Table 1 The impact of prenatal maternal psychological distress on human brain and behavioral development in the offspring.
Article | Subject size | Maternal distress measure | Imaging modality | Age at scan | Child behavior measure | Age at behavioral testing | Results |
|---|---|---|---|---|---|---|---|
Wu et al. [4] | 119 | STAI; PSS; EPDS at 24–40 GW | sMRI; MRS | 24–40 GW | – | – | Maternal trait anxiety was associated with smaller fetal left HIP volume. Maternal anxiety and stress were associated with increased fetal cortical gyrification in the frontal lobe and temporal lobe. Elevated maternal depression was associated with decreased creatine and choline levels in the fetal brain. |
De Asis-Cruz et al. [33] | 50 | STAI, PSS, EPDS at 24–39 GW | rs-fcMRI | 24–39 GW | – | – | Region specific changes in connectivity associated with trait and state anxiety, for example, FC between the superior frontal regions and somatosensory cortices correlated positively with trait and state anxiety scores. |
Pradhan et al. [103] | 131 | PSS, STAI at 18–37 GW | MRS | 18–37 GW | – | – | Eleveted maternal stress and anxiety were associated with higher levels of lactate in the fetal brain. Higher levels of lactate and scyllo-inositol in fetuses from the pandemic cohort vs pre-COVID pandemic. |
Van Den Heuvel et al. [106] | 64 | CES-D, STAI, PSWQ, PSS, SWLS at MRI visit | rs-fcMRI | 20–39 GW | subscale of CBC, actigraphy data analyses | 3 and 5 yrs | Increased maternal stress and negative affect were associated with increased sleep problems during toddlerhood and weakened fetal CRB-insular FC; altered fetal FC did not mediate association between maternal negative affect and toddler sleep problems. |
Thomason et al. [201] | 118 | CES-D, STAI-T, PSWQ, PSS, SWLS | rs-fcMRI | 26–39 GW | – | – | Increased maternal prenatal negative affect/stress was associated with alterations in fetal frontoparietal, striatal, and temporoparietal connectivity. |
Rajagopalan et al. [91] | 45 | Coronavirus Perinatal Experiences-Impact Survey; Brief Coping Orientation to Problems Exposed questionnaire | sMRI; rs-fcMRI | 24–38 GW | – | – | Increased maternal perception of pandemic-related stress was associated with increased normalized fetal brainstem volume and reduced global fetal brain temporal functional variance. |
Hendrix et al. [107] | 77 | PSS, CES-D, STAI; maternal cortisol at MRI visit | rs-fcMRI | 32.82±3.86 GW | – | – | Maternal distress positively correlated with HIP connectivity to the right posterior parietal cortex, this relationship was moderated by fetal sex; higher maternal cortisol associated with increased coupling between HIP and dorsal anterior cingulate cortex, left medial PFC. |
Wu et al. [35] | 140 | STAI; PSS; EPDS at 21–40 GW | sMRI | 21–40 GW | – | – | Maternal stress and anxiety were associated with smaller left and right HIP and CRB volumes among women with fetal congenital heart disease. Impaired HIP regions were noted in the medial aspect of left HIP head and inferior aspect of right HIP head and body. Impaired CRB regions were noted in the anterior superior aspect of vermal and paravermal regions and the left CRB lobe. |
Wu et al. [34] | 97 | STAI; PSS; EPDS at 24–40 GW | sMRI; MRS | 24–40 GW | Bayley-III; ITSEA; PSI-SF | 18 mos | Prenatal maternal stress was negatively associated with infant cognitive performance, and this association was mediated by fetal left HIP volume. |
Lu et al. [32] | 202 | STAI; PSS; EPDS at MRI visit | sMRI | 26.1–35.3 GW | – | – | Elevated maternal anxiety and stress were associated with smaller fetal HIP and CRB volumes. Higher trait anxiety was associated with lower white matter volume. Elevated maternal anxiety and depression were associated with higher cortical sulcal depth. |
