Abstract
Background:
Prenatal opioid exposure has been associated with developmental deficits during infancy, but the literature is limited by simple group comparisons and lack of appropriate controls. Previously published research with the current sample documented unique associations between prenatal opioid exposure and developmental outcomes at three and six months, but less is known about associations later in infancy.
Method:
The current study examined pre- and postnatal opioid and polysubstance exposure as predictors of parent-reported developmental status at 12 months of age. Participants were 85 mother-child dyads, oversampled for mothers taking opioid treatment medications during pregnancy. Maternal opioid and polysubstance use were reported using the Timeline Follow-Back Interview during the third trimester of pregnancy or up to one month postpartum and updated through the child’s first year of life. Seventy-eight dyads participated in a 12-month assessment, including 68 with parent-reported developmental status on Ages and Stages Questionnaire.
Results:
At 12 months, average developmental scores fell within normal ranges and prenatal opioid exposure was not significantly related to any developmental outcomes. However, more prenatal alcohol exposure was significantly related to worse problem-solving scores, and this relationship remained after controlling for adjusted age and other substance exposure.
Conclusion:
Although findings await replication with larger samples and more comprehensive measures, results suggest that unique developmental risks of prenatal opioid exposure may not persist through the first year of life. Effects of prenatal exposure to co-occurring teratogens, such as alcohol, may become apparent as children exposed to opioids develop.
Keywords: Prenatal opioid exposure, Medication-assisted treatment, Polysubstance use, Timeline follow-back interview, Early development
1. Introduction
Opioid use among pregnant women is rising (Ko et al., 2020), mirrored by an increase in infants affected by neonatal abstinence syndrome (NAS; Conradt et al., 2019). NAS refers to infant withdrawal symptoms, including breathing and feeding problems, tremors, and high-pitched cries, following sudden discontinuation of exposure to substances used by the mother during pregnancy (Kocherlakota, 2014). Opioid maintenance therapy (OMT), pharmacotherapy replacement with a full or partial mu agonist, is the recommended treatment for pregnant women with opioid use disorders (OUD). OMT has well-established advantages for the mother and infant, including reducing withdrawal symptoms, relapse likelihood, and risks associated with illicit opioid use (ACOG, 2017). However, extended use of opioids late in pregnancy, including OMT, increases risk of NAS and raises concerns about effects of prenatal opioid exposure on later development (Conradt et al., 2019).
1.1. Prenatal opioid exposure and child development
Research evaluating associations between prenatal opioid exposure and early development is mixed. One meta-analysis documented worse functioning among children exposed versus not exposed to opioids (Andersen et al. 2020), whereas another found most opioid-exposed children had no deleterious neurodevelopmental outcomes through 36 months (Kaltenbach et al., 2018). Discrepancies may relate to varied timing of assessments across development. Some research shows initial differences associated with opioid exposure attenuating across early infancy (Marcus et al., 1984; Van Baar et al., 1994), whereas other studies show emerging deficits (Van Baar et al., 1994).
Few studies examine neurodevelopmental outcomes of prenatal opioid exposure beyond early infancy, complicating efforts to assess longevity of effects (Conradt et al., 2019). Yeoh and colleagues (2019) found children with prenatal opioid exposure had significantly lower cognitive development scores than controls between 6 and 24 months. In another study, methadone-exposed children showed worse mental and psychomotor development than non-exposed children at 12 months (Johnson et al., 1984). More longitudinal research is needed to clarify neurodevelopmental outcomes associated with prenatal opioid exposure beyond early infancy.
1.2. Limitations of existing literature
Existing research is limited by a lack of statistical controls for confounds, including prenatal polysubstance exposure. Compared to opioid-naive mothers, mothers who use opioids have a higher likelihood of using other known teratogens (e.g., alcohol, cigarettes; Azuine et al., 2019). Indeed, a recent meta-analysis found prenatal opioid exposure was not significantly related to cognitive development when groups were matched on prenatal tobacco exposure (Nelson et al., 2020). Polysubstance exposure in utero may confer its own developmental risks (Moe & Slinning, 2001) and increase the likelihood of NAS (Jansson et al., 2017).
