Neurodevelopmental Outcomes of Children Born to Opioid-Dependent Mothers: A Systematic Review and Meta-Analysis

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NEURODEVELOPMENTAL OUTCOMES OF CHILDREN BORN TO OPIOID-DEPENDENT MOTHERS: A SYSTEMATIC REVIEW AND META-ANALYSIS Samantha J. Lee PhD , Samudragupta Bora PhD , Nicola Austin MBChB, DM , Anneliese Westerman BA , Jacqueline M.T. Henderson PhD PII: DOI: Reference:

S1876-2859(19)30457-7 https://doi.org/10.1016/j.acap.2019.11.005 ACAP 1436

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Academic Pediatrics

Received date: Accepted date:

30 April 2019 12 November 2019

Please cite this article as: Samantha J. Lee PhD , Samudragupta Bora PhD , Nicola Austin MBChB, DM , Anneliese Westerman BA , Jacqueline M.T. Henderson PhD , NEURODEVELOPMENTAL OUTCOMES OF CHILDREN BORN TO OPIOID-DEPENDENT MOTHERS: A SYSTEMATIC REVIEW AND META-ANALYSIS, Academic Pediatrics (2019), doi: https://doi.org/10.1016/j.acap.2019.11.005

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NEURODEVELOPMENTAL OUTCOMES OF CHILDREN BORN TO OPIOIDDEPENDENT MOTHERS: A SYSTEMATIC REVIEW AND META-ANALYSIS Samantha J. Lee, PhDa, Samudragupta Bora, PhDb, Nicola Austin, MBChB, DMc, Anneliese Westerman, BAa, & Jacqueline M.T. Henderson, PhDa Affiliations: aSchool of Psychology, Speech and Hearing, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand ([email protected]; [email protected]; [email protected]); bMothers, Babies and Women’s Health Program, Mater Research Institute, Faculty of Medicine, The University of Queensland, South Brisbane, Queensland 4101, Australia ([email protected]); cDepartment of Paediatrics, University of Otago, PO Box 4345 Christchurch 8140, New Zealand ([email protected]). Address correspondence to: Jacki Henderson, School of Psychology, Speech and Hearing, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand. [[email protected]], +64 (3) 369 4358. ORCID iD: https://orcid.org/0000-0003-4781-0361 Keywords: Prenatal Opioid Exposure; Prenatal Exposure Delayed Effects; Analgesics; Opioid; Child Development; Meta-Analysis Running header: A meta-analysis of prenatally opioid-exposed children’s outcomes Abstract word count: 249 Main text word count: 3758 Funding sources: This study was supported by the Health Research Council of New Zealand (grant number 14/584 to [to JMTH]), the Canterbury Medical Research Foundation Post Graduate Publishing Bursary (grant number Lee_BUR2018-001 [to SJL]), and Lottery Health

Research (grant number 352179 [to SJL]). The funding sources had no involvement in the preparation or completion of this manuscript. Conflict of interest: The authors have no potential conflicts of interest to disclose. Declarations of interest: None.

MeSH KEYWORDS

Prenatal Exposure Delayed Effects; Heroin; Opiate Substitution Treatment; Methadone; Buprenorphine; Narcotics; Analgesics; Opioid; Opioid-Related Disorders; Neurodevelopmental Disorders; Cognition; Intelligence; Psychomotor Performance; Language Development; Child Behavior; Child; Infant; Meta-analysis

ABSTRACT Background: Children born to opioid-dependent mothers are at risk of adverse neurodevelopment. The magnitude of this risk remains inconclusive. Objectives: To conduct a meta-analysis of studies that assessed neurodevelopmental outcomes of children aged 0 to 12 years born to opioid-dependent mothers, compared with children born to non-opioid-dependent mothers, across general cognitive, language, motor, and social-emotional domains. Data Sources: PubMed, CINAHL, PsycINFO, and Google Scholar databases. Study Eligibility Criteria: English-language publications between January 1993 and November 2018, including prenatally opioid-exposed and non-opioid-exposed comparison children, reporting outcomes data on standardized assessments. Study Appraisal and Synthesis Methods: Two reviewers independently extracted data. Pooled standardized mean differences (SMDs) were analyzed using random effects models. Risk of bias was assessed with the Newcastle-Ottawa Quality Assessment Scale. Results: Across 16 studies, individual domain outcomes data were examined for between 93 to 430 opioid-exposed and 75 to 505 non-exposed infants/children. Opioid-exposed infants and children performed more poorly than non-exposed infants and children across all outcomes examined, demonstrated by lower infant cognitive (SMD=0.77) and psychomotor scores (SMD=0.52), lower general cognition/IQ (SMD=0.76) and language scores (SMD=0.65–0.74), and higher parent-rated internalizing (SMD=0.42), externalizing (SMD=0.66), and attention problems (SMD=0.72). Limitations: Most studies examined early neurodevelopment; only three reported school-age outcomes thereby limiting the ability to assess longer-term impacts of prenatal opioid exposures.

