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

Emily S Barrett; Alexandra Sullivan; Tomomi Workman; Yuhong Zhang; Christine T Loftus; Adam A Szpiro; Alison Paquette; James W MacDonald; Michael Coccia; Roger Smith; Maria Bowman; Alicia Smith; Karen Derefinko; Ruby H N Nguyen; Qi Zhao; Sheela Sathyanarayana; Catherine Karr; Kaja Z LeWinn; Nicole R Bush

doi:10.1016/j.psyneuen.2024.106994

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

Psychoneuroendocrinology. 2024 May:163:106994. doi: 10.1016/j.psyneuen.2024.106994. Epub 2024 Feb 16.

Authors

Emily S Barrett¹, Alexandra Sullivan², Tomomi Workman³, Yuhong Zhang³, Christine T Loftus³, Adam A Szpiro⁴, Alison Paquette⁵, James W MacDonald³, Michael Coccia⁶, Roger Smith⁷, Maria Bowman⁷, Alicia Smith⁸, Karen Derefinko⁹, Ruby H N Nguyen¹⁰, Qi Zhao⁹, Sheela Sathyanarayana¹¹, Catherine Karr¹², Kaja Z LeWinn¹³, Nicole R Bush¹⁴

Affiliations

¹ Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ, USA; Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ, USA. Electronic address: [email protected].
² Center for Health and Community, University of California, San Francisco, CA, USA; Department of Psychiatry and Behavioral Sciences, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
³ Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA.
⁴ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁵ Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; Seattle Children's Research Institute, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.
⁶ Center for Health and Community, University of California, San Francisco, CA, USA.
⁷ Mothers and Babies Research Centre, Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.
⁸ Department of Gynecology and Obstetrics, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, USA.
⁹ Department of Preventive Medicine, University of Tennessee Health Sciences Center, Memphis, TN, USA.
¹⁰ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
¹¹ Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; Seattle Children's Research Institute, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹² Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹³ Department of Psychiatry and Behavioral Sciences, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
¹⁴ Center for Health and Community, University of California, San Francisco, CA, USA; Department of Psychiatry and Behavioral Sciences, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA; Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.

PMID: 38387218
DOI: 10.1016/j.psyneuen.2024.106994

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.

MeSH terms

Child, Preschool
Corticotropin-Releasing Hormone
Female
Fetal Development
Humans
Male
Placenta
Pregnancy
Prenatal Care
Prenatal Exposure Delayed Effects*
Problem Behavior*

Substances

Corticotropin-Releasing Hormone