific interest in studying adverse programming effects of the ‘environmental’ factor maternal psychosocial stress in pregnancy on offspring neurodevelopment.
A non-systematic search in PubMed using the terms maternal stress and child/offspring development, crudely reflecting all articles that have been published on programming effects of prenatal stress, yielded a total of 3824 articles, of which the majority (62.8%) were published in the past decade (Figure 1).
Evidence from Human Studies
Translating the findings from animal studies to human populations is challenging. There is evidence that transient fluctuations in early experiences such as stress could have greater long-term impacts in small, short-lived species compared with large, long-lived species such as humans.
This implies greater buffering of the negative effects of early-life stress in humans compared to animals . Furthermore, human studies on prenatal stress rely on observations of a wide variety of stressful experiences, traumatic events and mood disorders, which are commonly clustered under the term stress both in the scientific literature as well as in public press.
Stress may refer to common daily hassles (e.g., work- or parenting-related), but also to severe traumatic experiences such as domestic violence or the death of a close relative. Another category is formed by the acute stress caused by natural disasters, terrorist attacks, or wars. Thus, stress is used as an umbrella term for a whole range of phenomena reflecting different types of negative experiences or feelings ranging from uncomfortable (mild) to extremely traumatic (severe).
It seems unlikely that all these types of stress induce a similar biochemical response in the pregnant women and that they have similar consequences for the offspring. Mild to moderate stress is also highly common.
For example, in healthy populations of pregnant women across the globe, mild to moderate stress is reported by more than half of respondents [6,7]. If this level of stress would lead to an impaired neurodevelopment of the unborn child following the fetal programming paradigm, the majority of children alive today would be affected.
The number of women who experience more severe forms of stress during their pregnancy is substantially lower. For example, intimate partner violence (IPV) or post-traumatic stress disorder (PTSD) during pregnancy are reported by much smaller numbers of women, 3% and 3.3% for IPV and PTSD respectively [8,9].
‘Internal’ causes of stress, such as psychopathology including a clinical depressive disorder or a general anxiety disorder affect respectively 11.9%  and 4.1–15%  of pregnant women. However, studies that use a screening tool to identify women at risk of developing a depressive or anxiety disorder report much higher numbers: up to 25% during pregnancy [11,12]
The substantial differences in percentages of pregnant women experiencing these various types of prenatal ‘stress’ reflects the unique nature of each stressor, in terms of its cause, symptoms and treatment. The potential consequences for child neurodevelopment of each distinctive type of stress should be distinguished accordingly, because they are likely to be very different.
The conceptualization and quantification of ‘stress severity’ is extremely challenging, and cut-off scores for ‘severe’ symptoms of stress, depression, or anxiety vary among studies. Nevertheless, studies on associations between extreme prenatal stress, for example caused by the death of a loved one or a natural disaster, and child (neuro)development in humans generally suggest that severe prenatal stress is associated with an increased risk for preterm birth, low birth weight, and a wide variety of neurodevelopmental, behavioral, and emotional disorders as well as impaired cognitive function.
For example, women who experienced the death or serious illness of a close relative during pregnancy or in the 6 months before conception gave birth to babies with an average weight of 27 grams lighter compared to babies born from women who did not experience such an event . Another study showed that severe objective stress during pregnancy caused by an Ice Storm in the Canadian Provence of Quebec resulting in 40 days of power loss was associated with lower IQ scores of the offspring at age 5.5 years .
In contrast to these severe forms of stress, studies on milder forms of prenatal stress, such as elevated anxiety and depression symptoms without an actual clinical diagnosis, daily hassles, or parenting stress, do not consistently show an increased risk for poorer neurodevelopment in children [15,16].
For example, in one study, prenatal depression, anxiety, and daily stress symptoms were measured during the second trimester in financially stable, well-nourished women without traumatic experiences in pregnancy.
Neither depression, nor anxiety, nor non-specific stress predicted poorer child development at age two, suggesting that in non-clinical populations, stress is not harmful for the developing child’s brain .
Another important consideration in interpreting human studies that describe associations between prenatal stress and child neurodevelopmental outcomes is their fundamental inability to prove a causal relationship.
Some of these studies use a cross-sectional design, where women are asked to recall their pregnancy and report whether they were stressed at the time. This is highly susceptible to recall bias, as mothers of children with behavioral deficits may be more prone to report prenatal stress in retrospect.
Observational studies, in which women are prospectively followed from pregnancy onwards, eliminate recall bias. However, observational studies are hampered by the presence of co-occurring risk factors that may relate to both prenatal stress as well as an altered child developmental trajectory, such as socioeconomic status or smoking behavior. Additionally, postnatal alterations in maternal behavior likely explain at least part of the associations observed between prenatal stress and child neurodevelopment.
This is reflected by the fact that in many studies associations between prenatal stress and an adverse neurodevelopmental outcome in children disappear after adjusting for postnatal maternal mood .
Consequences for Society
The growing body of literature on prenatal stress and child neurodevelopment has led to increased attention for prenatal stress and following recommendations to prevent stress during pregnancy [15,18,19,20]. Although these recommendations are aimed at preventing prenatal stress, they may paradoxically induce it. In the non-pregnant population, it has been shown that the perception that stress impacts health is associated with poor (mental) health .
The increased awareness about stress among women of childbearing age was reflected in a poll we recently conducted on an online platform (www.womb-project.nl) among platform visitors (mostly women between 18–40 years of age). In this poll, stress during pregnancy was chosen by 32% of the voting women of reproductive age, above other topics including smoking, nutrition, sleep, exercise, and infant attachment as a topic related to child development that “requires more attention from researchers”.
