Additive drug-specific and sex-specific risks associated with co-use of marijuana and tobacco during pregnancy: Evidence from 3 recent developmental cohorts (2003–2015)

Background: Methodologic challenges related to the concomitant use (co-use) of substances and changes in policy and potency of marijuana contribute to ongoing uncertainty about risks to fetal neurodevelopment associated with prenatal marijuana use. In this study, we examined two biomarkers of fetal neurodevelopmental risk—birth weight and length of gestation—associated with prenatal marijuana use, independent of tobacco (TOB), alcohol (ALC), other drug use (OTH), and socioeconomic risk (SES), in a pooled sample (N = 1191) derived from 3 recent developmental cohorts (2003–2015) with state-of-the-art substance use measures. We examined differential associations by infant sex, and multiplicative effects associated with co-use of MJ and TOB. Methods: Participants were mother-infant dyads with complete data on all study variables derived from Growing Up Healthy (n = 251), Behavior and Mood in Babies and Mothers (Cohorts 1 and 2; n = 315), and the Early Growth and Development Study (N = 625). We estimated direct effects on birth weight and length of gestation associated with MJ, TOB, and co-use (MJ x TOB), using linear regression analysis in the full sample, and in male (n = 654) and female (n = 537) infants, separately. Results: Mean birth weight and length of gestation were 3277 g (SD = 543) and 37.8 weeks (SD = 2.0), respectively. Rates of prenatal use were as follows: any use, n = 748 (62.8%); MJ use, n = 273 (22.9%); TOB use, n = 608 (51.0%); co-use of MJ and TOB, n = 230 (19.3%); ALC use, n = 464 (39.0%); and OTH use n = 115 (9.7%.) For all infants, unique effects on birth weight were observed for any MJ use [B(SE) = −84.367(38.271), 95% C.I. −159.453 to −9.281, p =.028], any TOB use [B(SE) = −0.99.416(34.418), 95% C.I. −166.942 to −31.889, p =.004], and each cigarette/day in mean TOB use [B(SE) = −12.233(3.427), 95% C.I. −18.995 to −5.510, p <.001]. Additional effects of co-use on birth weight, beyond these drug-specific effects, were not supported. In analyses stratified by sex, while TOB use was associated with lower birth weight in both sexes, MJ use during pregnancy was associated with lower birth weight of male infants [B(SE) = −153.1 (54.20); 95% C.I. −259.5 to −46.7, p =.005], but not female infants [B(SE) = 8.3(53.1), 95% C.I. −96.024 to 112.551, p =.876]. TOB, MJ, and their co-use were not associated with length of gestation. Conclusions: In this sample, intrauterine co-exposure to MJ and TOB was associated with an estimated 18% reduction in birth weight not attributable to earlier delivery, exposure to ALC or OTH drugs, nor to maternal SES. We found evidence for greater susceptibility of male fetuses to any prenatal MJ exposure. Examination of dose-dependence in relationships found in this study, using continuous measures of exposure, is an important next step. Finally, we underscore the need to consider (a) the potential moderating influence of fetal sex on exposure-related neurodevelopmental risks; and (b) the importance of quantifying expressions of risk through subtle alterations, rather than dichotomous outcomes.