Advertising Disclaimer »

Discover Pediatric Collections on COVID-19 and Racism and Its Effects on Pediatric Health

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
Download PDF

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.

    References

    1. ↵
      1. National Institute on Drug Abuse
      2. US Department of Health and Human Services
      . Research Report Series: Prescription Drug Abuse. NIH Publication Number 15-4881. Bethesda, MD: National Institute on Drug Abuse, US Department of Health and Human Services; 2014
    2. ↵
      1. Mack KA,
      2. Jones CM,
      3. Paulozzi LJ; Centers for Disease Control and Prevention (CDC)
      . Vital signs: overdoses of prescription opioid pain relievers and other drugs among women–United States, 1999-2010. MMWR Morb Mortal Wkly Rep. 2013;62(26):537–542pmid:23820967
      OpenUrlPubMed
    3. ↵
      1. Paulozzi LJ,
      2. Mack KA,
      3. Hockenberry JM; Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, CDC
      . Vital signs: variation among states in prescribing of opioid pain relievers and benzodiazepines - United States, 2012. MMWR Morb Mortal Wkly Rep. 2014;63(26):563–568pmid:24990489
      OpenUrlPubMed
    4. ↵
      1. Ailes EC,
      2. Dawson AL,
      3. Lind JN, et al; Centers for Disease Control and Prevention (CDC)
      . Opioid prescription claims among women of reproductive age United States, 2008-2012. MMWR Morb Mortal Wkly Rep. 2015;64(2):37–41pmid:25611168
      OpenUrlPubMed
    5. ↵
      1. Jones CM,
      2. Logan J,
      3. Gladden RM,
      4. Bohm MK
      . Vital signs: demographic and substance use trends among heroin users - United States, 2002-2013. MMWR Morb Mortal Wkly Rep. 2015;64(26):719–725pmid:26158353
      OpenUrlPubMed
    6. ↵
      1. Bateman BT,
      2. Hernandez-Diaz S,
      3. Rathmell JP, et al
      . Patterns of opioid utilization in pregnancy in a large cohort of commercial insurance beneficiaries in the United States. Anesthesiology. 2014;120(5):1216–1224pmid:24525628
      OpenUrlCrossRefPubMed
    7. ↵
      1. Desai RJ,
      2. Hernandez-Diaz S,
      3. Bateman BT,
      4. Huybrechts KF
      . Increase in prescription opioid use during pregnancy among Medicaid-enrolled women. Obstet Gynecol. 2014;123(5):997–1002pmid:24785852
      OpenUrlCrossRefPubMed
    8. ↵
      1. Maeda A,
      2. Bateman BT,
      3. Clancy CR,
      4. Creanga AA,
      5. Leffert LR
      . Opioid abuse and dependence during pregnancy: temporal trends and obstetrical outcomes. Anesthesiology. 2014;121(6):1158–1165pmid:25405293
      OpenUrlCrossRefPubMed
    9. ↵
      1. Hudak ML,
      2. Tan RC; Committee on Drugs; Committee on Fetus and Newborn; American Academy of Pediatrics
      . Neonatal drug withdrawal. Pediatrics. 2012;129(2). Available at: www.pediatrics.org/cgi/content/full/129/2/e540pmid:22291123
      OpenUrlAbstract/FREE Full Text
    10. ↵
      1. Center for Substance Abuse Treatment
      . Substance Abuse Treatment: Addressing the Specific Needs of Women. Treatment Improvement Protocol (TIP) Series, No. 51. HHS Publication No. (SMA) 14-4426. Rockville, MD: Substance Abuse and Mental Health Services Administration, US Department of Health and Human Services; 2009
    11. ↵
      1. Kelly L,
      2. Dooley J,
      3. Cromarty H, et al
      . Narcotic-exposed neonates in a First Nations population in northwestern Ontario: incidence and implications. Can Fam Physician. 2011;57(11):e441–e447pmid:22084474
      OpenUrlAbstract/FREE Full Text
    12. ↵
      1. Källén B,
      2. Borg N,
      3. Reis M
      . The use of central nervous system active drugs during pregnancy. Pharmaceuticals (Basel). 2013;6(10):1221–1286pmid:24275849
