Intrauterine Opioid Exposures and Congenital Heart Disease

Abstract

The rise in opioid use has impacted women of childbearing age, leading to a surge in children born following intrauterine opioid exposure. While previous studies have suggested associations between opioid exposure in utero and congenital heart disease, there has been limited high-quality data supporting this association. There have been no models testing the effects of sustained opioid exposure on cardiac development or exploration of underlying mechanisms of opioids resulting in CHD. To fill the gap in available literature I pursued three aims. First, I analyzed large deidentified national databases (Vizient and Mariner 170) and identified a significantly increased incidence of both moderate-severe and minor CHD in neonates with substantial opioid exposure (exhibiting withdrawal at birth). This query demonstrated that compared to controls there was increased pulmonary artery stenosis, atrioventricular septal defects, and defects of the aorta. Second, I performed a detailed patient-level analysis of mother-infant dyads with CHD and without CHD in a cohort of infants with substance exposures. This revealed that illicit opioids were used in 100% of CHD dyads, significantly more than non-CHD dyads. Third, I established experimental models in Zebrafish and human cardiac organoids to assess developmental consequences of commonly prescribed opioid, buprenorphine. In zebrafish, buprenorphine exposure resulted in abnormal cardiac morphology, increased chamber size, and cardiac malformations, while co-treatment with naloxone did not mitigate these effects. In human cardiac organoids, buprenorphine impaired differentiation and resulted in dose dependent effects on cardiac conduction. These findings support a link between sustained opioid exposure and disrupted cardiac development and highlight the need for further investigations and patient monitoring.