Conclusions and Implications of Findings: Children born to opioid-dependent mothers are at modest- to high-risk of adverse neurodevelopment at least to middle childhood. Future studies should identify specific clinical and social factors underlying these challenges to improve outcomes.

NEURODEVELOPMENTAL OUTCOMES OF CHILDREN BORN TO OPIOIDDEPENDENT MOTHERS: A SYSTEMATIC REVIEW AND META-ANALYSIS

The prevalence of opioid use among pregnant women has dramatically increased over the past two decades,1,2 evidenced by an increase of 1.19 to 5.63 per 1000 hospital births per year over the period of 2000 to 2009 in the United States.2 In light of the current opioid epidemic, these rates are likely to continue to increase. This is a global health concern with the maternal morbidities associated with substance dependency, alongside the adverse effects of prenatal opioid exposure on infant’s clinical and neurodevelopmental outcomes.3-7 Beyond early childhood, however, there remains a gap in the literature examining the longer-term neurodevelopmental outcomes of children prenatally exposed to opioids. In contrast, the adverse neonatal outcomes associated with prenatal opioid exposure are well documented, and include premature delivery, small for gestational age,3,4 reduced brain growth and abnormal neural development,5-7 and Neonatal Abstinence Syndrome (NAS), or Neonatal Opioid Withdrawal Syndrome.8 Infants with NAS experience central nervous system irritability, autonomic over-reactivity, gastrointestinal dysfunction, and respiratory distress, and often require extended pharmacological treatment and hospitalization.8,9 NAS affects more than 5 per 1,000 hospital births, with a five-fold reported increase in the United States since 2000: these rates are also likely to rise.2,10 Children born to opioid-dependent mothers are also at increased risk of exposure to postnatal psychosocial adversities (poverty, caregiver psychopathology, compromised parenting),4,11,12 thereby increasing the risk of long-term suboptimal neurodevelopmental outcomes. Two published meta-analyses reported poorer neurodevelopmental outcomes for opioid-exposed children relative to their non-opioid-exposed peers, including lower cognitive and psychomotor scores during infancy,13,14 and at preschool age.13 Poorer social-emotional

outcomes were also reported in a narrative synthesis,14 and a meta-analysis,13 however, data from the latter study were pooled from measures that were not directly comparable (standardized measures of social development vs. non-standardized, observational ratings of infant attention). Recent data describing opioid-exposed children’s emotional and behavior problems have not yet been quantitatively synthesized. Furthermore, significant shortcomings of the meta-analyses are reflected by the few empirical studies in this field, and the paucity in long-term follow-up studies, with between only five and eight infant and preschool outcome studies reviewed, respectively.13,14 The historical nature of the included empirical studies is a further limitation in these meta-analyses, thus resulting in a wide range in the quality of the published evidence. Taking together the recent increase in empirical studies15-20 alongside recent data describing the younger cohorts at school age, there is a need for a contemporary meta-analysis to confirm findings reported in the earlier meta-analyses. This is necessary to elucidate the longer-term influence of prenatal opioid exposure across different developmental domains. Moreover, it is of fundamental importance to include an investigation of social-emotional outcomes given their critical influence on other domains21 and trajectories of developmental pathways in highrisk populations. Thus, a systematic review and meta-analysis of contemporary empirical studies were performed to investigate the neurodevelopmental outcomes of children prenatally exposed to opioids relative to non-exposed children across the first 12 years in the domains of general cognition, language, motor, and social-emotional outcomes.

METHODS A systematic search of PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, and Google Scholar electronic databases, limited to a 25-

year period (January 1, 1993 to November 30, 2018) was conducted. Search terms were developed in consultation with an academic librarian, including broad keywords and MeSH terms. Various combinations of the following terms were used: opiate, opioid, heroin, methadone, buprenorphine, prenatal exposure, follow up, neurodevelopment, development, cognition, intelligence, psychomotor, motor, language, education, school performance, achievement, social, behavior, delay, impairment, deficit, outcome. An example of the electronic search strategy is provided in online Supplementary Table 1. Studies were included if they met the following criteria: (1) sample included children aged 0 to 12 years, (2) with prenatal exposure to an opioid substance including either illicit and/or licit/prescribed opioids (measured through maternal self-report, medical records/prescriptions, and/or analysis of biological samples), (3) included a non-opioid exposed comparison group, (4) was a cohort, case-control, or cross-sectional study, and (5) reported neurodevelopmental outcome data (general cognition/IQ, executive function, language, educational achievement, motor skills, social-emotional/mental health). If no studies were identified that were in addition to those already included in previous metaanalyses, then a new meta-analysis was not conducted for that particular outcome domain. Studies were excluded if they met any of the following criteria: (1) non-human population, (2) no comparison group, (3) prenatal opioid exposure not explicitly specified (e.g., drug-exposed, NAS diagnosis), (4) non-English language publication, (5) non-peerreviewed publication, (6) non-original publication (e.g., case report, review, systematic review, meta-analysis etc.), and (7) original publication reporting outcomes exclusively from an intervention trial. Randomized controlled trials were excluded in order to examine outcomes for children prior to any possible intervention effects. Electronic database search results were imported to EndNote X9, where duplicates were discarded. Two reviewers (SJL, AW) independently conducted title and abstract