      OpenUrlCrossRefPubMed
    13. ↵
      1. Ludlow JP,
      2. Evans SF,
      3. Hulse G
      . Obstetric and perinatal outcomes in pregnancies associated with illicit substance abuse. Aust N Z J Obstet Gynaecol. 2004;44(4):302–306pmid:15282000
      OpenUrlCrossRefPubMed
    14. ↵
      1. Olofsson M,
      2. Buckley W,
      3. Andersen GE,
      4. Friis-Hansen B
      . Investigation of 89 children born by drug-dependent mothers. I. Neonatal course. Acta Paediatr Scand. 1983;72(3):403–406pmid:6880727
      OpenUrlPubMed
    15. ↵
      1. Cleary BJ,
      2. Donnelly JM,
      3. Strawbridge JD, et al
      . Methadone and perinatal outcomes: a retrospective cohort study. Am J Obstet Gynecol. 2011;204(2):139.e1–139.e9
      OpenUrlCrossRefPubMed
      1. Saleh Gargari S,
      2. Fallahian M,
      3. Haghighi L,
      4. Hosseinnezhad-Yazdi M,
      5. Dashti E,
      6. Dolan K
      . Maternal and neonatal complications of substance abuse in Iranian pregnant women. Acta Med Iran. 2012;50(6):411–416pmid:22837120
      OpenUrlPubMed
    17. ↵
      1. Greig E,
      2. Ash A,
      3. Douiri A
      . Maternal and neonatal outcomes following methadone substitution during pregnancy. Arch Gynecol Obstet. 2012;286(4):843–851pmid:22584603
      OpenUrlCrossRefPubMed
    18. ↵
      1. Little BB,
      2. Snell LM,
      3. Klein VR,
      4. Gilstrap LC III,
      5. Knoll KA,
      6. Breckenridge JD
      . Maternal and fetal effects of heroin addiction during pregnancy. J Reprod Med. 1990;35(2):159–162pmid:2304039
      OpenUrlPubMed
    19. ↵
      1. Vucinovic M,
      2. Roje D,
      3. Vucinovic Z,
      4. Capkun V,
      5. Bucat M,
      6. Banovic I
      . Maternal and neonatal effects of substance abuse during pregnancy: our ten-year experience. Yonsei Med J. 2008;49(5):705–713pmid:18972589
      OpenUrlPubMed
      1. Smith MV,
      2. Costello D,
      3. Yonkers KA
      . Clinical correlates of prescription opioid analgesic use in pregnancy. Matern Child Health J. 2015;19(3):548–556pmid:24951127
      OpenUrlPubMed
    21. ↵
      1. Ostrea EM,
      2. Chavez CJ
      . Perinatal problems (excluding neonatal withdrawal) in maternal drug addiction: a study of 830 cases. J Pediatr. 1979;94(2):292–295pmid:762627
      OpenUrlCrossRefPubMed
    22. ↵
      1. Hulse GK,
      2. Milne E,
      3. English DR,
      4. Holman CD
      . The relationship between maternal use of heroin and methadone and infant birth weight. Addiction. 1997;92(11):1571–1579pmid:9519499
      OpenUrlCrossRefPubMed
    23. ↵
      1. Jacobson JL,
      2. Jacobson SW,
      3. Sokol RJ,
      4. Martier SS,
      5. Ager JW,
      6. Shankaran S
      . Effects of alcohol use, smoking, and illicit drug use on fetal growth in black infants. J Pediatr. 1994;124(5 pt 1):757–764pmid:8176567
      OpenUrlCrossRefPubMed
    24. ↵
      1. Brown HL,
      2. Britton KA,
      3. Mahaffey D,
      4. Brizendine E,
      5. Hiett AK,
      6. Turnquest MA
      . Methadone maintenance in pregnancy: a reappraisal. Am J Obstet Gynecol. 1998;179(2):459–463pmid:9731853
      OpenUrlCrossRefPubMed
    25. ↵
      1. Rosen TS,
      2. Johnson HL
      . Children of methadone-maintained mothers: follow-up to 18 months of age. J Pediatr. 1982;101(2):192–196pmid:6178811
      OpenUrlCrossRefPubMed
    26. ↵
      1. Kahila H,
      2. Saisto T,
      3. Kivitie-Kallio S,
      4. Haukkamaa M,
      5. Halmesmäki E
      . A prospective study on buprenorphine use during pregnancy: effects on maternal and neonatal outcome. Acta Obstet Gynecol Scand. 2007;86(2):185–190pmid:17364281
      OpenUrlCrossRefPubMed
