Concerns have been raised about the widespread use of opioid analgesics in the general population, and specifically among pregnant women.
In women of reproductive age, U.S. claims data for the years 2008-2012 indicate that 39.4% of Medicaid-enrolled women and 27.7% of privately insured women had at least one opioid analgesic prescription claim.1 Among pregnant women, approximately 4.4% reported use of opioid analgesics any time in the month before and throughout gestation in a sample of 11,724 control mothers who participated in the National Birth Defects Prevention Study (NBDPS) 1998-2011.2
Previous studies of first-trimester exposure to opioid analgesics have shown inconsistent associations with selected major congenital anomalies. A 2011 analysis of 1,693 first-trimester codeine-exposed pregnancies enrolled in the Norwegian Mother and Child Cohort Study found no evidence of an increased risk of major birth defects overall (odds ratio, 0.8; 95% confidence interval, 0.5-1.1), compared with 65,316 unexposed pregnancies. However, this study had insufficient power to examine modest associations with most specific major birth defects.3
In contrast, two recent case-control studies have demonstrated significantly increased risks for early pregnancy opioid analgesic use and specific defects.
Broussard et al (2011) used data from the NBDPS 1997-2005 to test hypotheses related to specific defect associations previously reported in the literature, as well as to explore associations with additional defects. Therapeutic opioid use in early pregnancy was reported by 2.6% of 17,449 case mothers and 2.0% of 6,701 control mothers. The authors confirmed associations with some specific heart defects, (for example, conoventricular septal defects, atrioventricular septal defects, and hypoplastic left heart syndrome), and spina bifida, with ORs ranging from 2.0 to 2.7. In exploratory analysis, gastroschisis was also significantly associated with opioid analgesic exposure in early pregnancy (OR, 1.8; 95% CI, 1.1-2.9). Although additional analyses were performed stratified by specific opioid product (codeine, hydrocodone, oxycodone, meperidine), as might be expected, the most commonly used products (codeine and hydrocodone) were linked to a greater number of elevated ORs for specific defects.4
In the second case-control study, Yazdy et al (2013) used data collected in four cities in the United States and Canada and from two birth defect registries between 1998 and 2010 to examine periconceptional opioid use and risk for neural tube defects. The adjusted OR for spina bifida, comparing mothers of malformed infants with mothers of non-malformed infants, was 2.5 (95% CI, 1.3-5.0). To help rule out the possible contribution of recall bias, a sensitivity analysis was also conducted comparing mothers of malformed infants with mothers of infants with other malformations not implicated in the Broussard NBDPS study. The adjusted OR in this secondary analysis was somewhat attenuated but remained significantly elevated (adjusted OR, 2.2; 95% CI, 1.1-4.1).5
The usual limitations apply to these large case-control studies, including the potential for mothers to inaccurately recall the use of, and specific gestational timing of, exposure to these medications. However, the sensitivity analysis conducted in the Yazdy et al study suggests that this bias did not account for the association between opioid analgesics and spina bifida. Although a wide range of important potential confounders were considered in both studies, unmeasured confounding could be a contributing factor. For example, it would be useful to have a comparison group of pregnant women with similar indications but no treatment with opioid analgesics during embryogenesis.
From a clinical perspective, given the proportion of unplanned pregnancies and the high prevalence of opioid analgesic dispensing in the United States, the potential for pregnancy should be considered when these medications are prescribed for women in their reproductive years. In a recognized pregnancy, to date, the risks reported for early pregnancy exposure are generally modest for specific defects. The rarity of even the most common of these specific defects means that these elevated ORs translate to very low absolute risks for any individual pregnancy.
As with other medications with a similar profile, need for the medication should be considered at the time of prescribing, and if an opioid analgesic is needed, consider the lowest effective dose of the most effective medication given for the shortest period of time necessary.
References
1. MMWR Morb Mortal Wkly Rep. 2015; 64:37-41 .
2. Birth Defects Res A Clin Mol Teratol. 2015 Aug;103(8):703-12 .
3. Eur J Clin Pharmacol. 2011 Dec;67(12):1253-61 .
4. Am J Obstet Gynecol. 2011 Apr;204(4):314.e1-11 .
5. Obstet Gynecol. 2013 Oct;122(4):838-44 .
Dr. Chambers is professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She receives no industry funding for the study of opioid analgesic medications in pregnancy. She does receive research funding for studies of other medications and vaccines in pregnancy from Amgen, AbbVie, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Pfizer, Roche-Genentech, Sanofi-Genzyme, Seqirus, Takeda, Teva, UCB. Email her at obnews@frontlinemedcom.com.