screenings for relevant studies. Reference lists from published reviews were also handsearched. Full-text screening was conducted, with discrepancies resolved by a third reviewer (JMTH). Care was taken to include data from each cohort only once for each domain outcome, thus ensuring sample independence. For duplicate cohorts, the article that reported data from the latest follow-up (oldest age) or for the larger sample was selected. For this meta-analysis, infant general cognitive development (i.e., Bayley Mental Development Index scores) and child IQ were treated as separate outcomes, and therefore the same cohort could be represented in both of these domains. Two reviewers (SJL, AW) independently extracted and verified the following information from each article: authors and year of publication, study location, sample size at recruitment, sample size at final data collection phase, age(s) at which follow-up occurred, type of prenatal opioid exposure, measure(s) used to determine prenatal opioid and other drug exposures, prescribed dose of maternal opioid substitute during pregnancy (if applicable), percent of exposed children treated for NAS, composition of the comparison group, percent of male children, measures used to assess the neurodevelopmental outcomes included in the current meta-analysis, whether or not a blinded assessor conducted the assessment, and the covariates examined in relation to the neurodevelopmental outcomes. Means and standard deviations for each outcome measure were extracted. In several cases, study authors were contacted by email to request further information. If no response from the corresponding author was received within seven days, a reminder was sent. Various tests to measure general cognition, psychomotor skills, language, and socialemotional outcomes were used across studies. A few excluded studies (n=4) reported other outcomes that we intended to include (e.g., executive functions, educational achievement), however the data from those reports were insufficient or unstandardized, and thus could not be used for a meta-analysis. It was also intended to analyze outcomes separately for infants,

preschool, and school-age children, however this was not possible for all outcomes due to a paucity of studies, particularly of school-age children. We were able to analyze cognitive development data separately for infants and older children, with preschool and school-age children’s IQ data analyzed together. For psychomotor development, no new studies in the preschool developmental period were identified that were in addition to those reported in an existing meta-analysis.13 Therefore, only infant psychomotor data were analyzed in the current meta-analysis. For language outcomes there were only two studies, both reporting preschool children’s data. Finally, due to a small number of studies, infant, preschool, and school-age children’s social-emotional outcome data were analyzed together. The potential risk of bias for the included studies was evaluated according to the Newcastle-Ottawa Quality Assessment Scale (NOS).22 Two reviewers (SJL, SB) independently scored each of the studies. Studies were scored from 0 to 9, with 0 indicating low quality and high risk of bias, and 9 indicating high quality and low risk of bias. Statistical analyses The statistical data analyses were performed in Review Manager, version 5.3. Random effects meta-analyses were used to calculate summary estimates, with the standardized mean difference (SMD) and 95% confidence interval (CI) as the measure of effect size. Where studies had conducted independent subgroup analyses, a combined effect across subgroups was calculated. Heterogeneity among studies was assessed visually by examining the forest plots, and quantitatively using the Q and I2 statistics. Where evidence of moderate to high heterogeneity was observed, the jackknife sensitivity analysis was conducted to evaluate whether a single study significantly affected the results, by excluding each study one at a time and then repeating the analysis.23 Results from the sensitivity analyses are presented in online Supplementary Tables 2 to 5, with the most important modifications reported in-text.

RESULTS Study Selection Figure 1 shows the study selection flow diagram. Our search strategy provided 4,702 unique articles. Following a title and abstract screen, 76 articles underwent full-text screen, and 16 were identified as eligible for inclusion in the meta-analysis. The final number of studies for each domain are as follows: infant general cognition (n=9), infant psychomotor development (n=7), preschool and school-age general cognition (n=5), preschool language development (n=2), preschool and school-age internalizing behavior (n=4), externalizing behavior (n=4), and attention problems (n=4). Study Characteristics The characteristics of the included studies are presented in Table 1. In total, 16 studies representing 11 unique cohorts were included. Cohorts were born in Germany (n=1), United States of America (n=1), Australia (n=1), Norway (n=2), New Zealand (n=1), Israel (n=1), Finland (n=2), United Kingdom (Scotland, n=1), and The Netherlands (n=1). At recruitment, the opioid-exposed group sample sizes ranged from 15 to 133, and comparison group sample sizes from 13 to 256. Overall retention rates, representing the number of children with outcome data to the final follow-up, ranged from poor to excellent (47% to 93%). The majority of the studies followed their sample to preschool age; only three studies (two cohorts) examined children older than age 5 years. Of the 11 opioid-exposed cohorts, two were prenatally exposed to illicit heroin, four to prescribed methadone, two to heroin and/or methadone, one to illicit buprenorphine, one to prescribed buprenorphine, and one to either prescribed methadone or buprenorphine studied as one combined group. A multi-method approach (self-report or confirmed opioid substitution therapy enrollment in addition to toxicology results) to determine prenatal opioid