Ramphal et al. [122] | 112 | Composite SES score from various sources measured at birth | rs-fcMRI | 39.3 ± 1.2 wks | ITSEA | 2 yrs | Low SES at birth, which has been linked to maternal stress has also been correlated with altered neonatal striatal and medial prefrontal connectivity, which in turn mediated the relationship with low socio-economic status and behavioral inhibition at two years of age |
Moog et al. [14] | 86 | PSS in early, mid and late pregnancy | sMRI | 5–64 days | Bayley-III | 6 and 12 mos | Maternal PSS was inversely associated with newborn left HIP volume. Newborn left HIP volume was positively associated with infant social-emotional development across the first year after birth. |
Lautarescu et al. [92] | 413 | EPDS at prenatal 22–40 GW and postnatal 36.57–44.71 GW | DTI | 36.57–44.71 weeks PMA | CBC; Q-CHAT; BSID-III; Parenting Scale | 18 mos | Maternal depression was positively associated with infant fiber density in the uncinate fasciculus, with left uncinate fasciculus fiber density, in turn, positively associated with social-emotional abilities in toddlerhood. Higher maternal depression predicted toddler social-emotional difficulties, but this relationship was not mediated by fiber density in the left uncinate fasciculus. |
Groenewold et al. [86] | 124 | BDI at 28–32 GW | sMRI | 2–6 weeks after birth | – | – | Larger volumes in the right AMY and bilateral caudate nucleus were observed in prenatal maternal depression exposed compared to unexposed infants. Larger HIP volume in prenatal maternal depression exposed females only. |
Qiu et al. [36] | 175 | STAI at 26 GW | sMRI | At birth; 6 mos | – | – | No influence of maternal anxiety on HIP volumes at birth. Neonates with maternal anxiety showed slower growth of bilateral HIP volumes over first 6 months compared to neonates with no antenatal maternal anxiety. |
Qiu et al. [18] | 146 | STAI at 26 GW | sMRI | Newborn | – | – | Negative associations of maternal anxiety with cortical thickness in bilateral precentral gyrus and the dorsolateral PFC. Positive associations of maternal anxiety with cortical thickness in the right ventrolateral PFC and the right superior parietal cortex and precuneus. |
Lautarescu et al. [202] | 251 | STAI; SLE in the past yr before study | DTI | 37.86–45.71 GW | – | – | Higher SLE scores were associated with higher axial, radial, and mean diffusivity in the left uncinate fasciculus, and higher axial diffusivity in the right uncinate fasciculus in preterm infants at term age. |
Graham et al. [93] | 34 | STAI; BDI during late pregnancy | DTI | 2 wks after birth | – | – | Maternal STAI scores negatively correlated with FA values in the left orbitofrontal, prefrontal, and middle frontal WM, and the right middle frontal WM; BDI scores negatively correlated with FA values in one cluster in right middle frontal WM. |
Rifkin-Graboi et al. [15] | 157 | EPDS at 26 GW | sMRI; DTI | 6–14 days | – | – | Lower FA and axial diffusivity but not volume in the right AMY in the infants of mothers with high vs. those with low-normal EPDS scores. |
Rifkin-Graboi et al. [16] | 54 | STAI at 26 GW | DTI | 5–17 days | – | – | Elevated maternal anxiety was associated with reduced FA in right insular cortex, middle occipital and inferior temporal regions, angular gyrus, uncinate fasciculus, posterior cingulate, parahippocampus, dorsolateral prefrontal, inferior frontal regions, and inferior fronto-occipital fasciculus, and bilateral superior temporal and left postcentral regions. |
Lehtola et al. [89] | 123 | SCL-90 and EPDS at 14, 24 and 34 GW | sMRI | 2–5 wks | – | – | Prenatal maternal SCL + EPDS sum score was negatively associated with newborn left and right AMY volumes in males only. |