Other confounding variables relate to rearing environment. Because opioid use co-occurs with poverty, sociodemographic disadvantage may account for developmental differences (Konijnenberg & Melinder, 2011). One review found that controlling for environmental risk eliminated significant differences in developmental outcomes associated with prenatal opioid exposure (Conradt et al., 2019). Relatedly, postnatal substance use may contribute to developmental risk, confounding efforts to isolate prenatal exposure’s effects. In research on opioid use during pregnancy, postnatal substance use is rarely assessed. However, Hickey and colleagues (1995) found effects of both in-utero and postnatal opioid exposure on attention. Researchers have called for more longitudinal studies controlling for environmental confounds to clarify unique effects of prenatal opioid exposure (Conradt et al., 2019).
1.3. The current study
The current study examined links between continuous variation in total opioid exposure and mother-reported development at 12 months, accounting for sociodemographic factors, prenatal polysubstance exposure, and postnatal maternal substance use. This represents an extension of a paper examining neurodevelopmental outcomes of prenatal opioid and polysubstance exposure at three and six months (Labella et al., 2021). At previous timepoints, average developmental scores fell into the normal range. However, an inverse relationship emerged between total opioid exposure and mother-reported fine motor skills at three months and communication skills at six months, and findings persisted controlling for polysubstance exposure and sociodemographic covariates. Additionally, total opioid exposure conferred risk for prematurity (Labella et al., 2021).
The current study followed the same sample to 12 months, providing longitudinal insights regarding prenatal opioid and polysubstance exposure through the first year of life and incorporating statistical controls for postnatal substance use. We hypothesized that higher prenatal opioid exposure would be uniquely associated with worse cognitive, motor, and behavioral parent-reported development at 12 months, controlling for other prenatal and postnatal substance exposure. We evaluated sociodemographic factors, birth outcomes, and intervention status as covariates.
2. Methods
2.1. Participants
Participants were 85 mother-child dyads (82 mothers of 85 children, including one set of twins and two sibling pairs). Sixty-two mothers of 65 children were enrolled in a randomized controlled trial evaluating an attachment-based parenting program (modified Attachment and Biobehavioral Catch-up; mABC) adapted for mothers on OMT during pregnancy (ClinicalTrials.gov, NCT03891628). Mothers in the OMT group reported prescribed use of methadone (n = 48) and/or buprenorphine (n = 21) during the target pregnancy, with four mothers reporting non-simultaneous use of both medications. Twenty mothers matched on educational attainment (i.e., no more than baccalaureate education) but not on OMT were enrolled as a non-OUD comparison group and invited to complete all research assessments. Consistent with the prior publication (Labella et al., 2021), participants were combined into a single sample, oversampled for opioid exposure.
Mothers ranged in age from 18.8 to 40.8 years (M = 29.2, SD = 4.5), were predominantly White (63.4%) and of low socioeconomic status; one-quarter (25.6%) reported less than a high school education and almost half (43.9%) had a yearly household income below $10,000. Children were identified as White (37.2%), Multiracial (36.4%), or Black (26.9%), and half were identified as female (51.8%).
2.2. Procedures
The University of Delaware Institutional Review Board approved study procedures. After providing informed consent, mothers completed the baseline assessment during their third trimester or up to one-month postpartum, when they reported demographics and prenatal substance use to date. Mothers on OMT were randomized to receive mABC or a developmentally focused active comparison intervention. All dyads were invited to complete follow-up assessments when children were three, six, and 12 months old, adjusted for prematurity, and parents reported on child demographics, developmental status, and their own substance use (see online supplemental Figure 1 for a diagram of study flow).
