Introduction

It is estimated that about 13% of pregnant women in the United States suffer from an anxiety related disorder, and 13.3% from a mood disorder, including depression.1 Published evidence has shown that there are negative effects of antenatal depression and anxiety on offspring, including hyperactivity and inattention in boys, emotional problems in both boys and girls, and atopic disorders including asthma.2-3 However, less is known about why these negative effects would happen. Evaluating infant’s brain development right after birth provides an opportunity to link maternal depression/anxiety during pregnancy with later unfavorable neurodevelopmental outcomes. In this study, diffusion tensor imaging (DTI) was utilized to examine brain white matter microstructural development in newborns from mothers who had normal pregnancy and were recruited for evaluation of depression and anxiety symptoms at ~36 weeks of gestation. The goal of this study is to see whether there are significant associations between infants’ white matter development and their mothers’ depression and anxiety test scores.

Methods

This is a prospective study in which healthy pregnant women were recruited and studied at ~36 weeks of pregnancy, and their newborns were studied at age ~2 weeks. Inclusion criteria for the pregnant women included: singleton pregnancy, <36 weeks of pregnancy, and ≥ 18 years of age. Exclusion for the pregnant women included: hypertension, diabetes, or other preexisting medical conditions known to influence fetal growth, medications known to influence fetal growth, recreational drug, tobacco, or alcohol use while pregnant, pregnancy conception with assisted fertility treatment, and medical conditions developed during pregnancy (such as gestational diabetes, preeclampsia) suspected to influence fetal growth. Infants born preterm (<37 weeks of gestation), with congenital defects, small for gestational age, with a low Apgar score or any other medical complications at birth affecting development were also excluded. Maternal anxiety and depression scores were obtained using the State-Trait Anxiety Inventory (STAI) and Beck Depression Inventory, Second Edition (BDI-II), which were both administered by a licensed psychological examiner at ~36 weeks of pregnancy. Both the state (S) result and the trait (T) result of the STAI examination were obtained, yielding a total of three psychological scores per maternal subject. In addition, maternal IQ was also assessed using the Wechsler Abbreviated Scale of Intelligence, Second Edition (WASI-II). At around age 2 weeks, the infants underwent an MRI examination of the brain at natural sleep without sedation using a Siemens PRISMA scanner and a 20-channel head coil. Pulse sequences included 3D T1 and T2 weighted images to screen for structural abnormalities by neuroradiologists, and diffusion weighted images with b value ranging from 0 to 1500 and diffusion directions uniformly distributed in 99 directions. In total, 34 infants had both valid DTI data and valid STAI data from their mothers; and 32 of them also had valid BDI data from their mothers. Fractional anisotropy (FA) maps for these infants were calculated using the scanner software and were exported to a workstation with FSL (version 6.0, created by the Oxford Center for Functional MRI of the Brain, Oxford, UK) installed on a VMware Linux virtual machine (VMware, Palo Alto, Calif) for post-processing. Through the use of FSL’s tract-based spatial statistics (TBSS) toolbox, each image was eroded slightly and end slices zeroed to remove outliers. The FA image sets were then registered to each other using nonlinear transformation to find the most representative image set which then consequently served as the target images. Each FA data set was then centered and layered on top of the target images, and a mean FA map and white matter skeleton for all subjects were then generated. All FA maps were then projected onto the FA skeleton to create a 4D FA maps dataset encompassing all subjects and subsequently used for statistical analysis. Voxel-wise correlation analyses were utilized in TBSS to evaluate associations between FA values and BDI/STAI scores. Each correlation analysis was computed with 2000 permutations and compared with the empirical null distribution to correct for multiple comparisons. Effects of potential confounders were adjusted by including as covariates in the correlation analyses. These covariates included postmenstrual age (gestational age at birth plus age at MRI) which has been shown strong effects on infant white matter development, and maternal IQ as well as infant sex.

Results

As shown in Figure 1, voxel-wise TBSS analysis accounting for potential cofounders showed that maternal state anxiety (S-STAI and T-STAI scores) negatively correlated with infant FA values in multiple areas of white matter tracts. These areas include frontal white matter, internal capsules, corpus callosum, and the limbic system. In addition, multiple white matter regions also showed a trend of negative correlations (P<0.10, corrected) between maternal depression (BDI scores) and FA values. Higher BDI/STAI scores in the pregnant women, which implies more symptomatic for depression and anxiety, correlated with lower FA values in some brain regions in their newborns, which implies less white matter development.

Conclusion

Our results demonstrated that healthy full-term infants born from uncomplicated pregnancies of mothers with higher S-STAI, T-STAI, and BDI scores have lower white matter development (as indicated by lower FA values) in multiple brain regions. Maternal depression/anxiety, even at a subclinical level, may negatively impact the in utero brain development.

Acknowledgements

This project was supported by NIH/NIGMS 1P20GM121293-6283. The PI and his research team was also supported by USDA/ARS 6251-51000-006-00D