      1. Burns L,
      2. Conroy E,
      3. Mattick RP
      . Infant mortality among women on a methadone program during pregnancy. Drug Alcohol Rev. 2010;29(5):551–556pmid:20887580
      OpenUrlCrossRefPubMed
    28. ↵
      1. Habel L,
      2. Kaye K,
      3. Lee J
      . Trends in reporting of maternal drug abuse and infant mortality among drug-exposed infants in New York City. Women Health. 1990;16(2):41–58pmid:2368425
      OpenUrlCrossRefPubMed
    29. ↵
      1. Patrick SW,
      2. Davis MM,
      3. Lehmann CU,
      4. Cooper WO
      . Increasing incidence and geographic distribution of neonatal abstinence syndrome: United States 2009 to 2012. J Perinatol. 2015;35(8):650–655pmid:25927272
      OpenUrlCrossRefPubMed
    30. ↵
      1. Baldacchino A,
      2. Arbuckle K,
      3. Petrie DJ,
      4. McCowan C
      . Neurobehavioral consequences of chronic intrauterine opioid exposure in infants and preschool children: a systematic review and meta-analysis. BMC Psychiatry. 2014;14:104pmid:24708875
      OpenUrlPubMed
    31. ↵
      1. Baldacchino A,
      2. Arbuckle K,
      3. Petrie DJ,
      4. McCowan C
      . Erratum: neurobehavioral consequences of chronic intrauterine opioid exposure in infants and preschool children: a systematic review and meta-analysis. BMC Psychiatry. 2015;15:134pmid:26108949
      OpenUrlPubMed
    32. ↵
      1. Matthews TJ,
      2. MacDorman MF,
      3. Thoma ME
      . Infant mortality statistics from the 2013 period linked birth/infant death data set. Natl Vital Stat Rep. 2015;64(9):1–30pmid:26270610
      OpenUrlPubMed
    33. ↵
      1. Russo CA,
      2. Elixhauser A
      . Hospitalizations for Birth Defects, 2004. Statistical Brief #24. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. Rockville, MD: Agency for Healthcare Research and Quality, US Department of Health and Human Services; 2006
    34. ↵
      1. Broussard CS,
      2. Rasmussen SA,
      3. Reefhuis J, et al; National Birth Defects Prevention Study
      . Maternal treatment with opioid analgesics and risk for birth defects. Am J Obstet Gynecol. 2011;204(4):314.e1–314.e11
      OpenUrlCrossRefPubMed
    35. ↵
      1. Yazdy MM,
      2. Mitchell AA,
      3. Tinker SC,
      4. Parker SE,
      5. Werler MM
      . Periconceptional use of opioids and the risk of neural tube defects. Obstet Gynecol. 2013;122(4):838–844pmid:24084542
      OpenUrlCrossRefPubMed
    36. ↵
      1. Blinick G
      . Fertility of narcotics addicts and effects of addiction on the offspring. Soc Biol. 1971;18:S34–S39pmid:5125949
      OpenUrlPubMed
    37. ↵
      1. Blinick G,
      2. Jerez E,
      3. Wallach RC
      . Methadone maintenance, pregnancy, and progeny. JAMA. 1973;225(5):477–479pmid:4740334
      OpenUrlCrossRefPubMed
    38. ↵
      1. Blumenthal S,
      2. Bergner L,
      3. Nelson F
      . Low birth weight of infants associated with maternal heroin use: New York City, 1966-67 and 1970-71. Health Serv Rep. 1973;88(5):416–418pmid:4707685
      OpenUrlCrossRefPubMed
    39. ↵
      1. Bracken MB,
      2. Holford TR
      . Exposure to prescribed drugs in pregnancy and association with congenital malformations. Obstet Gynecol. 1981;58(3):336–344pmid:7266953
      OpenUrlPubMed
    40. ↵
      1. Bracken MB
      . Drug use in pregnancy and congenital heart disease in offspring. N Engl J Med. 1986;314(17):1120pmid:3960086
      OpenUrlPubMed
    41. ↵
      1. Chasnoff IJ,
      2. Hatcher R,
      3. Burns WJ
      . Polydrug- and methadone-addicted newborns: a continuum of impairment? Pediatrics. 1982;70(2):210–213pmid:7099786
      OpenUrlAbstract/FREE Full Text
    42. ↵
      1. Cleary BJ,
