Prenatal glucocorticoids and maternal smoking during pregnancy independently program adult nicotine dependence in daughters: a 40-year prospective study

Abstract

Background: Maternal smoking during pregnancy (MSDP) is an independent risk factor for offspring nicotine dependence (ND), but mechanisms remain unknown. We investigated prenatal glucocorticoid (cortisol) and androgen (testosterone) associations with offspring ND over 40 years and the possibility that prenatal glucocorticoids and androgens would mediate links between MSDP and offspring ND.

Methods: Participants were 1086 mother-adult offspring pairs (59% female) from the New England Family Study, a 40-year longitudinal follow-up of the Collaborative Perinatal Project. MSDP was assessed prospectively at each prenatal visit. Maternal cortisol, testosterone, and cotinine (nicotine metabolite) were assayed from third trimester maternal sera. Offspring lifetime ND was assessed via structured interview.

Results: Significant bivariate associations emerged for: 1) MSDP/cotinine and lifetime ND; and 2) maternal cortisol and lifetime ND, for daughters only. In multivariate models, maternal cortisol and MSDP/cotinine remained significantly and independently associated with increased odds of lifetime ND of daughters. However, cortisol did not mediate the MSDP-lifetime ND relation. No associations emerged between maternal testosterone and offspring ND.

Conclusions: Results provide the first evidence in support of prenatal glucocorticoid programming of adult ND over 40 years in daughters only. Our study highlights two independent prenatal pathways leading to increased risk for ND in daughters: elevated prenatal glucocorticoids and MSDP/nicotine exposure. Daughter-specific effects of glucocorticoid and MSDP programming over 40 years highlight the breadth and persistence of sexually dimorphic programming effects in humans. Results do not support androgen programming of offspring ND.

Keywords: Androgen; cortisol; cotinine; glucocorticoid; maternal smoking during pregnancy; nicotine dependence; programming; testosterone.

Figure 1

Prenatal glucocorticoids and maternal smoking independently predict nicotine dependence in adult daughters (n =544). NOTES. Separate regression models were analyzed to derive path coefficients (standard errors) for each endogenous variable (normal linear regression for maternal cortisol, logistic regression for offspring ND). Results were identical using Structural Equation Modeling to simultaneously estimate all path coefficients. Each regression model controlled for maternal race (Caucasian vs. Other), maternal age at delivery (pure quadratic term), gravida (square root transformed), and socioeconomic status (continuous). Maternal smoking included 3 categories: none (did not smoke; n=218), low (<15 cigarettes per day; n=110), high (15+ cigarettes per day; n=216). Dashed line from MSDP to maternal cortisol highlights the non-significance of this path coefficient. *p<.05 † before including maternal cortisol in the model; †† after including maternal cortisol in the model.