Sex-specific associations between placental corticotropin releasing hormone and problem behaviors in childhood

Abstract

Placental corticotropin-releasing hormone (pCRH) is a neuroactive peptide produced in high concentrations in mid-late pregnancy, during key periods of fetal brain development. Some evidence suggests that higher pCRH exposure during gestation is associated with adverse neurodevelopment, particularly in female offspring. In 858 mother-child dyads from the sociodemographically diverse CANDLE cohort (Memphis, TN), we examined: (1) the slope of pCRH rise in mid-late pregnancy and (2) estimated pCRH at delivery as a measure of cumulative prenatal exposure. When children were 4 years-old, mothers reported on problem behaviors using the Child Behavior Checklist (CBCL) and cognitive performance was assessed by trained psychologists using the Stanford-Binet Intelligence Scales. We fitted linear regression models examining pCRH in relation to behavioral and cognitive performance measures, adjusting for covariates. Using interaction models, we evaluated whether associations differed by fetal sex, breastfeeding, and postnatal neighborhood opportunity. In the full cohort, log-transformed pCRH measures were not associated with outcomes; however, we observed sex differences in some models (interaction p-values≤0.01). In male offspring, an interquartile (IQR) increase in pCRH slope (but not estimated pCRH at delivery), was positively associated with raw Total (β=3.06, 95%CI: 0.40, 5.72), Internalizing (β=0.89, 95%CI: 0.03, 1.76), and Externalizing (β=1.25, 95%CI: 0.27, 2.22) Problem scores, whereas, in females, all associations were negative (Total Problems: β=-1.99, 95%CI: -3.89, -0.09; Internalizing: β=-0.82, 95%CI: -1.42, -0.23; Externalizing: β=-0.56, 95%CI: -1.34, 0.22). No associations with cognitive performance were observed nor did we observe moderation by breastfeeding or postnatal neighborhood opportunity. Our results provide further evidence that prenatal pCRH exposure may impact subsequent child behavior in sex-specific ways, however in contrast to prior studies suggesting adverse impacts in females, steeper mid-gestation pCRH rise was associated with more problem behaviors in males, but fewer in females.

Keywords: CRH; Child behavior; DOHaD; Neurodevelopment; Placental corticotropin releasing hormone; Sex differences.

Figure 1.. Fully adjusted multiple linear regression models examining two measures of pCRH (log pCRH at delivery and pCRH slope) in relation to child behavior (CBCL scores)¹ and cognitive performance (IQ)² at age 4. Sex-specific estimates were derived from reparameterized models.³ Log(pCRH slope) was rescaled by IQR (0.047).

CBCL: Child Behavior Checklist; FSIQ: full scale intelligence quotient; IQ: intelligence quotient 1 Adjusted for maternal age, child age at study visit, pre-eclampsia/gestational hypertension, birth order, maternal education, household income, insurance status, marital status, child opportunity index, maternal cotinine, duration of breastfeeding, childhood secondhand smoke exposure, maternal pre-pregnancy BMI, alcohol use in pregnancy, prenatal vitamin use. Models looking at all children are additionally adjusted for child sex. 2 Models with IQ as the outcome include the covariates above plus maternal IQ. 3 The n’s are 844 and 858, respectively, for models examining CBCL scores and IQ scores. Reparameterized models include the full cohort (male and female) while also permitting the estimation of slopes for each level of the moderator (e.g., for males and females) without sacrificing power by stratifying the sample. For analyses of CBCL scores, the sample includes 418 males and 426 females. For analyses of IQ, the sample includes 421 males and 437 females.