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Review Article

Maternal Use of Opioids During Pregnancy and Congenital Malformations: A Systematic Review

Jennifer N. Lind, Julia D. Interrante, Elizabeth C. Ailes, Suzanne M. Gilboa, Sara Khan, Meghan T. Frey, April L. Dawson, Margaret A. Honein, Nicole F. Dowling, Hilda Razzaghi, Andreea A. Creanga and Cheryl S. Broussard
Pediatrics June 2017, 139 (6) e20164131; DOI: https://doi.org/10.1542/peds.2016-4131
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Abstract

CONTEXT: Opioid use and abuse have increased dramatically in recent years, particularly among women.

OBJECTIVES: We conducted a systematic review to evaluate the association between prenatal opioid use and congenital malformations.

DATA SOURCES: We searched Medline and Embase for studies published from 1946 to 2016 and reviewed reference lists to identify additional relevant studies.

STUDY SELECTION: 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, duplicate review process.

DATA EXTRACTION: Data on study characteristics, opioid exposure, timing of exposure during pregnancy, congenital malformations (collectively or as individual subtypes), length of follow-up, and main findings were extracted from eligible studies.

RESULTS: 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 specific malformation.

LIMITATIONS: Variabilities in study design, poor study quality, and weaknesses with outcome and exposure measurement.

CONCLUSIONS: 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.

  • Abbreviations:
    MMT —
    methadone maintenance treatment
    NAS —
    neonatal abstinence syndrome
    OMT —
    opioid maintenance treatment
    OUD —
    opioid use disorder
    VSD —
    ventricular septal defect

    • Opioids are powerful substances that bind to opioid receptors in the brain and body and are capable of producing numerous physiologic effects, including reduced perception of pain and euphoria.1 Some prescription opioids (eg, methadone and buprenorphine) are also used to treat opioid use disorder (OUD). The use, misuse, and abuse of prescription and illicit opioids in the United States have increased dramatically in recent years, particularly among women. Between 1999 and 2010, women experienced a >400% increase in prescription opioid overdose deaths, and for every overdose death, there were 30 more opioid misuse/abuse emergency department visits.2

    Overprescribing practices appear to be driving the epidemic. In 2012 alone, prescribers wrote an estimated 259 million opioid prescriptions nationwide, which is equivalent to 82.5 opioid prescriptions per 100 persons in the United States.3 Among insured, reproductive-aged women, on average, more than one-quarter filled a prescription for an opioid medication each year during 2008 to 2012.4 Rates of illicit opioid use, including heroin abuse and dependence, are also increasing. From 2002 to 2013, the incidence of women reporting past-year abuse or dependence on heroin increased 100%.5

    Opioid use is high among pregnant women in the United States as well, with an estimated 14% to 22% of women receiving an opioid prescription during pregnancy.6,7 From 1998 to 2011, the prevalence of opioid abuse or dependence among pregnant women during hospitalizations for delivery increased 127%.8 The high rates of prescription and illicit opioid use are a significant public health concern, not only for women, but also for their infants. Opioids have the ability to cross placental and blood-brain barriers, thereby posing risks for fetuses and newborns who are exposed to such drugs in utero.9 Spontaneous abortion, premature rupture of membranes, preeclampsia, abruption placentae, and fetal death are all potential obstetric complications of prenatal opioid exposure.10 Adverse neonatal outcomes that have been associated with opioid use during pregnancy include preterm birth,11–19 small for gestational age,15,19–21 lower birth weight,10,13,14,18,19,21,22 reduced head circumference,17,23–25 and sudden infant death.26–28 Neonatal abstinence syndrome (NAS) is another adverse outcome commonly reported in newborns prenatally exposed to opioids. The incidence of NAS diagnoses increased nearly fivefold in the United States during 2000 to 2012, which suggests an increasing number of opioid-exposed pregnancies.29 Neurodevelopmental outcomes of prenatally exposed infants are an additional area of concern, because a recent meta-analysis reported significant impairments in cognitive, psychomotor, and observed behavioral outcomes in infants and preschool-aged children with chronic intrauterine opioid exposure.30,31

    The potential teratogenic effects of maternal opioid use during pregnancy are also an area of great public health concern. Congenital malformations are serious, often costly medical conditions that can cause lifelong challenges. They are a leading cause of infant death in the United States, accounting for 20% of all deaths during the first year of life.32 Furthermore, an estimated $2.6 billion was spent in 2004 in total hospital costs for children and adults with congenital malformations, and it is likely that costs have increased since that time.33 Congenital malformations can occur at any time during pregnancy, but the first trimester is typically the most vulnerable period. Some malformations can be prevented by identifying modifiable risk factors, such as exposure to teratogenic substances, during this critical period. Two recent studies funded by the Centers for Disease Control and Prevention have linked opioid use during early pregnancy to congenital malformations.34,35 These studies report a twofold increased risk for some congenital heart defects, neural tube defects, and gastroschisis and highlight the need for a review of the entire body of evidence related to this critical, yet less discussed, public health concern.

