Safety and Pharmacogenetics of Oxycodone in Post-Cesarean Analgesia and Breastfeeding Dyads: A Proactive Approach to Precision Medicine

<b>Background</b>: The aim of the study is (1) to assess safety of opioids in nursing mothers after cesarean delivery and in breastfed infants and (2) to evaluate the role of CYP2D6 genetics in maternal and infant clinical outcomes after cesarean delivery. <b>Methods</b>: A total of 210 mother-infant dyads were enrolled after cesarean delivery. Oxycodone 5 mg orally was administered every 4-6 h as needed as part of a standardized opioid-sparing ERAS protocol. Primary outcomes were opioid-related adverse effects, including maternal respiratory depression (RD) and postoperative nausea and vomiting (PONV) and neonatal composite side effects (i.e., RD monitoring, sedation, and limpness). <b>Results</b>: In total, 77% of mothers received opioids during postpartum hospital stay, none experienced respiratory depression, 13% reported PONV, and composite opioid-related side effects were observed in 13% of neonates. Compared to mothers without opioid consumption, higher in-hospital opioid consumption was borderline significantly associated with a higher risk of neonatal composite side effects (adjusted relative risk, aRR = 3.79; 95%CI: 1.01-14.28; <i>p</i> = 0.07), with a similar trend toward higher risk in maternal PONV (aRR = 2.56; 95%CI: 0.70-9.29; <i>p</i> = 0.36). Mothers with a CYP2D6 ultra-rapid metabolizer phenotype also showed higher rates of PONV and neonatal composite side effects compared with normal or intermediate phenotypes, although these associations were not statistically significant. <b>Conclusions</b>: Higher maternal in-hospital opioid consumption is associated with a higher risk of neonatal composite side effects. Using the lowest effective doses of opioids as needed could reduce the risk of opioid-related side effects in neonates. Preoperative genotyping may help identify mothers and breastfed neonates at increased risk for opioid-related adverse outcomes. Additional studies are needed to evaluate preoperative genotyping and to evaluate the causality of increased neonatal adverse outcomes.