2.3. Measures
2.3.1. Maternal substance use
Pre- and postnatal exposure to prescribed and illicit substances was assessed using the Timeline Follow-Back Interview (TLFB), a reliable measure validated against biomarkers of substance use (Brown et al., 1998; Schuetze et al., 2008).
Prenatal substance exposure was assessed at baseline and updated at the six-month assessment for participants who were pregnant at baseline. Consistent with Labella et al. (2021), one variable capturing prenatal opioid exposure was created summing the proportion of pregnancy days involving opioid treatment medication (OTM), prescription opioid use for pain relief, and illicit opioid use (i.e., heroin use, prescription analgesic misuse, and OTM misuse). Given known teratogenic effects of alcohol and tobacco (Schuetze et al., 2008; Testa et al., 2003), we calculated the average number of cigarettes and standard drinks per week during pregnancy. To account for additional substance exposure, a prenatal polysubstance risk score was computed by tallying the number of additional non-opioid substances used during pregnancy, with a possible range of 0–9: marijuana, e-cigarettes, prescription stimulant misuse, prescription sedative misuse, cocaine, inhalants, hallucinogens, methamphetamines, and ecstasy.
Postnatal substance use was reported at the six-month and 12-month research assessments. A postnatal opioid exposure variable was created, summing the proportion of postnatal days involving OTM, prescription opioid use for pain relief, and illicit opioid use. The postnatal polysubstance exposure variable was computed by tallying the number of non-opioid substances used, with a possible range of 0–11. To minimize multiple comparisons, alcohol and tobacco were incorporated into the postnatal polysubstance exposure score and not examined separately.
2.3.2. Child developmental status
Parents reported their children’s development at the 12-month visit using the Ages and Stages Questionnaire-Third Edition (ASQ-3), a reliable and valid screening measure of developmental concerns in five domains: communication, fine motor, gross motor, problem-solving, and personal-social (Squires & Bricker, 2009). Parents indicated children’s mastery of milestones on a three-point scale, and items were summed using standard procedures to yield domain scores ranging from 0 to 60, with empirically derived cut-off scores indicating areas of clinical concern. Continuous domain scores were used for focal analyses.
Two custodial grandmothers completed the 12-month ASQ-3 for children whose mothers had lost custody. All other reporters were biological mothers. Twelve parents completed the ASQ-3 late (age of testing M = 13.5 months, SD = 2.3, range = 12.2 – 24.3) due to difficulty scheduling research assessments during the window of eligibility (typically due to the COVID-19 pandemic). Significance judgments and approximate effect sizes did not change when excluding these children, so results with the full sample are reported.
2.3.3. Non-substance-related covariates
At the baseline assessment, mothers reported their age, racial/ethnic identity, educational attainment (rated on a five-point scale from 1-Less than high school to 5-Baccalaureate degree), and household income (rated on a seven-point scale from 1-Less than $10,000 to 7-More than $100,000). Mothers reported child racial/ethnic identity, sex assigned at birth, birthdate, and birthweight at follow-up research assessments. Gestational age was calculated in weeks using the difference between a child’s mother-reported estimated due date and actual birthdate. A dichotomous variable captured premature birth before 37 weeks’ gestation. Age at the 12-month assessment was calculated in days and adjusted for prematurity for children born before 37 weeks.
2.4. Missing data
Out of 85 enrolled dyads, 78 participated in the 12-month research assessment; three dyads previously withdrew due to busyness and four were unresponsive to scheduling. Ten additional dyads did not have 12-month ASQ-3 data due to infant death (n = 2), custody loss (n = 5), or questionnaire non-completion (n = 3). Percent missing data ranged from 0% (demographics, birth outcomes) to 20% (12-month ASQ-3). Those without ASQ-3 data had higher levels of prenatal polysubstance exposure (M = 1.35, SD = 0.99) than those with ASQ-3 data (M = 0.82, SD = 0.83; t[83] = 2.26, p = 0.03). Children did not significantly differ on demographic variables or prenatal opioid, alcohol, or cigarette exposure. Since missingness was conditioned on variables included in the analysis, data were assumed to be missing at random. Full-information maximum likelihood (FIML) was used to generate unbiased parameter estimates, retaining the full baseline sample for all analyses.