exposure was taken in the majority of studies, with only two relying on maternal selfreport.18,24 Three studies reported the opioid-dependent mothers’ mean prescribed methadone dose during pregnancy, which ranged from 20mg/day to >86mg/day. Only one study reported the mean dose of prescribed buprenorphine, which was 13mg/day. Eleven studies reported the percentage of opioid-exposed infants that required treatment for neonatal opioid withdrawal symptoms, which ranged from between 48% and 91% infants. The composition of the comparison groups differed across studies, with some recruiting comparison infants based on selected a priori infant perinatal risk factors25,26 and maternal social/obstetric factors.27-29 Two comparison cohorts were selected as environmental controls, that is, the children were living in a lower socio-economic or drug abuse lifestyle environment, or they were living in a higher socio-economic environment that matched the opioid-exposed children’s foster family environment.16-18,24,29 Other studies randomly recruited comparison group children from local health care centers20,30-34 and one study randomly recruited a regionally representative comparison group.15 Five studies reported that neurodevelopmental assessments were administered and/or scored by examiners blinded to the child’s study group/exposure history. Most studies examined additional risk factors in relation to the children’s neurodevelopmental outcomes. These were predominantly additional drug exposures (i.e., alcohol, tobacco, and cannabis), perinatal factors such as gestational age and birth weight, and maternal social background factors including socioeconomic status and/or maternal education. Few studies examined potential environmental intervening factors. Risk of Bias Overall, the quality of the included studies indicated a medium to low risk of bias (Table 1). Nine studies fulfilled criteria for good quality (Newcastle-Ottawa Quality Assessment Scale [NOS] score ≥7), six were fair (score 5–6), and one was poor (score ≤4).

Study shortcomings included a lack of a representative opioid-exposed cohort (n=5), a lack of examiner blinding (n=11), and low retention rates (n=8). Infant Cognition and Psychomotor Development Nine studies involving 430 exposed and 505 non-exposed infants examined cognitive performance (Figure 2). Opioid-exposed infants had lower cognition scores than non-exposed infants (SMD = -0.77 [95% CI, -1.06 to -0.48]). However, there was significant heterogeneity across studies. The summary effect size remained in the moderate to high range following sensitivity analyses. The exclusion of Ornoy et al. (1996) reduced the heterogeneity from high (I2 = 74%) to moderate (I2 = 53%; Supplementary Table 2). Seven studies involving 354 exposed and 400 non-exposed infants examined infant psychomotor performance (Figure 2). Opioid-exposed infants had lower psychomotor scores than non-exposed infants (SMD = 0.52 [95% CI, -0.78 to -0.25]). In sensitivity analyses, the summary effect size remained moderate with the exclusion of Ornoy et al. (1996), but the heterogeneity was reduced (I2 = 66% to 46%; Supplementary Table 3). Preschool and School-Age Cognition and Language Development Five studies involving 217 exposed and 200 non-exposed children examined general cognition/IQ (Figure 3). Opioid-exposed children had lower IQ scores compared with nonexposed children (SMD = -0.76 [95% CI, -1.25 to -0.28]). There was significant heterogeneity across study effect sizes, but the summary effect remained in the moderate/large range with the exclusion of each study (Supplementary Table 4). The exclusion of Ornoy et al. (2016) reduced the heterogeneity from high (I2 = 82%) to moderate (I2 = 65%). Two studies assessed opioid-exposed preschool children’s language development, including expressive (93 exposed, 75 non-exposed) and receptive (93 exposed, 76 nonexposed) language skills (Figure 3). Opioid-exposed children had lower expressive (SMD = -

0.65 [95% CI, -0.97 to -0.34]) and receptive language scores (SMD = -0.74 [95% CI, -1.12 to -0.36]) than non-exposed children. Preschool and School-Age Social-Emotional Development Data for internalizing and externalizing problems were examined for 215 exposed and 231 non-exposed preschool and school-age children (Figure 4). Opioid-exposed children had higher internalizing scores than non-exposed children (SMD = 0.42 [95% CI, 0.17 to 0.68]). Opioid-exposed children had higher externalizing scores than non-exposed children (SMD = 0.66 [95% CI, 0.32 to 1.00]). There was significant heterogeneity in the effect sizes for externalizing behavior. The exclusion of Levine and Woodward (2018) attenuated the summary effect estimate (0.51) and reduced the heterogeneity (I2 = 66% to 22%). With the exclusion of Ornoy et al. (2016), the effect size estimate increased (0.81) and the heterogeneity reduced (I2 = 31%; Supplementary Table 5). Data for parent-rated attention problems were examined from 208 exposed and 219 non-exposed preschool and school-age children (Figure 4). Opioid-exposed children had higher attention problem scores than nonexposed children (SMD = 0.72 [95% CI, 0.42 to 1.02]).