Acosta et al. [87] | 105 | EPDS at 14, 24 and 34 GW | sMRI | 11–54 days | – | – | EPDS scores were weakly positively associated with right AMY volume in infants with a low polygenic risk score for major depressive disorder (PRS-MDD) and weakly negatively in infants with a high PRS-MDD. EPDS at 24 GW showed a sex-specific interaction with PRS-MDD. |
Hashempour et al. [17] | 84 | EPDS at 14, 24 and 34 GW | DTI | 11–54 days | – | – | Compared with girls, boys exposed to greater maternal depressive symptoms during 14 GW showed higher left AMY MD. |
Dean et al. [94] | 101 | EPDS, STAI at 28 and 35 GW | DWI | 18–50 days | – | – | Elevated maternal depression and anxiety were associated with decreased neurite density and increased mean, radial, and axial diffusivity in right frontal white matter microstructure. Lower FA and intracellular volume fraction in females and higher FA and intracellular volume fraction in males exposed to elevated maternal depression and anxiety. |
Scheinost et al. [19] | 26 | Retrospective review for diagnosis of depression and/or anxiety in the maternal medical chart | sMRI; rs-fcMRI | 35–40 wks PMA | – | – | Preterm neonates with exposure to prenatal stress show less connectivity between the left AMY and the thalamus, the hypothalamus, and the peristriate cortex. Exposure to prenatal stress exacerbates reductions in limbic connectivity in very premature newborns, such that AMY and subcortical FC was reduced in stress-exposed vs non-exposed preterm infants. |
Scheinost et al. [108] | 46 | PSS, RADS, PDQ during the 2nd and 3rd trimesters | rs-fcMRI | 40–44 wks PMA | mobile conjugate reinforcement task | 4 mos | Maternal distress during the 3rd trimester was associated with weaker HIP-cingulate cortex and HIP-temporal lobe FC in newborns. 2nd trimester cortisol levels were linked to reduced HIP-cingulate FC and increased HIP-temporal FC; weaker bilateral HIP and posterior cingulate cortex connectivity linked to higher maternal depression; connectivity between the HIP and dorsal anterior cingulate cortex, which was inversely associated with maternal stress, was also noted to be positively correlated with infant memory. |
Rajasilta et al. [112] | 21 | EPDS, anxiety subscale of SCL-90 at 24 GW | rs-fcMRI | 42.43–46.43 wks PMA | – | – | Composite depression and anxiety scores positively associated with the amplitude of regional neuronal activity in the newborn medial PFC. |
Brady et al. [110] | 319 | SES and crime data from various sources | rs-fcMRI | 28–41 wks PMA | – | – | Reduced AMY and anterior DMN connectivity in newborn offspring of women exposed to high prenatal psychosocial stress and who are living in neighborhoods with high property or violent crimes. |
Graham et al. [117] | 70 | cortisol 5 times/day for 4 consecutive days in early, mid, and late gestation; CES-D over the first 2 years of life | rs-fcMRI | 3.65 ± 1.72 wks | CBC | 24 mos | Higher cortisol levels correlated with greater AMY connectivity to networks like the DMN and emotion regulation circuitry; AMY connections that are strongly correlated with maternal cortisol levels predicted internalizing scores on the CBC at 2 years of age; this effect of cortisol on outcomes was observed in females only. |
Posner et al. [111] | 64 | PSS, HAM-D, CES-D at 34–37 GW | rs-fcMRI | 5.8 ± 1.7 wks | – | – | Heightened depression during the 3rd trimester were associated with reduced connectivity to PFC circuits around 5 weeks of life. |
Manning et al. [113] | 75 | EPDS, PROMIS Anxiety scale, SSEQ prenatally and 3 mos postpartum | DTI; rs-fcMRI | 92 ± 14 days | – | – | Prenatal maternal distress was associated with higher FA in the right uncinate fasciculus and lower MD in the right amygdala prefrontal white matter tract. In infants of women who were pregnant during the COVID-19 pandemic and who had low social support, there was a weaker connectivity between the right AMY and superior orbitofrontal cortex. |