      2. Eogan M,
      3. O’Connell MP, et al
      . Methadone and perinatal outcomes: a prospective cohort study. Addiction. 2012;107(8):1482–1492pmid:22340442
      OpenUrlCrossRefPubMed
    43. ↵
      1. Daud AN,
      2. Bergman JE,
      3. Bakker MK, et al
      . P-glycoprotein-mediated drug interactions in pregnancy and changes in the risk of congenital anomalies: a case-reference study. Drug Saf. 2015;38(7):651–659pmid:26017034
      OpenUrlCrossRefPubMed
    44. ↵
      1. Davis RC,
      2. Chappel JN
      . Pregnancy in the context of narcotic addiction and methadone maintenance. Proc Natl Conf Methadone Treat. 1973;2:1146–1152pmid:4808261
      OpenUrlPubMed
    45. ↵
      1. Ellwood DA,
      2. Sutherland P,
      3. Kent C,
      4. O’Connor M
      . Maternal narcotic addiction: pregnancy outcome in patients managed by a specialized drug-dependency antenatal clinic. Aust N Z J Obstet Gynaecol. 1987;27(2):92–98pmid:3675451
      OpenUrlCrossRefPubMed
    46. ↵
      1. Fajemirokun-Odudeyi O,
      2. Sinha C,
      3. Tutty S, et al
      . Pregnancy outcome in women who use opiates. Eur J Obstet Gynecol Reprod Biol. 2006;126(2):170–175pmid:16202501
      OpenUrlCrossRefPubMed
    47. ↵
      1. Gillogley KM,
      2. Evans AT,
      3. Hansen RL,
      4. Samuels SJ,
      5. Batra KK
      . The perinatal impact of cocaine, amphetamine, and opiate use detected by universal intrapartum screening. Am J Obstet Gynecol. 1990;163(5 pt 1):1535–1542pmid:2240103
      OpenUrlCrossRefPubMed
    48. ↵
      1. Green L,
      2. Ehrlich S,
      3. Finnegan L
      . The use of tricyclic antidepressants in methadone maintained pregnant women and infant outcome. NIDA Res Monogr. 1988;81:266–272pmid:3136370
      OpenUrlPubMed
    49. ↵
      1. Harper RG,
      2. Solish GI,
      3. Purow HM,
      4. Sang E,
      5. Panepinto WC
      . The effect of a methadone treatment program upon pregnant heroin addicts and their newborn infants. Pediatrics. 1974;54(3):300–305pmid:4416175
      OpenUrlAbstract/FREE Full Text
    50. ↵
      1. Iosub S,
      2. Fuchs M,
      3. Bingol N,
      4. Stone RK,
      5. Gromisch DS,
      6. Wasserman E
      . Incidence of major congenital malformations in offspring of alcoholics and polydrug abusers. Alcohol. 1985;2(3):521–523pmid:4040764
      OpenUrlPubMed
    51. ↵
      1. Jick H,
      2. Holmes LB,
      3. Hunter JR,
      4. Madsen S,
      5. Stergachis A
      . First-trimester drug use and congenital disorders. JAMA. 1981;246(4):343–346pmid:7241780
      OpenUrlCrossRefPubMed
    52. ↵
      1. Källén B,
      2. Reis M
      . Use of tramadol in early pregnancy and congenital malformation risk. Reprod Toxicol. 2015;58:246–251pmid:26482725
      OpenUrlPubMed
    53. ↵
      1. Kandall SR,
      2. Albin S,
      3. Gartner LM,
      4. Lee KS,
      5. Eidelman A,
      6. Lowinson J
      . The narcotic-dependent mother: fetal and neonatal consequences. Early Hum Dev. 1977;1(2):159–169pmid:617308
      OpenUrlCrossRefPubMed
    54. ↵
      1. Kivistö K,
      2. Tupola S,
      3. Kivitie-Kallio S
      . Prenatally buprenorphine-exposed children: health to 3 years of age. Eur J Pediatr. 2015;174(11):1525–1533pmid:26003659
      OpenUrlPubMed
    55. ↵
      1. Lacroix I,
      2. Berrebi A,
      3. Garipuy D, et al
      . Buprenorphine versus methadone in pregnant opioid-dependent women: a prospective multicenter study. Eur J Clin Pharmacol. 2011;67(10):1053–1059pmid:21538146
      OpenUrlCrossRefPubMed
    56. ↵
      1. Lam SK,
      2. To WK,
      3. Duthie SJ,
      4. Ma HK
      . Narcotic addiction in pregnancy with adverse maternal and perinatal outcome. Aust N Z J Obstet Gynaecol. 1992;32(3):216–221pmid:1445130
