Association of first trimester prescription opioid use with congenital malformations in the offspring: population based cohort study

Abstract

Objective To evaluate the risk of first trimester exposure to prescription opioids for major congenital malformations, previously reported to be associated with such exposure. Design Population based cohort study. Setting Nationwide sample of publicly and commercially insured pregnant women linked to their liveborn infants, nested in the Medicaid Analytic eXtract (MAX, 2000-14) and the MarketScan Research Database (MarketScan, 2003-15). Participants 1 602 580 publicly insured (MAX) and 1 177 676 commercially insured (MarketScan) pregnant women with eligibility from at least three months before pregnancy to one month after delivery; infants with eligibility for at least three months after birth. Interventions Use of prescription opioids was ascertained by requiring two or more dispensations of any opioid during the first trimester. Main outcomes measures Major malformations overall, cardiac malformations overall, ventricular septal defect, secundum atrial septal defect/patent foramen ovale, neural tube defect, clubfoot, and oral cleft, defined based on validated algorithms. Propensity score stratification was used to adjust for potential confounders and/or proxies for confounders. Estimates from each database were combined using meta-analysis. Results 70 447 (4.4%) of 1 602 580 publicly insured and 12 454 (1.1%) of 1 177 676 commercially insured pregnant women had two or more dispensations of an opioid during the first trimester. Absolute risk of malformations overall was 41.0 (95% confidence interval 39.5 to 42.5) per 1000 pregnancies exposed to opioids versus 32.0 (31.7 to 32.3) per 1000 unexposed pregnancies in the MAX cohort, and 42.6 (39.0 to 46.1) and 37.3 (37.0 to 37.7) per 1000, respectively, in the MarketScan cohort. Pooled unadjusted relative risk estimates were raised for all outcomes but shifted substantially toward the null after adjustment; for malformations overall (relative risk 1.06, 95% confidence interval 1.02 to 1.10), cardiovascular malformations (1.09, 1.00 to 1.18), ventricular septal defect (1.07, 0.95 to 1.21), atrial septal defect/patent foramen ovale (1.04, 0.88 to 1.24), neural tube defect (0.82, 0.53 to 1.27), and clubfoot (1.06, 0.88 to 1.28). The relative risk for oral clefts remained raised after adjustment (1.21, 0.98 to 1.50), with a higher risk of cleft palate (1.62, 1.23 to 2.14). Conclusions Prescription opioids used in early pregnancy are not associated with a substantial increase in risk for most of the malformation types considered, although a small increase in the risk of oral clefts associated with their use is possible.

Prescribed opioid analgesics in early pregnancy and the risk of congenital anomalies: a population-based cohort study

“…9 Evidence concerning the safety of opioid analgesics for pain in pregnancy is discrepant and limited. [10][11][12][13] Recent studies with Medi caid and private insurance health data from the United States suggested small increases in minor congenital anomalies and oral cleft anomalies with prenatal exposure to opioid analgesics. 10,14 Some studies have reported an increased risk of any anomaly, 15,16 heart anomalies, 7,[16][17][18] spina bifida, 7,19,20 oral cleft anomalies, 10,15,21 gastroschisis 7 and clubfoot 16,22,23 with exposure.…”

Prevalence and duration of prescribed opioid use during pregnancy: a cohort study from the Quebec Pregnancy Cohort

“…In the context of pregnancy, associations between prenatal opioid exposure and neonatal abstinence syndrome [16][17][18][19], as well as certain congenital malformations [10,20,21,45] have been reported in recent studies. Bateman et al [24], using the Medicaid Analytic eXtract (2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014) and MarketScan (2003MarketScan ( -2015 databases, have shown an increased risk of oral clefts associated with hydrocodone (RR 1.39, 95%CI 1.06-1.83) and oxycodone (RR 1.34, 95%CI 0.72-2.50) use in early pregnancy, but not with codeine (RR 0.74, 95%CI 0.40-1.37, 11 exposed cases), which is a weaker opioid. Furthermore, Wen et al [46], using Optum's deidentified Clinformatics Data Mart (2010-2017), have shown an increased risk of neurodevelopmental disorders in early childhood born to women receiving prescription opioids for longer duration, ≥14 days, (HR 1.70, 95%CI 1.05-2.96) or high doses (HR 1.22, 95%CI 1.01-1.54).…”

“…However, opioids are not the preferred treatments for these conditions [27,28], as they are not particularly opioid responsive and are manageable with other nonopioids medications, and nonpharmacological therapies, such as physical or psychotherapy [41]. Given the differences in the safety profile between strong opioids and the major weak opioid codeine [24,46], the increased use of strong opioids during pregnancy with longer treatment duration raises public health concerns.…”

“…Of note, two in three infants with neonatal abstinence syndrome was exposed to prescribed opioids during gestation [17,19]. Associations between maternal use of opioids in pregnancy and increased risk for birth defects [20][21][22][23][24] such as congenital heart defects [20,21], spina bifida [10,20], and oral clefts [24] have been reported in recent studies.…”

Management of cluster headache and other trigeminal autonomic cephalalgias in pregnancy and breastfeeding

“…Other acute treatments that are in use, but have little or no clear evidence of efficacy, include nasal application of lidocaine, noninvasive vagal stimulation and octreotide [2]. Guidelines do not recommend opioid treatment for primary headache disorders [40,41], and first trimester use is associated with a slightly increased risk of oral clefts [42].…”