In this study, were compared the maternal reports of CNS depression in breastfed infants exposed to Oxycodone with those in infants who were exposed to Codeine or Acetaminophen alone. The analysis reveals several important features of this potentially fatal adverse reaction: the maternal self-report of neonatal CNS depression is higher in neonates breastfed by mothers mediated with oxycodone than in infants breastfed by mothers medicated with acetaminophen.
Symptomatic infants of mothers medicated with Oxycodone were sleeping longer than asymptomatic infants. In most cases of CNS depression in the oxycodone and codeine cohort, the parents reported dramatic neonatal improvement when exposure of the opioid ceased. There was a dose-response relationship with mothers of symptomatic infants having consumed on average 50% more oxycodone and codeine per kg of maternal body weight. However, some mothers reported neonatal CNS depression when they were consuming as little as 0.03 mg/kg of oxycodone daily. Furthermore, there was a trend for mothers of symptomatic infants of using oxycodone or codeine for longer periods than mothers of asymptomatic infants. Our findings suggest that maternal CNS depression is a strong predictor of neonatal CNS depression for both oxycodone and codeine. When clinicians observe maternal CNS depression, they need to monitor the child for it as well. Finally, mothers medicated with oxycodone were more likely to experience CNS depressive adverse effects in addition to other adverse effects known to be associated with opioid use compared with mothers taking codeine.
Table . Maternal adverse event reported with oxycodone or codeine use during breastfeeding
|Oxycodone (n = 139)||Codeine (n = 139)|
|Sedation∗||92 (%)||21 (%)|
|Other concomitant adverse events|
|Nausea||19 (21)||4 (19)|
|Vomiting||8 (8.6)||2 (9.5)|
|Constipation||23 (25)||13 (62)|
|Dizziness||23 (25)||6 (29)|
|Weakness||8 (8.6)||6 (29)|
|Confusion||1 (1)||0 (0)|
|Rash||0 (0)||2 (9.5)|
Several differences in the 3 cohorts in this study need to be highlighted:
1.First, maternal indications for receiving acetaminophen or opioids were different in the cohorts. This is reflective of the general practice of prescribing Opioids for pain relief after caesarian delivery or episiotomy in Canada. Therefore, questions related to comparative efficacy among Codeine, Oxycodone, and Acetaminophen cannot be addressed by this study.
2. Second, with sequential statistical analysis, mothers in the codeine group were found to be significantly more likely than mothers in the oxycodone group to be first-time mothers. Arguably, the inexperience of first-time mothers may lead to hypervigilance and increased anxiety, which could translate to increased reporting of CNS depressive symptoms. Although we observed a similar incidence of neonatal CNS depression between oxycodone and codeine, parity could have biased these results, causing over-reporting of CNS depression in the codeine group.
3. Third, infants who were exposed to oxycodone via breast milk were slightly younger in the oxycodone group as compared with the codeine and acetaminophen groups. Pharmacodynamic modeling has revealed that compromised neonatal opioid clearance capacity (which is closely related to age) may predispose infants to CNS depressive adverse effects when exposed to maternal opioids. However, within the oxycodone group, there was no difference in PMA between symptomatic infants and asymptomatic infants.
The major limitation of this study was its retrospective nature, and thus the potential for recall bias was introduced. Furthermore, the population of mothers interviewed were self-selected because they took the initiative to call the Motherisk Program and ask for safety advice. It is possible that these women may have exhibited increased vigilance in monitoring their infants for symptoms of adverse drug reaction than the general population, but this increased attention would also likely improve recall of the event. The control group or acetaminophen cohort was deemed critical to account for non-specific features that may resemble neonatal CNS depression especially when they are based on maternal reports. In accordance, there is only one maternal-positive report of infant CNS depression when a mother was breastfeeding and consuming acetaminophen alone.
In conclusion, maternal consumption of Oxycodone is associated with an increased risk of CNS depression in the breastfed infant, such that 1 in 5 breastfed infants with mothers medicated with oxycodone experienced symptoms of CNS depression. Therefore, replacement of codeine by oxycodone during breastfeeding cannot be assumed to be safe for the child and the mother. In the future, prospective and pharmacogenetic studies are needed to investigate other factors related to maternal oxycodone use and neonatal CNS depression.