2.5. Plan for analysis
Bivariate associations were calculated linking substance exposure variables and ASQ-3 scores. Significant associations were followed up with multiple regressions controlling for adjusted age and other substance exposure (i.e., total pre- and postnatal opioid and polysubstance exposure, prenatal cigarettes, prenatal standard drinks per week). Maternal education, household income, child sex, child race (White versus non-White), gestational age, prematurity, and birthweight were evaluated as potential covariates for all outcomes.
Analyses were completed in R (R Core Team, 2016). Linear regressions predicting continuous outcomes were modeled in the package ‘lavaan’ using maximum likelihood estimation with robust standard errors and FIML to account for missing data. (Rosseel, 2012).
3. Results
3.1. Pre- and postnatal substance exposure
Percentages of children exposed to substances in the pre- and postnatal period are displayed in Table 1. As previously reported (Labella et al., 2021), proportion of pregnancy days on OMT ranged from 0 to 100% (M = 63.8, SD = 41.9). On average, illicit opioid use occurred on 9.4% of pregnancy days (SD = 18.7). In the postnatal period, proportion of days on OMT ranged from 0 to 100% (M = 65.8, SD = 43.3). On average, illicit opioid use occurred on 2.1% of postnatal days (SD = 7.5).
Table 1.
Percentage of children exposed pre- and postnatally to opioid and non-opioid substances.
| % with prenatal exposure | % with postnatal exposure | |
|---|---|---|
| Opioid exposure | ||
| Medication-assisted treatment | 76.5 | 75.0 |
| Methadone | 56.5 | 58.8 |
| Buprenorphine | 24.7 | 18.8 |
| Illicit opioid use | 52.4 | 26.3 |
| Heroin | 38.1 | 16.3 |
| OTM misuse | 11.9 | 10.0 |
| Pain prescription misuse | 14.3 | 3.8 |
| Non-opioid exposure | ||
| Tobacco | 86.9 | 75.0 |
| Alcohol | 35.7 | 42.5 |
| Marijuana | 41.7 | 41.3 |
| Cocaine | 23.8 | 11.3 |
| E-cigarettes | 6.0 | 16.3 |
| Methamphetamines | 4.8 | 1.3 |
| Stimulant misuse | 3.6 | 2.5 |
| Sedative misuse | 4.8 | 10.0 |
| Hallucinogens | 1.2 | 3.4 |
| Inhalants | 0 | 0 |
| Ecstasy | 0 | 1.3 |
| Other | 3.6 | 2.5 |
3.2. Developmental status at 12 months
At 12 months, all mean ASQ-3 scores fell in the normal range and most children scored above the clinical cutoff for normative development in each domain: communication (97.1%), gross motor (94.1%), fine motor (100%), problem-solving (98.6%), and personal-social (98.6%). Regarding candidate covariates, gestational age was positively associated with personal-social skills and birthweight was associated with gross motor skills (Table 1). Sociodemographic factors, prematurity, and intervention status were not significantly related to outcomes.
Bivariate associations calculated using full information maximum likelihood are presented in Table 2. ASQ-3 communication, gross motor, fine motor, and personal-social scores were not significantly related to prenatal or postnatal opioid exposure or non-opioid substance exposure variables. Problem-solving, however, was inversely associated with prenatal alcohol exposure (Table 2). In follow-up linear regressions, prenatal alcohol exposure continued to predict 12-month problem-solving skills (β = −0.24, p = .04) controlling for 12-month adjusted age, prenatal exposure to opioids, cigarettes, and polysubstance use, and postnatal exposure to opioid and polysubstance use (Table 3). Prenatal and postnatal polysubstance exposure were each uniquely associated with problem-solving in the full model, albeit in opposite directions (prenatal β = 0.31, p = .01, postnatal β = −0.21, p < .05).
