Confounding of the Comparative Safety of Prenatal Opioid Agonist Therapy

There has been a striking increase in rates of opioid use in pregnant women and in neonatal abstinence syndrome (NAS) in their infants in the United States and Canada. NAS is a drug withdrawal syndrome that most commonly manifests from in utero opioid exposure and affects the neonate’s postnatal life adaptation in critical areas of sleep, feeding, and autonomic function. NAS incidence rose from 1.20 to 3.39 per 1,000 American live-births from 2000 to 2009, and from 0.28 to 4.29 per 1000 Canadian live-births from 1992 to 2011.Total hospital charges for NAS grew from $190 to $720 million United States during this period. Significant increases in the rate of neonatal intensive care unit admissions for NAS, the median length of neonatal hospitalization for NAS, and neonatal receipt of pharmacotherapy for NAS in the Unites States from 2004 to 2014 were recently observed.

Studies have attributed this increase in NAS to rising rates of opioid addiction in pregnant women.Some cohort studies and randomized controlled trials (RCTs) have observed decreased NAS severity, lower risk of NAS treatment, and higher gestational age at birth , birth weight, body length and head circumference in buprenorphine vs. methadone exposed neonates. Evidence, however, is subject to bias from study drop out in RCTs and by confounding in cohort studies . A meta-analysis showed that confounding may account for some of the protective effect of buprenorphine vs. methadone on NAS severity, and that limited data on confounding of the comparative safety of buprenorphine vs. methadone on NAS are available.

Consequently, when the regression model is unadjusted for an important confounder-such as an important difference in clinical profile—the estimated measure of effect (i.e., risk ratio, mean difference) is a mix of the effect of prenatal opioid agonist exposure on NAS and the confounder effect on NAS. Confounding can attenuate, increase, or reverse the true effect of prenatal opioid exposure to buprenorphine vs. methadone on neonatal outcomes. The impact of confounding depends on the strength of the relationships between the confounder and the exposure, the confounder and the outcome, and the prevalence of the confounder.