    The objective of this report was to systematically review the available literature on maternal opioid use during pregnancy and congenital malformations.

    Methods

    Data Sources

    We identified relevant articles by searching electronic databases, using a combination of opioid- and congenital malformation–related Medical Subject Headings search terms and keywords (Supplemental Materials) for human studies published in the English language. We used the Ovid platform (Ovid Technologies, Inc) to conduct literature searches of Medline (1946 to present) and Embase (1988 to 2016, week 7) for publications indexed through February 19, 2016. We combined and deduplicated the results into a single EndNote X7.5 (Thomson Reuters) library. In addition, we reviewed the reference lists of included publications to identify additional relevant studies.

    Study Selection

    We included publications in this review if they: (1) were full-text journal articles (we excluded abstracts); (2) reported the results of original epidemiologic research (we excluded case reports, case series, editorials without original data, commentaries without original data, review papers, clinical guidelines, small descriptive studies [<100 participants], and duplicate reports); (3) reported on exposure to opioids during pregnancy (we excluded reports based on exposures during labor/delivery only); and (4) reported the presence or absence of congenital malformations (collectively or as individual subtypes) as an outcome. For simplicity, hereafter, we refer to distinct publications as “studies” and note overlapping data (when known) in Table 1.

    View this table:
    TABLE 1

    Characteristics of Studies Included in a Systematic Review of Prenatal Opioid Exposure and Congenital Malformations (n = 68)

    We assessed study eligibility in 3 phases, title review, abstract review, and full-text review, using standardized, duplicate review by coauthor pairs. If either reviewer specified that the study should be included during any of the review phases, it was flagged to be included in the next phase of review. If both reviewers independently determined that a study should be excluded, it was excluded without additional review. During the review phases, we excluded any duplicate studies that were missed in the EndNote deduplication process.

    To systematically extract data, we identified data items of interest and created an electronic data extraction form. We then pilot tested and revised the extraction form as needed. During the data extraction phase, the studies were divided between 2 reviewers. After independently extracting data from their assigned studies, the reviewers exchanged studies and checked the extracted data for completeness. Discrepancies were resolved through discussion and, when necessary, by consulting additional coauthor reviewers.

    Study Quality Assessment

    We assessed the quality of observational studies included in this review by using modified versions of the (1) Methodological Evaluation of Observational Research–Observational Studies of Risk Factors of Chronic Diseases criteria for studies with comparison groups and (2) Methodological Evaluation of Observational Research–Observational Studies of Population Incidence or Prevalence of Chronic Diseases criteria for large descriptive studies.90 We selected these validated quality assessment checklists because of their ability to distinguish between the external and internal validity of study findings.90 The specific study qualities that we assessed included generalizability, sampling method, sampling frame selection bias, response rate, outcome measurement, exposure measurement, exposure intensity/dose, information bias, differential data collection, differential measurement, and confounding. In the absence of established definitions, we defined “gold standard” methods of assessing outcomes and exposures as outcomes measured in a standard, valid, and reliable way and precise and/or accurate assessment of exposures, respectively.

    Results

    Our searches of the Medline and Embase databases yielded a total of 20 114 potentially relevant publications, whose titles and abstracts were reviewed (Fig 1). Duplicates and studies deemed ineligible were excluded, leaving a total of 890 studies to be examined in detail. Of the 890 studies reviewed, 62 met our inclusion criteria. We identified an additional 6 relevant studies by reviewing the reference lists of these eligible studies. We summarize the characteristics of the 68 studies included in this review in Table 1.

    FIGURE 1
    FIGURE 1

    Flowchart for inclusion of studies in a systematic review of prenatal opioid exposure and congenital malformations.

    Studies With an Unexposed Comparison Group

    We included 46 studies with a comparison group unexposed to opioids during pregnancy that investigated associations between prenatal opioid exposure and congenital malformations; 13 were case-control studies and 33 were cohort studies.