Humphreys et al. [109] | 33 | CRISYS, LSCR at prenatal visit | rs-fcMRI | 4.81±0.93 months | – | – | Reduced functional coupling between AMY and mPFC in stress-exposed infants, in contrast to structural connectivity between these two areas that increased with maternal stress. |
Qiu et al. [37] | 24 | EPDS at 26 GW and 3 mos postpartum | rs-fcMRI | 66.58 ± 1.82 PMA | – | – | Elevated maternal depression in the 2nd trimester linked to increased AMY connectivity to areas of the brain involved in socio-emotional processing and memory at 6 months. |
Lebel et al. [25] | 52 | EPDS in each trimester of pregnancy and at 3 mos postpartum | sMRI; DTI | 2.6–5.1 yrs | – | – | Maternal 2nd trimester EPDS scores negatively correlated with children’s cortical thickness in right inferior frontal and middle temporal regions and with radial and mean diffusivity in lateral portions of the uncinate, inferior fronto-occipital, and arcuate fasciculi. Postpartum EPDS scores negatively correlated with children’s right superior frontal cortical thickness and with diffusivity in white matter originating from that region. |
Hay et al. [95] | 54 | EPDS at 11, 16.8 and 31.5 GW and 3 mos postpartum | DTI | 2.85–6 yrs | CBC | Within 6 mos of the MRI | 3rd trimester EPDS scores were associated with higher MD in the AMY-frontal tract and the cingulum. Altered structural connectivity between the AMY and frontal cortex mediated the relationship between 3rd trimester maternal depression and child externalizing behavior in males only. |
Wen et al. [39] | 235 | EPDS at 26 GW and 3 mos postpartum; Beck’s Depression Inventory-II at 1, 2, 3 and 4.5 yrs | sMRI; DTI | 4.5 yrs | – | – | Greater prenatal maternal depressive symptoms were associated with larger right AMY volume in girls only. Increased postnatal maternal depressive symptoms were associated with higher right AMY FA in the overall sample and girls, but not in boys. |
Acosta et al. [90] | 28 | EPDS at 14, 24 and 34 GW, 3, 6 mos and 1, 2, and 4 yrs postpartum. SCL-90-Revised at 14, 24 and 34 GW, 3, 6 mos and 2, 4 yrs. PRAQ-R2 at 24 and 34 GW | sMRI | 4 yrs | – | – | Elevated depressive symptoms of the early 2nd trimester, after controlling for prenatal maternal general anxiety, were related to smaller right AMY volumes in the overall sample. Higher depressive symptoms of the 3rd trimester were associated with smaller right AMY volumes in boys compared to girls. |
Acosta et al. [22] | 27 | PRAQ-R2 at 24 and 34 GW; EPDS and SCL-90-Revised at 14, 24, and 34 GW | sMRI | 4 yrs | Strength and Difficulties Questionnaire | 4 yrs | Higher pregnancy-related anxiety in the 2nd trimester was related to greater left-relative AMY volume in girls vs. boys. Both maternal pregnancy-related anxiety and child’s AMY volume are related to child emotional and behavioral difficulties. The left AMY volume may partly mediate sex-specific associations between pregnancy-related anxiety and child behavioral difficulties. |
Soe et al. [114] | 128 | EPDS, BDI-III at 26 GW, 3 mos, 1, 2, 3, and 4.5 yrs after birth | rs-fcMRI | 4.4–4.8 yrs | – | – | Greater maternal depression associated with weakened AMY connectivity of the AMY to the cortico-striatal circuitry, particularly in the insula, putamen, orbitofrontal cortex, and temporal pole in young girls. |
Donnici et al. [115] | 54 | EPDS, SCL-90-Revised during the 2nd trimester and 12 wks postpartum | rs-fcMRI; sMRI | 3–7 yrs | – | – | Elevated maternal anxiety in the 2nd trimester linked to greater negative AMY connectivity to bilateral somatosensory cortices and left inferior parietal lobule. |
