Maternal Use of Opioids During Jennifer N. Lind, PharmD, MPH, a, b Julia D. Interrante, MPH, a, c Elizabeth C. Ailes, PhD, MPH, a Suzanne M. Gilboa, PhD, a PregnancySara Khan, MSPH, a, d, e Meghan T. Frey, and MA, MPH, a CongenitalApril L. Dawson, MPH, a Margaret A. Honein, PhD, MPH, a a a, b f, g a Malformations:Nicole F. Dowling, PhD, Hilda Razzaghi, PhD, MSPH, A Andreea Systematic A. Creanga, MD, PhD, Cheryl Review S. Broussard, PhD CONTEXT: abstract Opioid use and abuse have increased dramatically in recent years, particularly OBJECTIVES: among women. We conducted a systematic review to evaluate the association between prenatal DATA SOURCES: opioid use and congenital malformations. We searched Medline and Embase for studies published from 1946 to 2016 and STUDY SELECTION: reviewed reference lists to identify additional relevant studies. We included studies that were full-text journal articles and reported the results of original epidemiologic research on prenatal opioid exposure and congenital malformations. We assessed study eligibility in multiple phases using a standardized, DATA EXTRACTION: duplicate review process. Data on study characteristics, opioid exposure, timing of exposure during pregnancy, congenital malformations (collectively or as individual subtypes), length of RESULTS: follow-up, and main findings were extracted from eligible studies. Of the 68 studies that met our inclusion criteria, 46 had an unexposed comparison group; of those, 30 performed statistical tests to measure associations between maternal opioid use during pregnancy and congenital malformations. Seventeen of these (10 of 12 case-control and 7 of 18 cohort studies) documented statistically significant positive associations. Among the case-control studies, associations with oral clefts and ventricular septal defects/atrial septal defects were the most frequently reported specific malformations. Among the cohort studies, clubfoot was the most frequently reported LIMITATIONS: specific malformation. Variabilities in study design, poor study quality, and weaknesses with outcome CONCLUSIONS: and exposure measurement. Uncertainty remains regarding the teratogenicity of opioids; a careful assessment of risks and benefits is warranted when considering opioid treatment for women of reproductive age. aDivision of Congenital and Developmental Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia; bUS Public Health Service, Atlanta, Georgia; cOak Ridge Institute for Science and Education, Oak Ridge, Tennessee; dDepartment of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia; eCarter Consulting, Atlanta, Georgia; and fDepartment of International Health and gInternational Center for Maternal and Newborn Health, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland To cite: Lind JN, Interrante JD, Ailes EC, et al. Maternal Use of Opioids During Pregnancy and Congenital Malformations: A Systematic Review. Pediatrics. 2017;139(6):e20164131 Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 139, number 6, June 2017:e20164131 REVIEW ARTICLE Opioids are powerful substances risks for fetuses and newborns identifying modifiable risk factors, that bind to opioid receptors in the who are 9exposed to such drugs such as exposure to teratogenic brain and body and are capable of in utero. Spontaneous abortion, substances, during this critical producing numerous physiologic premature rupture of membranes, period. Two recent studies funded by effects, including reduced1 perception preeclampsia, abruption placentae, the Centers for Disease Control and of pain and euphoria. Some and fetal death are all potential Prevention have linked opioid use prescription opioids (eg, methadone obstetric complications10 of prenatal during early pregnancy34, 35 to congenital and buprenorphine) are also used opioid exposure. Adverse neonatal malformations. These studies to treat opioid use disorder (OUD). outcomes that have been– associated report a twofold increased risk for The use, misuse, and abuse of with opioid use during11 pregnancy19 – some congenital heart defects, neural prescription and illicit opioids in include preterm birth, 15, 19 21 tube defects, and gastroschisis and the United States have increased small for gestational10, 13,14, 18, age, 19, 21, 22 lower– highlight the need for a review of the dramatically in recent years, birth weight, – 17, 23 25 entire body of evidence related to particularly among women. Between reduced head circumference,26 28 this critical, yet less discussed, public 1999 and 2010, women experienced and sudden infant death. health concern. a >400% increase in prescription Neonatal abstinence syndrome The objective of this report was to opioid overdose deaths, and for every (NAS) is another adverse outcome systematically review the available overdose death, there were 30 more commonly reported in newborns literature on maternal opioid use opioid misuse/abuse2 emergency prenatally exposed to opioids. during pregnancy and congenital department visits. The incidence of NAS diagnoses malformations. increased nearly fivefold in the Overprescribing practices appear METHODS United States during 2000 to 2012, to be driving the epidemic. In 2012 which suggests an increasing number Data Sources alone, prescribers wrote an estimated 29 of opioid-exposed pregnancies. 