    Case-Control Studies

    The majority (8 of 13) of the included case-control studies were published from 1975 through 1998 (Table 2), before the current opioid epidemic.39,40,69–73,89 Seven studies evaluated aggregate opioid exposure34,35,39,70,71,79,83; of these, 2 studies also assessed congenital malformations associated with codeine and/or oxycodone exposure.35,39 Five studies focused specifically on codeine exposures.40,69,72,73,89 Most (7 of 13) studies did not specify the indications for maternal opioid exposure, and one of the included studies did not present risk estimates of congenital malformations in infants exposed to opioids.79

    View this table:
    TABLE 2

    Case-Control Studies With an Unexposed Comparison Group That Investigated Associations Between Prenatal Opioid Exposure and Congenital Malformations (n = 13)

    Ten case-control studies reported statistically significant positive associations between opioid exposure during pregnancy and congenital malformations.34,35,39,40,43,69–71,83,89 Studies evaluating opioid exposure in aggregate found that use during early pregnancy was associated with an increased risk of congenital malformations overall,39 as well as heart malformations overall,34 inguinal hernia with/without obstruction,39 ventricular septal defects (VSD)/atrial septal defects,34,39 oral clefts,39,70,71 dislocated hip/musculoskeletal defects,39 spina bifida,34,35 tetralogy of Fallot,34 hypoplastic left heart syndrome,34 right ventricular outflow tract obstruction defects,34 pulmonary valve stenosis,34 atrioventricular septal defects,34 isolated clubfoot,83 neural tube defects,35 and other heart and circulatory defects.39 Bracken and Holford39 also reported that exposure to opioids for the first time during the second trimester was associated with alimentary tract defects.

    Eight case-control studies evaluated exposures to specific types of opioids.35,39,40,43,69,72,73,89 Of these, 4 studies found codeine to be associated with an increased risk of: congenital malformations overall,39 heart malformations overall,40,69,89 VSD,89 and double-outlet right ventricle defects.89 In 2 studies by Shaw et al,72,73 codeine use in pregnancy was not significantly associated with congenital cardiac malformations or neural tube defects. Bracken40 initially reported an increased prevalence of heart malformations in codeine-exposed infants compared with unexposed infants; however, when Bracken40 recomputed the prevalence ratios to include infants with other malformations as the controls, the association was no longer statistically significant. Yazdy et al35 reported an increased risk of spina bifida with noncodeine opioid exposures. And Daud et al43 found an increased risk for respiratory malformations associated with prenatal exposure to morphine. However, in a study that evaluated first-trimester exposure to oxycodone, no increased risk of congenital malformations were reported.39

    Cohort Studies

    The 33 cohort studies with an unexposed comparison group included in our review were published from 1971 through 2015 (Table 3). Similar to the case-control studies, many (17 of 33) of the cohort studies were published before 1999.18,21,24,25,41,45,47,51,53,56,63,74,76,78,85,86,88 Methadone and heroin were the most common opioid exposures evaluated, with methadone maintenance treatment (MMT) as the most common indication for methadone exposure. Ten studies did not calculate risk estimates of congenital malformations in infants exposed to opioids,13,24,41,45,51,74,80,81,85,86 and in 5 studies, no congenital malformations were reported in any infant.25,26,57,78,84 Of the remaining 18 cohort studies that performed statistical tests to measure associations,12,15–19,21,47,52,53,56,63,65,66,76,77,87,88 7 reported statistically significant increased risks of congenital malformations as a result of prenatal opioid exposure.12,15,19,21,52,66,87 Four of the 7 studies assessed associations with opioid exposure in aggregate,12,19,21,66 reporting a statistically significant increased risk of congenital malformations overall in 3 studies19,21,66 and clubfoot (pes equinovarus) in 1 study.12

    View this table:
    TABLE 3

    Cohort Studies With an Unexposed Comparison Group That Investigated Associations Between Prenatal Opioid Exposure and Congenital Malformations (n = 33)

    Five of the 7 cohort studies that reported statistically significant increased risks evaluated associations between exposure to specific types of opioids and congenital malformations.12,15,52,66,87 In 2 studies by Källén et al,12,52 tramadol exposure in early pregnancy was associated with a statistically significant increased risk of clubfoot. Källén and Reis52 also reported an increased risk of congenital malformations overall, “relatively severe malformations” (authors excluded preauricular appendix, tongue tie, patent ductus arteriosus in preterm infants, single umbilical artery, undescended testicle, unstable hip or hip (sub)luxation, and nevus), heart malformations overall, and isolated cardiac septum malformations with tramadol exposure in early pregnancy, as well as congenital malformations overall, and “relatively severe malformations” with codeine exposure and an increased risk of heart malformations overall with the use of synthetic opioids in early pregnancy. The remaining 3 studies evaluated associations with methadone exposure; all studies reported an increased risk of malformations overall.15,66,87 Nørgaard et al66 also reported an increased risk of malformations associated with prenatal exposure to buprenorphine.

