Buprenorphine compared with methadone to treat pregnant women with opioid use disorder: a systematic review and meta‐analysis of safety in the mother, fetus and child

Introduction

The incidence of prescription and illicit opioid use during pregnancy has increased substantially in the United States since 2000, paralleling a similar escalation in the general population 1. Moreover, the prevalence of opioid use disorder (OUD) during pregnancy more than doubled between 1998 and 2011, to four per 1000 deliveries 2.

All pregnancies have a background risk of adverse consequences. Pregnant women with OUD have a higher frequency of additional risk factors for adverse pregnancy outcomes than pregnant women who do not use opioids. These risk factors include chronic viral infections, psychiatric conditions, poor health behaviors, adverse social conditions and inadequate prenatal care 3, 4.

Complete opioid abstinence throughout pregnancy is ideal for both mother and fetus, but acute withdrawal during pregnancy is not recommended 5, 6. Relapse rates are high and repeated cycles of intoxication and withdrawal are associated with significant fetal distress that can lead to placental insufficiency and consequent pregnancy loss, intrauterine growth restriction (IUGR) and preterm labor and birth 5, 7, 8, 9. The accepted treatment for OUD during pregnancy is long‐acting opioid agonist medication‐assisted treatment (OMAT), such as methadone (MET) or buprenorphine (BUP), within the context of a comprehensive program of obstetric care and psychosocial interventions 5, 8, 10, 11, 12, 13, 14. Adequate medication treatment maintains stable opioid blood levels that reduce maternal craving for and use of heroin or other opioids and improves prenatal care and fetal/infant outcomes compared with untreated opioid use or opioid withdrawal 11, 15, 16. MET maintenance treatment during pregnancy has been used widely since the early 1970s via daily visits to government‐regulated clinics 17. BUP maintenance treatment has been used increasingly since its approval in France in 1996 and the United States in 2002, partly because of its availability in the private practitioner setting and pharmacology that enables less than daily dosing, lower overdose risk and fewer drug interactions 11, 18. Three RCTs have been conducted comparing BUP and MET as OMAT in pregnancy, with a primary focus on multiple measures of neonatal abstinence syndrome (NAS) 19, 20, 21. Previous systematic reviews and meta‐analyses of these RCTs 5, 22 concluded that BUP and MET have similar efficacy for reducing pregnant women's opioid use but that neither opioid agonist was superior for all maternal, fetal and child outcomes 11. However, uncertainty was high regarding the conclusions due to the small body of evidence, particularly for outcomes other than NAS, due largely to their infrequency. For NAS, the meta‐analyses identified no difference between BUP and MET in the frequency of NAS requiring treatment, the amount of morphine or time required to treat or the length of hospitalization. However, the single, large RCT (n = 131) 19 observed significantly less severe NAS, based on 89% less morphine required to treat and 43% shorter hospitalization, compared with no difference in the two small RCTs (n = 14 20 and n = 21 21). No additional RCTs are available or likely to be performed, but the cumulative body of relevant observational studies has not been reviewed rigorously or synthesized quantitatively for any pregnancy outcomes.

The objectives of this review were to assess systematically all available evidence from clinical studies regarding the safety of buprenorphine compared with methadone treatment of opioid‐dependent pregnant women and provide quantitative treatment effect estimates for selected pregnancy outcomes, as feasible.

Methods

The conduct and reporting of this review conform with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement (Supporting information, Figure S1) 23.

Results

Of 1111 citations identified, 140 full‐text papers were assessed for eligibility, and 18 studies 18, 19, 20, 21, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 (reported in 23 papers 18, 19, 20, 21, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52) satisfied our inclusion criteria (Fig. 1). The only three RCTs 19, 20, 21 (six papers 19, 20, 21, 50, 51, 52) that have been conducted to date were included (223 participants; published 2005–10) (Supporting information, Table S2). Fifteen OBSs 18, 34, 35, 36, 37, 38, 39, 41, 42, 43, 44, 45, 46, 47, 48 (17 papers) 18, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 enrolled a total of 1923 participants in prospective 18, 34, 35, 36, 37, 38, 39, 41, 42, 45, 46, 47 (n = 12) or retrospective 43, 44, 48 (n = 3) cohort studies published 2001–15. No case–control studies were identified. The abuse‐deterrent combination BUP–naloxone formulation is prescribed increasingly as OMAT, particularly in the United States and Australia 53, 54. We included one study that treated women with BUP–naloxone 44, but considered it too clinically different from the other studies to include in quantitative analyses. However, sensitivity analyses indicated that effect estimates did not differ for any outcome, whether the BUP–naloxone study was included or excluded. Sample sizes were 15–609. Attrition ranged from 22% 20 to 33% 19 overall in the RCTs and was unbalanced between treatment groups in two RCTs 19, 20. The range of estimated gestational age at study enrollment was 6–37 weeks. The mother's average daily dose at delivery ranged from 5.1 to 18.7 mg for BUP and 35–99.4 mg for MET. Outcome definitions among the studies were generally consistent, except for maternal adverse events (AEs) and small for gestational age (SGA) (Table 1). Statistical heterogeneity was low among the main analyses except for growth outcomes [birth weight (two RCTs, I ² = 50%); LBW (two OBSs, I ² = 62%); and SGA (two OBSs, I ² = 50%)]. ROB was rated medium for each RCT (n = 3, Supporting information, Table S3) and medium (n = 9) 18, 38, 39, 40, 41, 42, 43, 48, 49 or high (n = 8) 34, 35, 36, 37, 44, 45, 46, 47 for all OBSs (Supporting information, Table S4). Twelve OBSs assessed the balance between treatment groups for various confounding factors at study enrollment (Supporting information, Table S2), but only two OBSs adjusted for confounding factors in estimating treatment effects 39, 48. If not provided through an integrated, comprehensive prenatal addiction treatment program, MET was generally administered by standalone clinics or pharmacies while BUP was provided by office‐based practitioners. Visual inspection of the funnel plot for preterm birth revealed no evidence of publication bias (Supporting information, Figure S2); no other outcomes had enough studies to yield a reliable funnel plot.