DISCUSSION In this systematic review and meta-analysis, the neurodevelopmental outcomes of children who were born to opioid-dependent mothers were compared with children born to non-opioid-dependent mothers during pregnancy. Results from 16 studies were consistent in showing that infants and children who were prenatally exposed to opioids performed more poorly than their non-exposed counterparts across all outcomes examined, as demonstrated by lower cognitive, psychomotor and language scores, and higher parent-rated internalizing, externalizing, and attention problem scores. These findings support and extend those of previous researchers who reported similar results. Baldacchino and colleagues conducted a

meta-analysis of five studies of opioid-exposed infant’s and children’s cognitive and psychomotor development, and observer-rated infant attention and social development. Findings of the current meta-analysis were in accordance with their results, which showed that opioid-exposed children performed worse than their non-exposed peers across these domains.13 The current meta-analysis provided additional information by including more recently published studies, and by analyzing preschool language data and parent-rated internalizing, externalizing and attention problem data across childhood. These findings strengthen the conclusion that children who are born to opioid-dependent mothers are at risk for longer-term neurodevelopmental problems across a wide range of domains. Further, our data are consistent with the results of a recent meta-analysis that reported lower cognitive and psychomotor performance amongst infants born to opioid-dependent mothers treated with methadone during pregnancy, compared with non-opioid-exposed controls.14 Taken together, findings suggest that being born to an opioid-dependent mother is a strong indicator for later neurodevelopmental problems. Several biological and socio-environmental risk factors may increase opioid-exposed children’s risk for longer-term adverse neurodevelopmental outcomes. Although examining the specific factors associated with opioid-exposed children’s elevated neurodevelopmental risk was outside the scope of the current study, there are several potential mechanisms at play. Briefly, prenatal exposure to opioid substances can have direct effects on neural development.5-7 Neurological alterations in opioid-exposed infants have been observed shortly after birth, before postnatal confounding environmental effects can influence neurodevelopment.5,6 However, potential neonatal confounders, including maternal concomitant use of cigarettes, alcohol, and other substances during pregnancy, as well as the increased risk of prematurity and other perinatal complications associated with opioidexposure, could also influence their neurodevelopmental outcomes.3-5

The postnatal environment that opioid-exposed children are raised in is proposed as either exacerbating their early biological vulnerability, or buffering them from any negative drug effects. With appropriate monitoring and an enriched early caregiving environment, these children have been reported to demonstrate optimized outcomes.35 Unfortunately, opioid-exposed children are more likely to be born into a multiple-risk social context, with their mothers typically coming from low socioeconomic family backgrounds themselves, and more often having educational underachievement, a lack of partner support, and comorbid psychiatric disturbance and poly-drug use problems than mothers without opioid dependence.11,30 Understanding whether prenatal opioid exposure has any independent effects on children’s neurodevelopmental outcomes or not is a difficult task for researchers. Some of the heterogeneity in effect sizes in the current meta-analysis might be explained by the differing levels of both pre and postnatal risk exposures that characterize opioid-exposed children. First, it is unclear from the current results whether the different types of opioids children were exposed to had any differential impact on their outcomes. Opioid-exposed children are not a homogenous group. First, children’s prenatal exposure to opioid substances, and their subsequent neurodevelopmental outcomes, may be impacted by genetic variations in opioid metabolism.36 Further, the effects of illicit compared to prescribed opioids, or the effects of different opioid substitutes, cannot be assumed to be equivalent. Children’s outcomes may be associated with differences in the pharmacological actions of these drugs, as well as the differences relating to maternal opioid-use history, polydrug use, treatment retention, and behavioral stability that are found across the different populations using them.37,38 The timing, frequency, and extent of maternal opioid use across pregnancy may also be of importance. Although a recent population-based study found that infants born to opioid-dependent women stabilized with methadone prior to conception had similar short-term outcomes compared to women who began treatment during their

pregnancies,38 children’s long-term outcomes have not been examined in relation to the timing of their exposure. Of importance, infants of the latter group of women in that study had up to a fourfold increase of removal by social services at the hospital.38 This demonstrates the increase in socio-familial issues associated with untreated opioiddependence during pregnancy which, importantly, are well known as having a critical influence on children’s neurodevelopmental outcomes.8 We performed subgroup analyses for infant cognitive outcomes, and results were no different when cohorts of illicit opioid-exposed children or prescribed opioid-exposed children were compared to controls. This same procedure was not possible with the other outcomes examined however, nor was an examination of methadone-exposed compared to buprenorphine-exposed children’s outcomes, given the small number of studies. A more indepth analysis to examine this pertinent issue will only be possible with a greater number of child outcome studies in future. Identifying opioid treatments with the greatest reduction in harm is central to the optimal management of opioid-dependence in pregnancy for the mother and fetus, recognizing that poly-drug use and confounding by indication will influence this to an extent.37 Also worthy of note is that the wide variation in care (e.g., pharmacologic, family-centered support) received by infants who are prenatally exposed to opioids during the neonatal period potentially influences later child risks.39,40 The composition of the comparison groups across studies was also variable. It would be expected to see greater between-group difference in studies that compared opioid-exposed children to low-risk and regionally representative groups than when opioid-exposed children were compared to groups that were similar on other, potentially confounding, factors. Nevertheless, with the exception of one cohort,18,24 group differences were found in studies where demographically similar opioid-exposed and non-exposed groups were compared. The expected direction of effect in all analyses was not followed in one cohort where the non-