      OpenUrlPubMed
    57. ↵
      1. Lendoiro E,
      2. González-Colmenero E,
      3. Concheiro-Guisán A, et al
      . Maternal hair analysis for the detection of illicit drugs, medicines, and alcohol exposure during pregnancy. Ther Drug Monit. 2013;35(3):296–304pmid:23666580
      OpenUrlPubMed
    58. ↵
      1. Lund IO,
      2. Skurtveit S,
      3. Engeland A,
      4. Furu K,
      5. Ravndal E,
      6. Handal M
      . Prescription drug use among pregnant women in opioid maintenance treatment. Addiction. 2013;108(2):367–376pmid:22882166
      OpenUrlPubMed
    59. ↵
      1. Maas U,
      2. Kattner E,
      3. Weingart-Jesse B,
      4. Schäfer A,
      5. Obladen M
      . Infrequent neonatal opiate withdrawal following maternal methadone detoxification during pregnancy. J Perinat Med. 1990;18(2):111–118pmid:2366131
      OpenUrlPubMed
    60. ↵
      1. Metz VE,
      2. Comer SD,
      3. Pribasnig A,
      4. Wuerzl J,
      5. Fischer G
      . Observational study in an outpatient clinic specializing in treating opioid-dependent pregnant women: neonatal abstinence syndrome in infants exposed to methadone-, buprenorphine- and slow-release oral morphine. Heroin Addict Relat Clin Probl. 2015;17(1):5–16
      OpenUrl
    61. ↵
      1. Meyer MC,
      2. Johnston AM,
      3. Crocker AM,
      4. Heil SH
      . Methadone and buprenorphine for opioid dependence during pregnancy: a retrospective cohort study. J Addict Med. 2015;9(2):81–86pmid:25622120
      OpenUrlPubMed
    62. ↵
      1. Miles J,
      2. Sugumar K,
      3. Macrory F,
      4. Sims DG,
      5. D’Souza SW
      . Methadone-exposed newborn infants: outcome after alterations to a service for mothers and infants. Child Care Health Dev. 2007;33(2):206–212pmid:17291325
      OpenUrlCrossRefPubMed
    63. ↵
      1. Naeye RL,
      2. Blanc W,
      3. Leblanc W,
      4. Khatamee MA
      . Fetal complications of maternal heroin addiction: abnormal growth, infections, and episodes of stress. J Pediatr. 1973;83(6):1055–1061pmid:4757521
      OpenUrlCrossRefPubMed
    64. ↵
      1. Newman RG
      . Results of 120 deliveries of patients in the New York City methadone maintenance treatment program. Proc Natl Conf Methadone Treat. 1973;2:1114–1121pmid:4808256
      OpenUrlPubMed
    65. ↵
      1. Nezvalová-Henriksen K,
      2. Spigset O,
      3. Nordeng H
      . Effects of codeine on pregnancy outcome: results from a large population-based cohort study. Eur J Clin Pharmacol. 2011;67(12):1253–1261pmid:21656212
      OpenUrlPubMed
    66. ↵
      1. Nørgaard M,
      2. Nielsson MS,
      3. Heide-Jørgensen U
      . Birth and neonatal outcomes following opioid use in pregnancy: a Danish population-based study. Subst Abuse. 2015;9(suppl 2):5–11pmid:26512202
      OpenUrlPubMed
    67. ↵
      1. Ramer CM,
      2. Lodge A
      . Neonatal addiction: a two-year study. Part I. Clinical and developmental characteristics of infants of mothers on methadone maintenance. Addict Dis. 1975;2(1–2):227–234pmid:1163366
      OpenUrlPubMed
    68. ↵
      1. Reddy AM,
      2. Harper RG,
      3. Stern G
      . Observations on heroin and methadone withdrawal in the newborn. Pediatrics. 1971;48(3):353–358pmid:5094335
      OpenUrlAbstract/FREE Full Text
    69. ↵
      1. Rothman KJ,
      2. Fyler DC,
      3. Goldblatt A,
      4. Kreidberg MB
      . Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol. 1979;109(4):433–439pmid:443241
      OpenUrlAbstract/FREE Full Text
    70. ↵
      1. Saxén I
      . The association between maternal influenza, drug consumption and oral clefts. Acta Odontol Scand. 1975;33(5):259–267pmid:1067727