Discussion

We synthesized the evidence from three RCTs and 15 OBSs that compared buprenorphine and methadone treatment of pregnant women with OUD. We calculated treatment‐related risk estimates for eight pregnancy‐related outcomes, including four without previous published meta‐analysis. Our work confirms and extends previous treatment risk estimates from limited RCT evidence by also synthesizing the available, larger body of observational study evidence.

Consistent with previous RCT‐based meta‐analyses 5, 22, we identified no statistically or clinically significant difference between BUP and MET in the risk estimates for spontaneous fetal death among the OBSs and across all studies. However, the paucity of events and small sample sizes limited the precision of estimates, ability to stratify by early versus late pregnancy losses and the confidence in our estimates of the relationship between fetal death and OMAT. The overall frequency of spontaneous fetal deaths in women with OUD among both study types was substantially lower than the estimated 15–20% in the general population. Further, most occurred after the first trimester, in contrast to three‐fourths of spontaneous losses during the first trimester in the general population 56, 57. This apparent underestimate is probably related to a delay by many opioid‐dependent pregnant women in seeking prenatal care until after completing the high‐risk first trimester 35, 58, 59 and insufficient reporting of time of enrollment in several studies 36, 37, 44, 45, 46. Our ability to assess the relationship between fetal death and OMAT was also limited substantially, given sparse and inconsistent patient‐level reporting of gestational timing (onset and duration) of BUP or MET treatment and important potential confounders 60, 61.

We found no difference in the risk of fetal/congenital anomalies by maternal treatment. The frequency and type of reported anomalies were broadly similar to what would be expected in the general population, with no particular patterns noted by treatment group. However, most studies characterized the reported defects poorly and failed to collect or describe relevant confounders adequately or even details of exposure to the opioid agonist, particularly during the critical first trimester. Moreover, no included study was powered to detect an increase in specific congenital anomalies, which occur rarely (≤ 1/1000 births), and sparse events and exposed pregnancies limited the precision of estimates. In addition, defects not readily apparent at birth may be under‐ascertained, as no studies evaluating congenital anomalies followed infants through the entire first year. Therefore, we have limited confidence in our effect estimates.

The risk of preterm birth was lower in BUP‐exposed infants compared with MET‐exposed infants. The risk reduction found was consistent between study types and with a previous meta‐analysis of the same RCTs examined in the present analysis 5. However, potentially confounding influences were not reported or adjusted for in any treatment effect estimates. Notwithstanding these limitations, we have moderate confidence in our findings.

Unadjusted birth weight and head circumference were significantly greater in infants of BUP‐treated mothers compared with MET‐treated mothers. The findings were consistent between study designs and with previous meta‐analyses 5, 22. We have moderate confidence in these treatment estimates, but adequate adjustment of confounding factors, particularly gestational age, and larger sample sizes would probably provide more stable and valid estimates of treatment effect. A very small body of observational studies showed no association between prenatal BUP or MET and LBW, IUGR or SGA. The sparse body of evidence limits confidence in the LBW, SGA and IUGR findings.

Fetal growth and birth parameters are influenced by sex, gestational age, multi‐fetal pregnancy, maternal cigarette smoking and use of other substances, and placental and anatomical factors 62. Studies in this review were inconsistent in describing whether they included multi‐fetal pregnancies and preterm births (both tend to be smaller) in analyses of growth parameters. Multi‐fetal pregnancies were infrequent and unlikely to significantly impact effect estimates differentially. However, failure to adjust for gestational age or exclude preterm births from growth parameter analyses may overestimate the effects of maternal BUP treatment due to BUP's associated significantly lower risk of preterm birth. We were unable to explore fully this confounding effect without patient‐level data. Aggregated source data for birth weight and head circumference also limited the clinical interpretation of treatment effect estimates because established norms, and thus minimally important differences, are sex‐ and gestational age‐dependent 63.