exposed comparison group included high-risk children living in familial drug-use environments that may have increased their risk for poor performance.18,24 A further limitation of the current meta-analysis, and something that should be explored in future research, is that the contribution of environmental intervening processes to opioid-exposed children’s outcomes across neurodevelopmental domains could not be examined. The included studies varied in their consideration of and adjustment for perinatal and social background risks, and very few studies to date have considered intervening factors including caregiving factors associated with maternal substance use disorders, such as psychiatric comorbidities, and how these affect child outcomes.8 Another noteworthy limitation includes that very few studies have conducted followup assessments of opioid-exposed children beyond the preschool developmental period.16-18 There was a wide range of follow-up rates (47 – 93%), and it is of concern that attrition in these high-risk samples represents impairment or lifestyle factors that may predispose children to poorer outcomes. It is possible that the findings of this meta-analysis underestimate the significance of the opioid-exposed children’s neurodevelopmental impairments. It is also of concern that opioid-exposed children’s early observed impairment will worsen with age, and that new impairments may emerge. Importantly, theories of cascading effects of impairment across domains suggest that problems in one domain, (e.g., social-emotional), will undermine functioning in one or more other domains (e.g., cognitive), particularly following a developmental transition such as starting school.21 Another key issue is that as opioid-exposed children transition from pre-school to school age, difficulties within new domains of functioning (e.g., executive, educational) may begin to emerge. Potentially, the effects of prenatal opioids, or other associated factors, on children’s longer-term outcomes may not become apparent until the child reaches an age at which skills within a certain domain of interest are developing.16

In conclusion, children born to opioid-dependent mothers have an increased risk for neurodevelopmental difficulties. This methodologically robust meta-analysis of 16 studies provided evidence for poorer development across the domains of general cognition, psychomotor, language, and social-emotional development among this high-risk group. Impairments across these domains are likely to have a large negative influence on opioidexposed children’s schooling, peer relationships, and mental health. Follow-up studies examining these salient middle childhood and adolescent outcomes will be necessary to understand the longer-term consequences of prenatal opioid exposure and opioid-exposed children’s early difficulties. Finally, given their complexity of several risk factors, long-term surveillance of a large number of prenatally opioid-exposed children is needed.

ACKNOWLEDGEMENTS Thank you to Kerry Gilmour and Margaret Paterson, librarians at the University of Canterbury, for their help and guidance with the original literature search. We would also like to thank those researchers who contributed requested data for this project. This study was supported by the Health Research Council of New Zealand (grant number 14/584 to [to JMTH]), the Canterbury Medical Research Foundation Post Graduate Publishing Bursary (grant number Lee_BUR2018-001 [to SJL]), and Lottery Health Research (grant number 352179 [to SJL]).

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Figure 1. Study selection flowchart

Cognition

25 27 28 15 26 16 24 30 31

Psychomotor

25 27 28 15 26 29 24

Figure 2. Forest plot of infant cognition and psychomotor performance scores

General cognition

28 20 16 18 32

Expressive language 28

32

Receptive language 28 32

Figure 3. Forest plot of general cognition scores at preschool and school age, and language scores at preschool age

Internalizing behavior

15

17 18 33

Externalizing behavior

15

17 18 33

Attention problems

15 34 17

18

Figure 4. Forest plot of social-emotional outcome scores at preschool and school age

Table 1. Characteristics of the Studies Cohort #a Place Author, y

#1

Germany

Bunikowski et al. (1998)25

#2

United States of America

Hans and Jeremy (2001)27

N at recruitment

N with data at final followup (% retention)

93;

69 (74%);

POE: 46

POE: 27 (59%)

NE: 47

NE: 42 (89%)

89;

78 (88%);

POE: 42

POE: 33 (79%)

NE: 47

NE: 45 (96%)

Age at followup (y)

POE type

Ascertainment of Drug Exposure

Mean OST dose, mg/day (range)

% NAS/ NOWS tx

Hunt et al. (2008)28

Australia

236;

111 (47%);

POE: 133

POE: 67 (50%)

NE: 103

NE: 44 (43%)

% male

Outcome data analyzed

Blinded assessor

Additional Predictors/ Covariatesb

NOS

1

Prescribed methadone (n=22) or illicit heroin (n=12)

Confirmed OST, heroin NR

NR

91

Selected from same hospital if nicotineexposed

POE: 56 NE: 47

Griffiths Mental Development Scale, Performance & Locomotor

NR

SB

6

4 mo., 8 mo., 1, 1.5, 2

Prescribed methadone

Confirmed OST, maternal urine, selfreport

20 (3 – 40)

NR

Selected from same hospital. Comparable maternal age, SES, race, education, parity

NR

Bayley Scales, MDI & PDI

Yes

PDE, B/IF, SB, CF

8

56

Matched for maternal age, height, ethnicity, and obstetric history

POE: 58

Bayley Scales, MDI & PDI (age 1.5)

NR

None

3

(dose across pregnancy)