van der Knaap et al. [116] | 39 | BSI at 20–25 GW and 3 yrs after birth | Task-based fMRI | 6–9 yrs | – | – | Increased AMY responsivity to pictures of negative emotional faces in children exposed to maternal depression in utero. |
Buss et al. [23] | 35 | Pregnancy anxiety scale at mean 19, 25, and 31 GW; PSS at 8 wks after birth | sMRI | 6–9 yrs | – | – | Maternal anxiety at 19 GW was associated with gray matter volume reductions in the PFC, the premotor cortex, the medial temporal lobe, the lateral temporal cortex, the postcentral gyrus as well as the CRB extending to the middle occipital gyrus and the fusiform gyrus. |
El Marroun et al. [20] | 636 | BSI at 20.6 GW and 3 yrs. | DTI | 6–9 yrs | – | – | Elevated prenatal maternal depressive symptoms were associated with higher MD in the uncinate fasciculus, and lower FA and higher MD in the cingulum bundle. |
El Marroun et al. [21] | 654 | BSI at 20.6 GW and 3 yrs. | sMRI | 6–10 yrs | – | – | Elevated prenatal maternal depressive symptoms were associated with a thinner superior frontal cortex and larger caudal middle frontal area in the left hemisphere. |
Buss et al. [26] | 65 | Maternal cortisol at 15, 19, 25, 31, and 37 GW | sMRI | 7 yrs | CBC | 7 yrs | Higher cortisol levels at 15 GW were associated with larger right AMY volume and more affective problems in girls. The association between maternal cortisol levels and children’s affective problems was partially mediated by AMY volume. |
Davis et al. [85] | 74 | PSS at 15, 19, 31, and 37 GW and 2 mos and 12 yrs after birth; CES-D at 12 yrs | sMRI | 7 yrs | Children’s Depression Inventory | 12 yrs | Prenatal maternal stress was associated with less cortical thickness primarily in frontal and temporal regions and with elevated depressive symptoms; child cortical thickness additionally correlated with adolescent depressive symptoms. |
Davis et al. [203] | 91 | Plasma cortisol, STAI, and CES-D at mean 19 and 31 GW; DBI at MRI visit | sMRI | 6–9 yrs | WISC-IV; Expressive Vocabulary Test-2 | 6–9 yrs | Elevated maternal cortisol levels during the 3rd trimester were associated with greater child cortical thickness primarily in frontal regions and enhanced child cognitive performance. |
Sarkar et al. [27] | 22 | SLE in pregnancy and since birth; EPDS at 17 months | DTI | 6–9 yrs | – | – | Maternal SLE was correlated positively with right uncinate fasciculus FA, and negatively with right uncinate fasciculus perpendicular diffusivity in children. |
Sandman et al. [24] | 81 | CES-D at 19, 25, and 31 GW | sMRI | 6–9 yrs | CBC | 6–9 yrs | Maternal depression at 25 GW was associated with cortical thinning, primarily in the right superior, medial orbital, and frontal pole regions of the PFC. The association between maternal depression at 25 GW and child externalizing behavior was mediated by cortical thinning in right prefrontal areas. |
Sandman et al. [204] | 97 | Maternal plasma measuring placenta corticotropin-releasing hormone at 15, 19, 25, 31, and 36 GW | sMRI | 6–9 yrs | Child Behavior Checklist | 6–9 yrs | Fetal exposure to elevated levels of placenta stress hormone (corticotropin-releasing hormone) was associated with cortical thinning, primary in temporal, paracentral, and frontal areas. At 19 GW, this association was stronger in girls vs. boys; at 31 GW, this association was globally in boys but locally in the temporal pole in girls. Reduced regional cortical volumes contribute to cognitive and emotional deficits in children. |
Zou et al. [205] | 3469 | BSI at prenatal, 2 mos, 3 and 10 yrs postpartum; EPDS at 2 mos | sMRI; DTI | 10 yrs | Brief Problem Monitor | 10 yrs | Children exposed to elevated maternal depression across the perinatal period had smaller gray and white matter volumes and lower white matter FA vs. non-exposed children. The gray matter volume mediated the association between postnatal maternal depressive symptoms and child attention problems. |