      OpenUrlCrossRefPubMed
    71. ↵
      1. Saxén I
      . Associations between oral clefts and drugs taken during pregnancy. Int J Epidemiol. 1975;4(1):37–44pmid:1116890
      OpenUrlAbstract/FREE Full Text
    72. ↵
      1. Shaw GM,
      2. Malcoe LH,
      3. Swan SH,
      4. Cummins SK,
      5. Schulman J
      . Congenital cardiac anomalies relative to selected maternal exposures and conditions during early pregnancy. Eur J Epidemiol. 1992;8(5):757–760pmid:1426180
      OpenUrlCrossRefPubMed
    73. ↵
      1. Shaw GM,
      2. Todoroff K,
      3. Velie EM,
      4. Lammer EJ
      . Maternal illness, including fever and medication use as risk factors for neural tube defects. Teratology. 1998;57(1):1–7pmid:9516745
      OpenUrlPubMed
    74. ↵
      1. Stimmel B,
      2. Adamsons K
      . Narcotic dependency in pregnancy. Methadone maintenance compared to use of street drugs. JAMA. 1976;235(11):1121–1124pmid:946208
      OpenUrlCrossRefPubMed
    75. ↵
      1. Thaithumyanon P,
      2. Limpongsanurak S,
      3. Praisuwanna P,
      4. Punnahitanon S
      . Perinatal effects of amphetamine and heroin use during pregnancy on the mother and infant. J Med Assoc Thai. 2005;88(11):1506–1513pmid:16471094
      OpenUrlPubMed
    76. ↵
      1. Thornton L,
      2. Clune M,
      3. Maguire R,
      4. Griffin E,
      5. O’Connor J
      . Narcotic addiction: the expectant mother and her baby. Ir Med J. 1990;83(4):139–142pmid:2081667
      OpenUrlPubMed
    77. ↵
      1. Uebel H,
      2. Wright IM,
      3. Burns L, et al
      . Reasons for rehospitalization in children who had neonatal abstinence syndrome. Pediatrics. 2015;136(4). Available at: www.pediatrics.org/cgi/content/full/136/4/e811pmid:26371197
      OpenUrlAbstract/FREE Full Text
    78. ↵
      1. van Baar AL,
      2. Fleury P,
      3. Soepatmi S,
      4. Ultee CA,
      5. Wesselman PJ
      . Neonatal behavior after drug dependent pregnancy. Arch Dis Child. 1989;64(2):235–240pmid:2467626
      OpenUrlAbstract/FREE Full Text
    79. ↵
      1. van Gelder MM,
      2. Reefhuis J,
      3. Caton AR,
      4. Werler MM,
      5. Druschel CM,
      6. Roeleveld N; National Birth Defects Prevention Study
      . Maternal periconceptional illicit drug use and the risk of congenital malformations. Epidemiology. 2009;20(1):60–66pmid:19057385
      OpenUrlPubMed
    80. ↵
      1. Walhovd KB,
      2. Moe V,
      3. Slinning K, et al
      . Volumetric cerebral characteristics of children exposed to opiates and other substances in utero. Neuroimage. 2007;36(4):1331–1344pmid:17513131
      OpenUrlCrossRefPubMed
    81. ↵
      1. Walhovd KB,
      2. Westlye LT,
      3. Moe V, et al
      . White matter characteristics and cognition in prenatally opiate- and polysubstance-exposed children: a diffusion tensor imaging study. AJNR Am J Neuroradiol. 2010;31(5):894–900pmid:20203117
      OpenUrlAbstract/FREE Full Text
    82. ↵
      1. Welle-Strand GK,
      2. Skurtveit S,
      3. Jones HE, et al
      . Neonatal outcomes following in utero exposure to methadone or buprenorphine: a National Cohort Study of opioid-agonist treatment of Pregnant Women in Norway from 1996 to 2009. Drug Alcohol Depend. 2013;127(1–3):200–206pmid:22841456
      OpenUrlCrossRefPubMed
    83. ↵
      1. Werler MM,
      2. Yazdy MM,
      3. Kasser JR, et al
      . Medication use in pregnancy in relation to the risk of isolated clubfoot in offspring. Am J Epidemiol. 2014;180(1):86–93pmid:24824985
      OpenUrlAbstract/FREE Full Text
    84. ↵
      1. White R,
      2. Thompson M,
      3. Windsor D,
      4. Walsh M,
      5. Cox D,