#3

Comparison group composition

1.5, 3

Prescribed methadone

Confirmed OST, maternal urine

NR

NE: 38

SBIS (age 3) Reynell Language Scale

Table 1. Characteristics of the Studies Cohort #a Place Author, y

#4

Norway

Konijnenberg et al. (2015/2016)

N at recruitment

N with data at final followup (% retention)

72;

67 (93%)

POE: 36

POE: 35 (97%)

NE: 36

NE: 32 (89%)

Age at followup (y)

4

POE type

Prescribed methadone (n=24) or buprenorphine (n=11)

Ascertainment of Drug Exposure

Confirmed OST, maternal urine, meconium, self-report

19,20

Mean OST dose, mg/day (range) 85.96 (0 – 260)

% NAS/ NOWS tx 63c

and 12.76 (3 – 24)

Comparison group composition

% male

Recruited through local health care centers based on their due date

POE: 54

A regionally representative group that was selected at random from the same hospital

POE: 57

Selected from the same hospital and matched for gestational age, birth weight, and maternal post code at delivery

NR

NE: 39

Outcome data analyzed

Blinded assessor

Additional Predictors/ Covariatesb

NOS

WPPSI-R, full scale IQ (provided by authors)

NR

PDE, B/IF, SB, CF

7

Bayley Scales, MDI & PDI (age 2)

Yes

PDE, B/IF, SB

8

No

PDE

8

(dose at delivery)

#5

New Zealand

Levine and Woodward (2018)15

210;

190 (90%);

POE: 100

POE: 87 (87%)

NE: 110

NE: 103 (94%)

2, 4.5

Prescribed methadone

Confirmed OST, maternal urine, meconium, self-report

62.4 (6.7 – 195)

88

(dose across pregnancy)

#6 McGlone and Mactier (2015)26

United Kingdom

152;

107 (70%);

POE: 102

POE: 81 (79%)

NE: 50

NE: 26 (52%)

6 mo.

Prescribed methadone

Self-report, maternal urine, infant urine, meconium

NR

48

NE: 46

SDQ (age 4.5)

Griffiths Mental Development Scales, Performance & Locomotor

Table 1. Characteristics of the Studies Cohort #a Place Author, y

#4

Norway

Melinder et al. (2013)34

N at recruitment

N with data at final followup (% retention)

72;

49 (68%);

POE: 36

POE: 26 (72%)

NE: 36

NE: 23 (64%)

Age at followup (y)

4

POE type

Prescribed methadone (n=18) or buprenorphine (n=8)

Ascertainment of Drug Exposure

Confirmed OST, maternal urine, meconium, self-report

Mean OST dose, mg/day (range) 85.00 (range, NR)

% NAS/ NOWS tx 61 and 87

and 13.13 (range, NR)

Comparison group composition

% male

Recruited through local health care centers based on their due date

POE: 44

Matched for family/foster family social background

POE: 60

Matched for family/foster family social background

POE: 56

NE: 50

Outcome data analyzed

Blinded assessor

Additional Predictors/ Covariatesb

NOS

Child Behavior Checklist, Attention subtest

NR

B/IF, SB

5

Bayley Scales II, PDI

No

B/IF, SB

7

Bayley Scales II, MDI (age 3)

No

B/IF, SB, CF

8

n/a

B/IF, SB

8

(dose at delivery)

#7

Norway Moe and Slinning (2001)29

#7

Norway

Nygaard et al. (2015)16

#7 Nygaard et al. (2016)17

Norway

136;

81 (60%);

POE: 78

POE: 36 (46%)

NE: 58

NE: 45 (78%)

130;

103 (79%);

POE: 72

POE: 55 (76%)

NE: 58

NE: 48 (83%)

130;

104 (80%);

POE: 72

POE: 57 (79%)

NE: 58

NE: 47 (81%)

1, 2, 3

1, 2, 3, 4.5, 8.5

Illicit heroin

Illicit heroin

Maternal urine, infant urine/blood, self-report

n/a

Maternal urine, infant urine/blood, self-report

n/a

77

79

NE: 55

NE: 60

WISC-R (age 8.5) 4.5, 8.5

Illicit heroin

Maternal urine, infant urine/blood, self-report

n/a

79

Matched for family/foster family social background

POE: 58 NE: 60

Child Behavior Checklist

Table 1. Characteristics of the Studies Cohort #a Place Author, y

#8

Israel

Ornoy et al. (1996)24

N at recruitment

339;

N with data at final followup (% retention) n/a

Age at followup (y)

6 mo. to 6

POE type

Illicit heroin

Ascertainment of Drug Exposure

Self-report

Mean OST dose, mg/day (range) n/a

% NAS/ NOWS tx 74

Comparison group composition

Four NE groups:

POE: 83

POE: 52

Outcome data analyzed

Bayley Scales, MDI & PDI

NE: 56 – 66

(up to age 2)

Children without prenatal opioid exposure that were raised by opioiddependent fathers

POE: 40

WISC-R

NE: 57

Child Behavior Checklist (short form)

