A study found evidence that prenatal alcohol exposure (PAE) and exposure to medications for opioid use disorder (MOUD) may perturb serotonin expression patterns, which has the potential to affect brain development and health across the lifespan of the child. These findings were published in Experimental Neurology.

This study sourced data from the Ethanol, Neurodevelopment, Infant and Child Health (ENRICH) cohort which recruited women with a singleton pregnancy at the University of New Mexico affiliated prenatal care clinics. The targeted cohorts were pregnant women with PAE (n=20), pregnant women who were receiving MOUD and did not use alcohol during pregnancy (n=28), pregnant women with MOUD and PAE (n=20), and healthy controls without substance exposure (n=20). For this study, tissues from participant placenta were collected and evaluated by RNA (ribonucleic acid) and proteomic analyses.

The cohorts were aged mean 26.6 to 28.5 years, 80.0%-95.0% were White, their perceived stress scores were 10.5-16.3 points, infants were born at 38.1-39.3 weeks’ gestation, and weighed 2856.6-3448.2 g. Significantly more of the substance-exposed infants were born with respiratory distress (P <.001) and the MOUD-exposed infants had symptoms of opioid withdrawal syndrome (P <.0001).

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In the multivariable regression analysis, nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) mRNA had a positive relationship with PAE (β, 0.41; P <.1) and a negative relationship with MOUD + PAE (β, -0.54; P <.1). Overall, there was an interaction observed between birth weight and placental tumor necrosis factor (TNF) -α mRNA expression (β, -0.0004; P <.05).

Alcohol exposure was found to have an independent effect on tryptophan hydroxylase (TPH1) mRNA (β, -0.78; P <.05) and serotonin transporter (SERT) mRNA (β, -0.01; P <.01) expression.

In the final model, 12% of the variance in interleukin (IL)-1b was explained by cohort, infant birth weight, and mode of delivery. Nearly a quarter of the variance in SERT (24%) was explained by cohort, maternal age, infant sex, and hepatitis infection status.

In the proteomics model, MOUD was negatively related with TNF-α protein expression (β, -0.12; P <.05).

Overall, placenta biomarkers had significant interactions between mode of delivery and IL-1b mRNA expression (β, -0.70; P <.05), infant male sex with IL-1b protein expression (β, -0.29; P <.01), infant birth weight with TNF-α mRNA expression (β, -0.0004; P <.05), maternal age with SERT mRNA expression (β, 0.001; P <.05), maternal viral hepatitis C with SERT mRNA expression (β, -0.02; P <.01), and maternal viral hepatitis C and TPH1 mRNA expression (β, 0.68; P <.05).

This study may have been biased by relying on self-reported substance use.

The study authors concluded, “To our knowledge, our study provides the first evidence that PAE may inhibit the important protective mechanism the serotonin transporter performs in human placenta while simultaneously promoting increased TPH1 protein expression. Together, this may result in increased 5-hydroxytryptamine in fetal circulation, which may significantly influence fetal neurodevelopment. Furthermore, it appears that MOUD and alcohol disturb the bidirectional, dynamic interaction between the placental immune and serotonin system.”


Ruyak SL, Noor S, DiDomenico J, et al. Effects of prenatal opioid and alcohol exposures on immune and serotonin factors in human placenta. Exp Neurol. 2022;353:114057. doi:10.1016/j.expneurol.2022.114057