    Studies With an Exposed Comparison Group

    We identified 15 eligible studies with an exposed comparison group, of which 14 were cohort studies36,42,46,48,50,55,58–61,67,68,75,82 and 1 was a cross-sectional study (Table 1).14 Eleven studies compared methadone exposure to other opioid exposures, including methadone detoxification,36 methadone with additional drugs,42 illicit opioids, such as heroin,14,46,67,68 MMT with tricyclic antidepressant exposure,48 slow-release oral morphine,60 and buprenorphine (Table 4).55,60,61,82 Other studies compared polydrug abuse (including opioids) to alcohol abuse alone,50 uncontrolled opioid abuse to methadone detoxification,59 opioid maintenance treatment (OMT) alone to OMT with other prescription medications,58 and heroin exposure to amphetamine exposure.75 Five studies did not specify which exposure groups the congenital malformations were observed in, making their findings difficult to interpret.14,42,59,60,67 No congenital malformations were reported in the main opioid-exposed groups in 4 other studies.36,48,68,75

    View this table:
    TABLE 4

    Studies With an Exposed Comparison Group That Investigated Associations Between Different Prenatal Opioid-Related Exposures and Congenital Malformations (n = 15)

    Only 3 of the 15 studies with an exposed comparison group performed statistical tests to compare findings between exposure groups, with mixed results.46,50,58 Fajemirokun-Odudeyi et al46 did not report significant differences in the percentage of congenital malformations between infants exposed to methadone and those exposed to heroin. Lund et al58 reported a significantly higher prevalence of major malformations in children exposed to OMT with other prescribed medications compared with those exposed to OMT alone, but the documented P value was > .05. Similarly, Iosub et al50 stated that there was a statistically significant lower percentage of infants with malformations in the polydrug-exposed group (14%) compared with the alcohol-only–exposed infants (33%). However, the documented P value was equal to .05.

    The remaining 3 studies compared buprenorphine and methadone exposures.55,61,82 Lacroix et al55 described similar malformation rates in buprenorphine-exposed and methadone-exposed infants, and the rates among both prenatally exposed groups were reported to be higher than the general French population. Welle-Strand et al82 compared infants prenatally exposed to buprenorphine to those prenatally exposed to methadone and reported 2 cases with malformations (spina bifida and gastroschisis) in the buprenorphine group, but no malformations in the methadone group. Meyer et al61 also reported 2 cases with malformations; 1 infant with an absent hand in the methadone-exposed group and 1 infant with isolated cleft palate in the buprenorphine-exposed group.

    Descriptive Studies

    We included 7 large studies (≥100 participants) that described prenatal opioid exposure and congenital malformations, but did not include any comparison group (Table 5).37,38,44,49,54,62,64 Three of the 7 studies described congenital malformations collectively.37,38,44 Blumenthal et al38 reported a higher prevalence of congenital malformations in the heroin-exposed group (12.7 per 1000 live births) than among all live births in New York City (10 per 1000 live births). Blinick et al37 did not observe any congenital malformations among 61 live births prenatally exposed to methadone and/or heroin. Davis and Chappel44 reported 4 congenital malformations among the 113 live births included in their study, 2 of which were exposed to methadone at conception; however, the authors stated that their findings of teratogenic and toxigenic effects of opioids were inconclusive.