Randomly recruited from well-baby clinics

NR

Bayley Scales III, Cognition

1. Addicted fathers (n=76)

NE: 256

% male

Blinded assessor

Additional Predictors/ Covariatesb

NOS

Yes

None

6

NR

B/IF

6

Yes

B/IF, SB, CF

6

2. Low SES/neglect (n=50) 3. Moderate/ high SES, but suspected delay (n=50) 4. Average SES, normal control (n=80)

#8

Israel

Ornoy et al. (2016)18

84:

n/a

5 to 16.5

Illicit heroin

Self-report

n/a

53

POE: 38 NE: 46

#9 Salo et al. (2009)30

Finland

41;

POE: 21 (75%)

POE: 28

NE: n/a – recruited at follow-up

NE: 13

3

Illicit buprenorphine

Infant urine

NR

NR

Table 1. Characteristics of the Studies Cohort #a Place Author, y

#10

Finland

Salo et al. (2010)31

N at recruitment

87;

N with data at final followup (% retention) n/a

Age at followup (y)

5 to 12 mo.

POE type

Prescribed buprenorphine

POE: 15

Ascertainment of Drug Exposure

Confirmed OST, maternal urine, selfreport

Mean OST dose, mg/day (range) NR

% NAS/ NOWS tx NR

Comparison group composition

Two NE groups:

% male

Outcome data analyzed

Blinded assessor

Additional Predictors/ Covariatesb

NOS

NR

Bayley Scales III, MDI

Yes

B/IF, SB, CF

5

1. Depressed mothers and their children (n=15)

NE: 72

2. Randomly recruited from well-baby clinics (n=57)

#4

Norway

Sarfi et al. (2013)33

#11 Van Baar and de Graaf (1994)32

Netherlands

74;

68 (92%);

POE: 38

POE: 33 (87%)

NE: 36

NE: 35 (97%)

70;

52 (74%);

POE: 35

POE: 22 (63%)

NE: 35

NE: 30 (86%)

2.5

3.5, 4, 4.5, 5.5

Prescribed methadone (n=24) or buprenorphine (n=12)

Confirmed OST,

Prescribed methadone and illicit heroind

Maternal urine, infant urine, self-report

NR

NR

Recruited through local health care centers based on their due date

NR

Child Behavior Checklist Internalizing & Externalizing

n/a

B/IF, CF

7

Mean, NR

83

Recruited based on lack of perinatal complications associated with prenatal drug exposure (low risk group)

POE: 48

Revision of the Amsterdam Children’s Intelligence Test (age 4.5, 5.5)

NR

PDE, B/IF, CF, ChF

7

maternal urine, meconium, self-report

(0 – 80)

(dose across pregnancy)

NE: 43

Reynell Language Scale

Table 1. Characteristics of the Studies Cohort #a Place Author, y a

N at recruitment

N with data at final followup (% retention)

Age at followup (y)

POE type

Ascertainment of Drug Exposure

Mean OST dose, mg/day (range)

% NAS/ NOWS tx

Comparison group composition

% male

Outcome data analyzed

Blinded assessor

Additional Predictors/ Covariatesb

NOS

Cohorts have been numbered for easy identification of duplicate cohorts examined across studies where different outcomes were assessed

b

PDE, additional prenatal drug exposures: tobacco, alcohol, cannabis, cocaine/other stimulants, benzodiazepines, anti-depressants, additional opioids. B/IF, birth/infant factors: sex, gestational age, birth weight, length, head circumference, neonatal opioid withdrawal treatment, opioid dose, APGAR score, breastfeeding status. SB, social background: maternal/parental age, ethnicity, education level, socio-economic status, marital status. CF, caregiving factors: maternal IQ/vocabulary, psychopathology/symptomology, parenting behavior, maternal vs. foster care status, home environment quality (Home Observation for Measurement of the Environment score). ChF: child factors, age at follow-up, IQ, behavior, attention, ADHD, inhibitory control. SF, study factors: site. c

No breakdown of the rates of NAS for BE and ME children provided.

d

Prenatal exposure to both methadone and heroin.

Other abbreviations: GCI, General Cognitive Index. MDI, Mental Development Index. NAS, neonatal abstinence syndrome. NE, non-exposed. NOS, Newcastle-Ottawa Scale. NOWS, neonatal opioid withdrawal syndrome. NR, not reported. PDI, psychomotor development index. POE, prenatally opioid-exposed. OST, opioid substitution treatment. SBIS, Stanford-Binet Intelligence Scales. SDQ, Strengths and Difficulties Questionnaire. SES, socioeconomic status. WISC-R, Wechsler Intelligence Scale for Children –Revised. WPPSI-R, Wechsler Preschool and Primary Scale of Intelligence – Revised.

What This Systematic Review Adds  Children born to opioid-dependent mothers are at risk of adverse neurodevelopment.  Exposed infants have lower general cognition and psychomotor scores than non-exposed infants.

 Exposed children have lower general cognition and language scores, and increased socialemotional problems compared to non-exposed children.

 Developmental surveillance of children born to opioid-dependent mothers is encouraged.  Researchers should continue to investigate the longer-term neurodevelopmental outcomes of children born to opioid-dependent mothers, and aim to elucidate specific clinical and psychosocial factors associated with these outcomes.