Data from three small studies provided preliminary and insufficient evidence that maternal BUP treatment may be associated with more favorable fetal neurobehavior than MET treatment. The developing fetal nervous system appeared more vulnerable to opioid‐related suppression earlier versus later in pregnancy with significantly less suppression of fetal heart rate and movement by BUP compared with MET, at least transiently at peak maternal exposure associated with once‐daily dosing 64. Split‐dose administration of MET has been associated with less fetal suppression 65.

One medium ROB RCT that collected and analyzed maternal AEs systematically found significantly fewer non‐serious AEs but no difference in serious AEs among BUP‐treated women versus MET‐treated women. Differential cardiovascular effects are plausible due to the established risk of QT‐interval prolongation and serious arrhythmia associated with MET 66, 67. Two high ROB OBSs with poorly characterized methods of collecting and analyzing AEs had discordant findings. In one study, with significantly more AEs in BUP‐treated women, the cohorts were comparable for several confounders but the MET‐treated women had more frequent study visits (a confounding co‐intervention) 41. The evidence regarding AEs is insufficient to draw a clinically meaningful conclusion in either direction. Future studies should collect and analyze treatment‐associated AEs during pregnancy in a systematic and standardized fashion and use an established system to code and analyze AEs descriptively 68.

A strength of this review is the inclusion of all available evidence regarding opioid agonist treatment during pregnancy, including data from well‐conducted observational cohort studies 69, 70, 71. Previous published systematic reviews and meta‐analyses included only three RCTs, with a total combined sample size of 223 drawn from seven university treatment centers in the United States and Austria. The addition of 1923 participants in 15 cohort studies conducted in six additional countries and among a wider range of clinical settings increased the precision, statistical power and generalizability of our findings. Furthermore, most outcomes examined were largely objective, documented routinely in clinical obstetric practice and thus less prone to detection bias from measurement error and lack of blinding. Concordance between the treatment‐related risk estimates from both the RCTs and OBSs bolstered confidence in the strength of the evidence for spontaneous fetal death, fetal/congenital anomalies, preterm birth, birth weight, head circumference and SGA.

The main limitations were the uneven quality of the studies and limited number of events and sample sizes, potentially providing low statistical power to detect between‐group differences. RCTs provide the most consistent and unbiased estimates of treatment effects, but high‐quality RCTs often are not available, particularly in vulnerable populations such as the one under study 68, 69. The complexities of both OUD and pregnancy present daunting challenges in the design, recruitment and conduct of rigorous clinical studies. Moreover, RCTs are generally not designed with sufficient sample size (especially for rare outcomes such as fetal death and congenital anomalies), follow‐up duration or population variability for results generalizable to the population at large. The RCTs included in this review were conducted rigorously, but suffered from relatively high levels of overall and differential attrition that increased the risk of selection bias and were not accounted for optimally in the published analyses 28, 70 Twelve of the 15 observational studies assessed baseline comparability of the cohorts for a few confounders or co‐interventions but did not adjust effect estimates for imbalances. For example, many studies did not assess, report or adjust for concomitant substance use during pregnancy as evaluated by urine toxicology or self‐report. Information on substance use would inform the interpretation of the OMAT‐related effects in terms of possible differences between the study participants.

Finally, maternal AEs and fetal/congenital anomalies (and, to a lesser extent, SGA) were defined inconsistently or ascertained among the studies that reported them, increasing clinical heterogeneity and limiting the opportunity to pool results among studies. In clinical studies, AEs are often not collected, analyzed or reported in a standardized and systematic fashion 68.

Conclusion

BUP treatment of maternal opioid use disorder during pregnancy was not associated with greater harms than MET treatment, and moderately strong evidence indicated lower risk of preterm birth, greater birth weight and larger head circumference with BUP. Our results confirm and extend previous RCT evidence and further inform benefit/risk assessment in clinical decision‐making regarding treatment of pregnant women with OUD, although evidence is currently insufficient to establish superior safety of either opioid agonist during pregnancy for all maternal, fetal and child outcomes examined.

Declaration of interests

Partial funding for this review was provided by Indivior PLC (formerly Reckitt Benckiser Pharmaceuticals) to Venebio Group, LLC. The review was conceived, designed, executed and reported by the authors, who had sole control over the literature selected, data analysis, interpretation and manuscript preparation. Indivior PLC was asked to review the final manuscript for proprietary information. The opinions and conclusions of the authors are their own and do not necessarily reflect the position of Indivior. At the time the work was conducted, B.K.Z., A.L.M., M.M.K., H.R.A., A.R.J. and E.L.M. were paid consultants of Venebio Group, LLC, which has had research and consulting agreements with Indivior PLC. H.E.J. has no financial ties to either Indivior PLC or Venebio Group, LLC, and did not receive any form of remuneration in the preparation or writing of this paper. All authors report no other potential conflicts of interest with the gaming, pharmaceutical, alcohol or tobacco industries.

Supporting information

Zedler, B. K. , Mann, A. L. , Kim, M. M. , Amick, H. R. , Joyce, A. R. , Murrelle, E. L. , and Jones, H. E. (2016) Buprenorphine compared with methadone to treat pregnant women with opioid use disorder: a systematic review and meta‐analysis of safety in the mother, fetus and child. Addiction, 111: 2115–2128. doi: 10.1111/add.13462.