259 million opioid prescriptions Neurodevelopmental outcomes of nationwide, which is equivalent prenatally exposed infants are an We identified relevant articles by to 82.5 opioid prescriptions per 3 additional area of concern, because searching electronic databases, 100 persons in the United States. – a recent meta-analysis reported using a combination of opioid- and Among insured, reproductive-aged significant impairments in cognitive, congenital malformation related women, on average, more than one- psychomotor, and observed Medical Subject Headings search quarter filled a prescription for an behavioral outcomes in infants and terms and keywords (Supplemental opioid medication each year during 4 preschool-aged children with chronic Materials) for human studies 2008 to 2012. Rates of illicit opioid 30, 31 intrauterine opioid exposure. published in the English language. use, including heroin abuse and We used the Ovid platform (Ovid dependence, are also increasing. The potential teratogenic effects Technologies, Inc) to conduct From 2002 to 2013, the incidence of of maternal opioid use during literature searches of Medline (1946 women reporting past-year abuse pregnancy are also an area of great to present) and Embase (1988 to or dependence on heroin increased 5 public health concern. Congenital 2016, week 7) for publications 100%. malformations are serious, often indexed through February 19, 2016. Opioid use is high among pregnant costly medical conditions that can We combined and deduplicated women in the United States as cause lifelong challenges. They are the results into a single EndNote well, with an estimated 14% to a leading cause of infant death in X7.5 (Thomson Reuters) library. In 22% of women receiving an opioid6, 7 the United States, accounting for addition, we reviewed the reference prescription during pregnancy. 20% of all deaths32 during the first lists of included publications to From 1998 to 2011, the prevalence year of life. Furthermore, an identifyStudy Selection additional relevant studies. of opioid abuse or dependence estimated $2.6 billion was spent among pregnant women during in 2004 in total hospital costs for hospitalizations for8 delivery children and adults with congenital We included publications in this increased 127%. The high rates malformations, and it is likely that review if they: (1) were full-text of prescription and illicit opioid costs33 have increased since that journal articles (we excluded use are a significant public health time. Congenital malformations can abstracts); (2) reported the results concern, not only for women, but occur at any time during pregnancy, of original epidemiologic research also for their infants. Opioids have but the first trimester is typically (we excluded case reports, case the ability to cross placental and the most vulnerable period. Some series, editorials without original blood-brain barriers, thereby posing malformations can be prevented by data, commentaries without Downloaded from www.aappublications.org/news by guest on September 25, 2021 2 LIND et al – original data, review papers, Research Observational Studies of investigated associations between clinical guidelines, small descriptive Risk Factors of Chronic Diseases prenatal opioid exposure and studies [<100 participants], and criteria for studies with comparison congenital malformations; 13 were duplicate reports); (3) reported groups and (2) Methodological case-control studies and 33 were – on exposure to opioids during Evaluation of Observational Case-Controlcohort studies. Studies pregnancy (we excluded reports Research Observational Studies of based on exposures during labor/ Population Incidence or Prevalence delivery only); and (4) reported the of Chronic Diseases criteria for large 90 The majority (8 of 13) of the included presence or absence of congenital descriptive studies. We selected case-control studies were published malformations (collectively or as these validated quality assessment from 1975 through 1998 (Table 2), individual subtypes) as an outcome.