Although we do not know the exact reasons why the majority of women of childbearing age chose stress as the most important topic to be studied, the poll results indicate that the topic highly appeals to women of childbearing age. As a scientific community, we should consider whether these apparent concerns are well-grounded, in particular since the majority of pregnant women is likely to experience some sort of stress. Distressing the majority of pregnant women by communicating to them that stress will directly harm their unborn child seems intuitively counterproductive. Warning women about the harmful effects of stress may merely induce more stress.
For example, a study including 3000 predominantly highly-educated white pregnant women measured psychosocial hassles, such as money worries, worries about the pregnancy, job problems, or fights with the partner. It appeared that 64% of women could be classified as experiencing medium to high stress. High prenatal stress (reported by 27% of participants) was a significant predictor of maternal reporting of gastrointestinal illness, respiratory illness, and total illness of the child during the first year, and also to more urgent care visits and emergency department visits concerning the child .
The general public could draw the immediate conclusion that worries about money or a fight with a partner during pregnancy leads to a child with fragile health. However, an important limitation in this study, acknowledged by the authors in the discussion section of this article, is that the questionnaires on child illnesses were completed by the mothers.
It is not inconceivable that women who report a lot of stress during their pregnancy are also more concerned later on about the health of their children and are thus more likely to seek medical aid compared to women who do not experience high stress. Moreover, more objective disease parameters, such as fever or actual hospitalization, were not increased in the children of mothers with high prenatal stress, indicating that in this study high prenatal stress did not seem to affect child disease risk. Such nuances are of great importance for the interpretation of study results and the subsequent recommendations that reach healthy pregnant women with occasional stress .
A final but no less important argument for reassuring pregnant women and eventually society about the effects of mild stress during pregnancy on child neurodevelopment is to alleviate the blame that is often placed on pregnant women themselves by society.
Typically, pregnant women are publicly blamed for any type of behavior or experience that may adversely affect the health of the fetus, regardless of the significance of the actual impact, while the substantial contribution from her partner, her direct social environment, and society are unjustly being underexposed . In fact, the role of society in the context of individual prenatal stress is substantial, and potentially modifiable.
Chronic stress, depression, and anxiety in the prenatal period are consistently more frequent in low- and middle-income countries (LMIC) [23,24]. Poverty, war, and domestic and/or sexual violence, which occur more often in LMIC, all contribute to the increased levels of stress, depression, and anxiety described in pregnant women [25,26]. Hence, there is a huge potential for improving maternal mental well-being globally by addressing these risk factors individually, which is pre-eminently a role for local governments and global health organizations.
An additional reason to apply caution in warning pregnant women for the dangers of prenatal stress for their child’s neurodevelopment is the lack of understanding we currently have about a clear mechanism providing a satisfactory explanation on how prenatal stress may affect the fetal brain in humans.
In preclinical studies, we can directly study the biological alterations on a cellular level in prenatally stressed animals. These studies have shown that various types of gestational stress and excess maternal and fetal plasma corticosterone levels can induce epigenetic changes, leading to a reduced glucocorticoid and mineralocorticoid receptor density in the hippocampus, accompanied by a greater and prolonged hypothalamic-pituitary-adrenal (HPA) response to stress in the offspring [4,27].
Directly examining brain tissue is not feasible in humans, and studies that indirectly assess the assumed biological mechanisms, for example by studying buccal cells, cord blood, or placental tissue, are still in its infancy . Increased HPA axis activity in the stressed pregnant woman resulting in higher levels of the human stress hormone cortisol has often been proposed as a key mediator linking maternal stress to an altered fetal neurodevelopment.
However, studies in overall healthy pregnant women with low to moderate levels of stress have not shown robust support for the hypothesis that prenatal stress directly increases maternal cortisol levels [28,29]. On the other hand, a study that included pregnant women with a clinically significant major depressive disorder did show a substantially altered cortisol dysregulation compared to healthy pregnant individuals .
This suggests that only in pregnant women with severe symptoms of ‘stress’, a substantial biological response in terms of heightened cortisol may be present. In line with findings from animal studies, depression and anxiety, as well as partner violence and war-related stress during pregnancy, have been associated with increased Deoxyribonucleic acid (DNA) methylation of fetal genes involved in the stress response in human studies .
However, DNA methylation studies in humans generally include small numbers. Additionally, in these studies, the alterations of DNA methylation have not yet been linked to long-term neurobehavioral changes in children, and the clinical relevance of changes in DNA methylation remains uncertain. Robust evidence from Randomized Controlled Trials that aim to investigate whether reducing prenatal stress by psychological treatments prevents epigenetic alterations, structural and functional brain measures and neurodevelopmental, behavioral, emotional, and cognitive deficits should provide further insight.
Such experimental trials in humans pose many methodological challenges and have only recently started to emerge. Some small studies have provided clues that treatment of clinically depressed pregnant women improves short-term infant outcomes and ameliorates DNA methylation of the glucocorticoid receptor gene in buccal cells [32,33].
However, these studies are underpowered, and substantially larger studies are warranted before we can conclude that prenatal psychological treatment of depression and anxiety has a beneficial effect on child neurodevelopment, and which biochemical alterations in the maternal-fetal compartment are involved.
Intervention studies directed at other stressors such as daily hassles, or bereavement induced by the death of a relative, and how this relates to the neurodevelopment of the child needs to be further investigated, because as each different type of stressor may initiate a different biological cascade with unique effects on child neurodevelopment.
Children’s National Hospital