    View this table:
    TABLE 5

    Large Descriptive Studies (≥100 Participants) on Prenatal Opioid Exposure and Congenital Malformations (n = 7)

    The remaining 4 studies reported on specific malformations observed with prenatal opioid exposure.49,54,62,64 Of the infants prenatally exposed to methadone and/or heroin described by Harper et al,49 congenital malformations were observed in 3 (ie, diaphragmatic hernia, bifid thoracic vertebrae, and polydactyly). Kivistö et al54 observed malformations in 10 out of 102 infants (ie, pulmonary artery stenosis; VSDs; primary vesicoureteral reflux grade III; primary vesicoureteral reflux grade III–IV with hydronephrosis; duplex thumb with left-sided duplex urinary collecting system; palatal cleft with ankyloglossia; Pierre Robin syndrome with undescended testicle; microtia with stenotic external ear canal; tetralogy of Fallot with bilateral inguinal hernias, multiple skeletal anomalies, and thymic aplasia; and mild hypospadias) prenatally exposed to buprenorphine. Of these, 5 infants had a major anomaly with functional or cosmetic significance, which was reported to be slightly higher than what is observed on average in the general population (3.4%). Miles et al62 reported 2 cases of cleft palate among infants exposed to methadone during pregnancy (either alone or in combination with illicit substances). Lastly, Newman64 reported malformations in 7 infants exposed to methadone (ie, heart murmurs [not generally considered a congenital malformation], hernia, bilateral foot deformity, imperforate anus, and esophageal defect).

    Study Quality

    We used 2 validated checklists to assess the quality of the 68 studies included in this review (Supplemental Figures 3-1, 3-2, 4, and 5).90 We also presented the distribution of the included studies with respect to their bias characteristics (Fig 2). Among the 46 studies with an unexposed comparison group, 76% were not generalizable, 61% had a high risk of bias based on their sampling frame, and 57% did not report response rates. Additionally, less than half of the studies assessed outcomes and exposures using gold standards (48% and 28%, respectively). However, 61% of the studies evaluated associations after adjusting for potential confounders.

    FIGURE 2
    FIGURE 2

    Risk of bias across studies included in a systematic review of prenatal opioid exposure and congenital malformations. (A) Studies with an unexposed comparison group (n = 46). (B) Studies with an exposed comparison group (n = 15). (C) Descriptive studies (n = 7).

    Among the 15 studies with an exposed comparison group, 87% were not generalizable, 80% had a high risk of bias based on their sampling frame, and 73% did not report response rates. Approximately half of these studies used gold standard assessments for the outcome and addressed confounding. However, because many of these studies used data collected from opioid treatment facilities, a much larger proportion (67%) of studies used gold standard measurements for exposure assessment than studies with an unexposed comparison group. Among the 7 descriptive studies, none were generalizable, all had a high risk of bias based on their sampling frame, and none reported response rates. Although only 43% of the descriptive studies had a low risk of bias in outcome assessment, 71% used gold standards to assess exposures.

    Discussion

    We included 68 studies in this systematic review, of which 30 (12 case-control and 18 cohort studies with an unexposed comparison group) performed statistical tests to measure associations between opioid exposure during pregnancy and congenital malformations. Of those 30 studies, 17 demonstrated statistically significant positive associations between prenatal opioid exposure and at least 1 congenital malformation (Supplemental Table 6); 10 were case-control studies and 7 were cohort studies. Among the 10 case-control studies, oral clefts and VSDs/ atrial septal defects were the most frequently reported specific malformations (reported in 3 studies each; Supplemental Table 7), followed by spina bifida, which was reported in 2 studies. Four of these studies also reported statistically significant positive associations with codeine exposure, where heart malformations were the most frequently reported (3 of 4) congenital malformations mentioned. Among the 7 cohort studies, 6 reported increased risks of congenital malformations overall with prenatal opioid exposure, and the most frequently reported specific malformation was clubfoot (reported in 2 studies).

    We have considerable concerns regarding the quality of the studies included in this review. There were no randomized controlled trials and few high-quality observational studies that evaluated the association between prenatal opioid use and congenital malformations. However, we acknowledge that this is a limitation of most medication-related studies in the pregnancy literature. The majority of the included studies lacked generalizability, failed to report response rates, and were older publications (published before 1999), which is a concern given the dramatic increases in opioid use since 1999.91 Although most of the case-control studies with an unexposed comparison group used appropriate sampling frames and methods, almost all of the other studies had flaws in their sampling frame. Many of the studies also had limitations with outcome and/or exposure measurement, which might have resulted in misclassification. Although the studies with an unexposed comparison group would be considered the highest quality of those included in this review, potential information biases were identified in half of them, and confounding was not properly addressed in many. Additionally, over half of the 68 studies included in this review were cohort studies. In general, population-based cohort studies are not ideal for assessing rare outcomes because most have insufficient power to assess specific congenital malformations. Thus, many of the included studies assessed congenital malformations as 1 homogenous, aggregate group. However, congenital malformations are etiologically heterogeneous, and examining all congenital malformations combined is unlikely to identify potentially teratogenic effects.92 This underpowering of cohort studies for rare outcomes likely explains why a much higher proportion of the case-control studies (10 of 12) documented statistically significant positive associations between prenatal opioid use and congenital malformations when compared with the cohort studies (7 of 18) included in this review. Furthermore, the majority of the studies included in this review had relatively small numbers of participants, which additionally limits their ability to assess the risk for congenital malformations due to insufficient power.