Table 2.
Descriptive statistics and bivariate associations among birth outcomes, prenatal and postnatal substance use, and developmental outcomes at 12 months.
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1. Gestational age | -- | ||||||||||||
| 2. Birthweight | 0.71*** | -- | |||||||||||
| Substance exposure variables | |||||||||||||
| 3. Prenatal alcohol | −0.05 | 0.10 | -- | ||||||||||
| 4. Prenatal cigarettes | −0.13 | −0.08 | 0.22* | -- | |||||||||
| 5. Prenatal polysubstance | −0.16 | −0.12 | 0.27* | 0.03 | -- | ||||||||
| 6. Prenatal opioid | −0.13 | −0.13 | −0.19 | 0.44*** | −0.02 | -- | |||||||
| 7. Postnatal polysubstance | −0.18 | −0.18 | −0.10 | 0.05 | 0.27* | 0.34** | -- | ||||||
| 8. Postnatal opioid | −0.11 | −0.16 | −0.26* | 0.41*** | 0.07 | 0.84*** | 0.35** | -- | |||||
| 12M Ages and Stages Questionnaire scores | |||||||||||||
| 9. Communication | 0.19 | 0.20 | 0.08 | 0.05 | 0.24 | −0.11 | −0.09 | 0.01 | -- | ||||
| 10. Gross motor | 0.24 | 0.30* | 0.07 | −0.14 | 0.15 | −0.04 | −0.07 | −0.12 | 0.60*** | -- | |||
| 11. Fine motor | 0.24 | 0.19 | −0.08 | −0.10 | 0.10 | −0.04 | −0.06 | 0.03 | 0.48*** | 0.61*** | -- | ||
| 12. Problem-solving | 0.20 | 0.13 | −0.21* | −0.10 | 0.20 | 0.08 | −0.08 | 0.18 | 0.56*** | 0.56*** | 0.65*** | -- | |
| 13. Personal-social | 0.27* | 0.14 | 0.02 | −0.13 | 0.22 | −0.04 | −0.09 | 0.09 | 0.68*** | 0.54*** | 0.65*** | 0.68*** | -- |
| Mean | 38.6 | 6.6 | 0.75 | 54.2 | 92.9 | 74.3 | 2.1 | 68.8 | 48.4 | 51.6 | 50.6 | 48.9 | 45.5 |
| Standard deviation | 2.1 | 1.4 | 3.5 | 44.7 | 0.9 | 45.6 | 1.5 | 44.0 | 11.1 | 13.2 | 9.5 | 11.5 | 13.0 |
n = 85 using full-information maximum likelihood.
p < .05,
p < .01,
p < .001
Table 3.
Predicting 12-month Ages and Stages Questionnaire problem-solving scores from pre- and postnatal substance exposure and covariates.
| β | p | R2 | |
|---|---|---|---|
| Prenatal alcohol exposure | −0.24 | 0.04 | 0.23 |
| Prenatal cigarette exposure | −0.17 | 0.22 | |
| Prenatal polysubstance exposure | 0.31 | 0.01 | |
| Prenatal opioid exposure | −0.07 | 0.78 | |
| Postnatal polysubstance exposure | −0.21 | 0.05 | |
| Postnatal opioid exposure | 0.32 | 0.18 | |
| Adjusted age | 0.20 | 0.06 |
n = 85 using full-information maximum likelihood.