      6. Charnaud B
      . Dexamphetamine substitute-prescribing in pregnancy: a 10-year retrospective audit. J Subst Use. 2006;11(3):205–216
      OpenUrl
    85. ↵
      1. Wilson GS,
      2. Desmond MM,
      3. Wait RB
      . Follow-up of methadone-treated and untreated narcotic-dependent women and their infants: health, developmental, and social implications. J Pediatr. 1981;98(5):716–722pmid:6164775
      OpenUrlCrossRefPubMed
    86. ↵
      1. Wilson GS
      . Clinical studies of infants and children exposed prenatally to heroin. Ann N Y Acad Sci. 1989;562:183–194pmid:2742276
      OpenUrlCrossRefPubMed
    87. ↵
      1. Wouldes TA,
      2. Woodward LJ
      . Maternal methadone dose during pregnancy and infant clinical outcome. Neurotoxicol Teratol. 2010;32(3):406–413pmid:20102736
      OpenUrlPubMed
    88. ↵
      1. Zelson C,
      2. Rubio E,
      3. Wasserman E
      . Neonatal narcotic addiction: 10 year observation. Pediatrics. 1971;48(2):178–189pmid:5560613
      OpenUrlAbstract/FREE Full Text
    89. ↵
      1. Zierler S,
      2. Rothman KJ
      . Congenital heart disease in relation to maternal use of Bendectin and other drugs in early pregnancy. N Engl J Med. 1985;313(6):347–352pmid:4010751
      OpenUrlCrossRefPubMed
    90. ↵
      1. Shamliyan TA,
      2. Kane RL,
      3. Ansari MT, et al
      . Development quality criteria to evaluate nontherapeutic studies of incidence, prevalence, or risk factors of chronic diseases: pilot study of new checklists. J Clin Epidemiol. 2011;64(6):637–657pmid:21071174
      OpenUrlCrossRefPubMed
    91. ↵
      1. Paulozzi LJ,
      2. Jones CM,
      3. Mack KA,
      4. Rudd RA; Centers for Disease Control and Prevention (CDC)
      . Vital signs: overdoses of prescription opioid pain relievers—United States, 1999–2008. MMWR Morb Mortal Wkly Rep. 2011;60(43):1487–1492pmid:22048730
      OpenUrlPubMed
    92. ↵
      1. Khoury MJ,
      2. James LM,
      3. Flanders WD,
      4. Erickson JD
      . Interpretation of recurring weak associations obtained from epidemiologic studies of suspected human teratogens. Teratology. 1992;46(1):69–77pmid:1641813
      OpenUrlCrossRefPubMed
    93. ↵
      1. Jones HE,
      2. Heil SH,
      3. O’Grady KE, et al
      . Smoking in pregnant women screened for an opioid agonist medication study compared to related pregnant and non-pregnant patient samples. Am J Drug Alcohol Abuse. 2009;35(5):375–380pmid:20180667
      OpenUrlCrossRefPubMed
    94. ↵
      1. ACOG Committee on Health Care for Underserved Women
      2. American Society of Addiction Medicine
      . ACOG committee opinion no. 524: opioid abuse, dependence, and addiction in pregnancy. Obstet Gynecol. 2012;119(5):1070–1076pmid:22525931
      OpenUrlCrossRefPubMed
    95. ↵
      1. Hackshaw A,
      2. Rodeck C,
      3. Boniface S
      . Maternal smoking in pregnancy and birth defects: a systematic review based on 173 687 malformed cases and 11.7 million controls. Hum Reprod Update. 2011;17(5):589–604pmid:21747128
      OpenUrlAbstract/FREE Full Text
    96. ↵
      1. Dowell D,
      2. Haegerich TM,
      3. Chou R
      . CDC guideline for prescribing opioids for chronic pain - United States, 2016. MMWR Recomm Rep. 2016;65(1):1–49pmid:26987082
      OpenUrlCrossRefPubMed
    Back to top

    In this issue

    Pediatrics
    Vol. 139, Issue 6
    1 Jun 2017
    View this article with LENS
    Email Article
    Request Permissions
    Article Alerts
    Citation Tools
    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
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
    Print
    Download PDF
    Insight Alerts

    Jump to section

    Subjects