    Limitations and Strengths

    It is important to acknowledge some additional limitations of this review. Restricting our literature search to the English language may have led to a lack of heterogeneity among the reported settings and populations. Additionally, restricting to full-text journal articles may have introduced publication bias by excluding any reports of negative findings that did not become full-text publications. Moreover, in instances of substance use, it is rare for only 1 substance to be misused or abused, making it difficult to evaluate and understand the effects of individual substances on birth outcomes.10 This challenge is compounded by the often absent or insufficient prenatal care observed in pregnant women with OUD, significantly higher rates of tobacco use among pregnant women with substance use disorders,93 and lifestyle issues associated with illicit drug use that expose pregnant women to sexually transmitted infections and other risks,94 all of which increase the risk for poor birth outcomes,94,95 additionally limiting our ability to draw conclusions from study findings. Finally, due to exposure measurement limitations and the overall poor quality of many of the studies included in this systematic review, we were unable to incorporate information on exposure intensity/dose or additionally group the studies by reasons for exposure (eg, illicit, maintenance treatment, or prescribed). Because several factors play a role in substance use among women, including ethnicity, culture, sexual orientation, and socioeconomic status, it is likely that the study populations varied based on the reasons for prenatal opioid exposure10; yet, many of the studies we included failed to properly address confounding, which additionally prevents the generalizing of study findings.

    Our review has a number of strengths. We attempted to address the potential for retrieval bias that is inherent in most reviews by using well-defined search terms in multiple electronic databases and by hand-searching the reference lists of eligible studies. Another strength was our use of a systematic, standardized, duplicate review process to identify eligible studies and ensure a relatively thorough retrieval of published literature on opioid use during pregnancy and congenital malformations. Finally, we used validated checklists to assess study quality, which allowed for more objective assessments.

    Conclusions

    Our findings in this systematic review have implications for future research and clinical practice. Well-designed studies with unexposed comparison groups that estimate measures of association are needed. Ideally, these studies should also have enough power to assess associations between specific opioids used during pregnancy and specific congenital malformations, rather than malformations and/or opioids as aggregate groups, and to adequately control for potential confounding factors, including polysubstance use and tobacco use. Given the uncertainty that remains regarding the teratogenicity of opioids, a careful evaluation of the potential risks and benefits is warranted when making clinical decisions regarding the use of opioid therapy in reproductive-aged and pregnant women. According to the recent Centers for Disease Control and Prevention Guideline for Prescribing Opioids for Chronic Pain, when opioids are being considered for reproductive-aged women to manage chronic pain, health care providers are encouraged to discuss (1) family planning and (2) how long-term opioid use might affect any future pregnancy.96 For health care providers caring for pregnant women taking opioid medications, the guidelines recommend that they (1) access appropriate expertise if considering tapering opioids, (2) offer medication-assisted therapy with buprenorphine or methadone to pregnant women with OUD, and (3) arrange for delivery at a facility prepared to monitor, evaluate for, and treat NAS.

    Acknowledgments

    This work was supported in part by an appointment to the Research Participation Program at the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the Centers for Disease Control and Prevention.

    Footnotes

      • Accepted March 7, 2017.
    • Address correspondence to Jennifer N. Lind, PharmD, MPH, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, 4770 Buford Hwy, Mailstop E-86, Atlanta, GA 30341. E-mail: jlind{at}cdc.gov

    • The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

    • FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

    • FUNDING: No external funding.

    • POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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    Pediatrics
    Vol. 139, Issue 6
    1 Jun 2017
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    Maternal Use of Opioids During Pregnancy and Congenital Malformations: A Systematic Review
    Jennifer N. Lind, Julia D. Interrante, Elizabeth C. Ailes, Suzanne M. Gilboa, Sara Khan, Meghan T. Frey, April L. Dawson, Margaret A. Honein, Nicole F. Dowling, Hilda Razzaghi, Andreea A. Creanga, Cheryl S. Broussard
    Pediatrics Jun 2017, 139 (6) e20164131; DOI: 10.1542/peds.2016-4131
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