4. Discussion
This study extended prior research to examine effects of continuous variation in prenatal opioid exposure on child development through the first year of life, controlling for key confounds. We hypothesized that more total opioid exposure would be associated with worse parent-reported cognitive, motor, and behavioral development. Hypotheses were not supported. Almost all developmental scores fell above clinical cut-offs, reinforcing previous evidence that few children with prenatal opioid exposure show developmental difficulties (Kaltenbach et al., 2018), and developmental scores were not significantly associated with prenatal opioid exposure. The current findings diverge from previously published findings demonstrating unique associations of prenatal opioid exposure with three-month fine motor skills and six-month communication skills in the current sample (Labella et al., 2021). Results align with previous findings that early deficits may not persist through later development (van Barr et al., 1994).
While prenatal opioid exposure had no significant associations with 12-month development, prenatal alcohol exposure was linked to poorer problem-solving skills. This association was not evident at early timepoints, suggesting deficits in higher-level skills may emerge later in infancy. Results replicate previous findings that even low levels of prenatal alcohol exposure relate to worse cognitive development at age one (Testa et al., 2003) and underscore the importance of monitoring prenatal alcohol exposure, especially given evidence of deficits persisting through adulthood (Moore & Xia, 2022).
Polysubstance exposure emerged as a unique predictor of problem-solving in multivariate analyses. Unexpectedly, prenatal polysubstance exposure was positively associated with parent-reported problem-solving, whereas postnatal polysubstance use was inversely linked. The latter finding is consistent with prior research documenting negative associations between postnatal exposure to parental substance use and developmental outcomes (Solis et al., 2012). However, effects should be interpreted with caution as they were not significant at the bivariate level.
At 12 months, higher gestational age and birthweight were associated with better personal-social and gross motor skills, respectively. This echoes initial findings from this sample revealing a significant bivariate relationship between prenatal opioid exposure and prematurity (Labella et al., 2021). Future research with larger samples should examine possible indirect effects of prenatal opioid use through adverse birth outcomes (Nørgaard et al., 2015).
Overall, results demonstrate that associations linking prenatal opioid exposure to developmental outcomes in early infancy may not persist through the first year of life, whereas prenatal alcohol use may be associated with worse problem-solving skills at 12 months (albeit within the normal range). This study has many strengths. First, use of the TLFB allows for an in-depth examination of continuous variation in pre- and postnatal opioid and polysubstance exposure, capturing nuanced self-report data that toxicology may not reliably detect (Roth et al., 2020). Additionally, evaluation and inclusion of relevant covariates (i.e., sociodemographic factors, prenatal polysubstance exposure, and postnatal substance use) strengthens confidence in results.
Limitations include small sample size, reliance on a parent-report screening measure of developmental concerns, and self-report of substance use. The modest number of participants prevented conducting moderation analyses by relevant demographic factors or correcting for multiple tests. A post-hoc power analysis indicated adequate power to detect medium or large effects, but not small effects (15% power if r = 0.10). Future research should examine similar questions in larger samples, incorporating objective developmental assessments. Additionally, future studies should validate the TLFB for opioid use in pregnancy using biomarkers and/or medical records as additional measures of substance use.
In conclusion, this study provides an important addition to the prenatal opioid exposure literature. Results suggest that while prenatal opioid exposure may be associated with developmental risks at three and six months, differences may not persist through 12 months. Although further research with larger samples is needed, data are encouraging regarding the use of OMT as standard care for pregnant women with OUD. Children born to mothers with OUD may still require careful monitoring due to their increased risk for prenatal exposure to other known teratogens with deleterious neurodevelopmental outcomes.
Supplementary Material
Prenatal opioid exposure was related to 3- and 6-month but not 12-month development
More prenatal alcohol exposure was linked to worse 12-month problem-solving skills
Alcohol effects persisted controlling for pre- and postnatal polysubstance use
Acknowledgements
This research was supported by funding awarded to the fourth author by the National Institutes of Health (R01 HD098525) and anonymous donors, and by an NRSA predoctoral fellowship from NIH/NIDA (F31DA050426) awarded to the second author. We would like to thank our participants, referral partners in the community, and study staff at the University of Delaware and William and Mary.
Footnotes
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Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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