Jones et al. [88] | 63 | Storm32; IES-R; interview questions | sMRI | 11.5 yrs | CBC | 11.5 yrs | In boys, subjective distress during late pregnancy was associated with larger right AMY/total brain volume, which explained higher levels of externalizing behavior. In girls, later gestational exposure to the ice storm was associated with larger AMY/total brain volume; higher levels of objective prenatal stress were associated with more externalizing problems, which was mediated by larger AMY/total brain volume. |
McKee et al. [38] | 127 | IES-R; Objective Ice Storm Hardship and Cognitive Appraisal Questionnaires | sMRI | 11.5 yrs | – | – | Prenatal maternal stress exposure led to altered bilateral HIP volumes, and volumetric changes in subfields CA1, subiculum and stratum radiatum/lacunosum-moleculare. A negative maternal cognitive appraisal of the storm’s consequences predicted smaller adolescent HIP volumes. |
Jensen et al. [96] | 393 | SLE at 18 GW, and 8, 21, 33, 47 mos, 12–16 yrs after birth | DTI; sMRI | 18–21 yrs men | – | – | Prenatal stress is associated with lower magnetization transfer ratio and myelin water fraction in the genu and/or splenium of the corpus callosum, and with lower magnetization transfer ratio in white matter. |
Mareckova et al. [31] | 93 | SLE during the first 20 GW | sMRI | 23–24 yrs | Profile of Mood States questionnaire | 23–24 yrs | Higher prenatal stress predicted more mood dysregulation, lower overall gray matter volume, and lower gray matter volume in mid-dorsolateral frontal cortex, anterior cingulate cortex, and precuneus in young adulthood. |
Mareckova et al. [30] | 85 | SLE at 20 GW, at birth, and 6, 18 mos after birth | sMRI | 23–24 yrs | Profile of Mood States questionnaire | 23–24 yrs | Early prenatal stress was associated with sex-dependent medium-to-large effects in cortical gyrification in large temporal, parietal, and occipital regions; Later perinatal stress was associated with sex-independent small-to-medium effects in smaller, more anterior regions. In females, early prenatal stress predicted higher cortical gyrification index in a large temporal region, which was further associated with mood disturbance in adulthood. |
Mareckova et al. [29] | 131 | Depression symptom questionnaire in midpregnancy, after birth, 6 and 18 mos after birth | sMRI | 23–24 yrs | Profile of Mood States questionnaire; STAI | 23–24 yrs | Elevated prenatal maternal depression showed a linear relationship with elevated brain age gap (i.e., the difference between chronological and structural brain age). Brain age gap further showed a quadratic relationship with anxiety and dysregulated mood in the adult offspring. |
Mareckova et al. [206] | 260 | EPDS at 20 GW, 2 wks, 6 and 18 mos after birth | sMRI | 23–24 yrs, repeat at 28, 30 yrs | – | – | Elevated prenatal maternal depression was associated with greater positive differences between structural and chronological brain age in adult offspring at late 20 s. |
Turk et al. [207] | 49 | Dutch version of the STAI at 12–22 GW | rs-fcMRI | 28 yrs | – | – | Exposure to high anxiety in utero linked to weakened connectivity between the medial PFC and inferior gyrus, left lateral PFC, and sensorimotor cortex. |
Favaro et al. [28] | 35 | Interview to recall stressful events during pregnancy; Hopkins-SCL; STAI | sMRI; rs-fcMRI | 14–40 yrs | – | – | Elevated prenatal stress was associated with decreased gray matter volume in the left medial temporal lobe and AMY and increased functional connectivity between the left medial temporal lobe and the pregenual cortex. |
