BACKGROUND AND AIMS: Opioid maintenance treatment (OMT) is recommended to opioid-dependent females during pregnancy. However, it is not clear which medication should be preferred. We aimed to compare neonatal outcomes after prenatal exposure to methadone (M) and buprenorphine (B) in two European countries. DESIGN: Nation-wide register-based cohort study using personalized IDs assigned to all citizens for data linkage. SETTING: The Czech Republic (2000-14) and Norway (2004-13). [Correction added after online publication on 26 April 2018: The Czech Republic (2000-04) corrected to (2000-14).] PARTICIPANTS: Opioid-dependent pregnant Czech (n = 333) and Norwegian (n = 235) women in OMT who received either B or M during pregnancy and their newborns. MEASUREMENTS: We linked data from health registries to identify the neonatal outcomes: gestational age, preterm birth, birth weight, length and head circumference, small for gestational age, miscarriages and stillbirth, neonatal abstinence syndrome (NAS) and Apgar score. We performed multivariate linear regression and binary logistic regression to explore the associations between M and B exposure and outcomes. Regression coefficient (β) and odds ratio (OR) were computed. FINDINGS: Most neonatal outcomes were more favourable after exposure to B compared with M, but none of the differences was statistically significant. For instance, in the multivariate analysis, birth weight was β = 111.6 g [95% confidence interval (CI) = -10.5 to 233.6 and β = 83.1 g, 95% CI = -100.8 to 267.0] higher after B exposure in the Czech Republic and Norway, respectively. Adjusted OR of NAS for B compared with M was 0.94 (95% CI = 0.46-1.92) in the Norwegian cohort. CONCLUSIONS: Two national cohorts of women receiving opioid maintenance treatment during pregnancy showed small but not statistically significant differences in neonatal outcomes in favour of buprenorphine compared with methadone.

Department of Addictology 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Global Public Health and Primary Care University of Bergen Bergen Norway

National Monitoring Centre for Drugs and Addiction Office of the Government of the Czech Republic Prague Czech Republic

Norwegian Centre for Addiction Research at the University of Oslo Oslo Norway

Norwegian institute of Public Health Oslo Norway

See more in PubMed

World Health Organization (WHO) . Guidelines for the Identification and Management of Substance Use and Substance Use Disorders in Pregnancy. Geneva: WHO; 2014. PubMed

Klaman S. L., Isaacs K., Leopold A., Perpich J., Hayashi S., Vender J. et al Treating women who are pregnant and parenting for opioid use disorder and the concurrent care of their infants and children: literature review to support national guidance. J Addict Med 2017; 11: 178–190. PubMed PMC

Connock M., Juarez‐Garcia A., Jowett S., Frew E., Liu Z., Taylor R. J. et al Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation. Health Technology Assess (Winchester, UK) 2007; 11: 1–171; iii–iv. PubMed

Věstník MZ ČR částka 3/2008—Standard substituční léčby [Journal of the Ministry of Health of the Czech Republic no. 3/2008—Standard of substitution treatment]. Prague: Ministerstvo zdravotnictví ČR [Ministry of Health of the Czech Republic]; 2008.

Bakstad B., Welle‐Strand G. Nasjonal retningslinje for gravide i legemiddelassistert rehabilitering (LAR) og oppfølging av familiene frem til barnet når skolealder [National Guidelines For Pregnant Women In Opioid Maintenenace Treatment (OMT) and Follow‐Up of Their Families Until the Children Reach School Age]. Oslo, Norway: Norwegian Directorate of Health; 2011.

Substance Abuse and Mental Health Services Administration . Federal Guidelines for Opioid Treatment Programs. HHS Publication No. (SMA) PEP15‐FEDGUIDEOTP . Rockville, MD: Substance Abuse and Mental Health Services Administration; 2015.

Finnegan L. P., Reeser D. S., Connaughton J. F. Jr. The effects of maternal drug dependence on neonatal mortality. Drug Alcohol Depend 1977; 2: 131–140. PubMed

Kandall S. R., Albin S., Lowinson J., Berle B., Eidelman A. I., Gartner L. M. Differential effects of maternal heroin and methadone use on birthweight. Pediatrics 1976; 58: 681–685. PubMed

Finnegan L. P., Connaughton J. F., Emrich J. P., Wieland W. F. Comprehensive care of the pregnant addict and its effect on maternal and infant outcome. Contemp Drug Prob 1972; 1: 795–809.

Walsh S. L., Preston K. L., Bigelow G. E., Stitzer M. L. Acute administration of buprenorphine in humans: partial agonist and blockade effects. J Pharmacol Exp Ther 1995; 274: 361–372. PubMed

Brogly S. B., Saia K. A., Walley A. Y., Du H. M., Sebastiani P. Prenatal buprenorphine versus methadone exposure and neonatal outcomes: systematic review and meta‐analysis. Am J Epidemiol 2014; 180: 686. PubMed

Zedler B. K., Mann A. L., Kim M. M., Amick H. R., Joyce A. R., Murrelle E. L. et al 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 2016; 111: 2115–2128. PubMed PMC

Bakstad B., Sarfi M., Welle‐Strand G. K., Ravndal E. Opioid maintenance treatment during pregnancy: occurrence and severity of neonatal abstinence syndrome. A national prospective study. Eur Addict Res 2009; 15: 128–134. PubMed

Debelak K., Morrone W. R., O'Grady K. E., Jones H. E. Buprenorphine + naloxone in the treatment of opioid dependence during pregnancy—initial patient care and outcome data. Am J Addict 2013; 22: 252–254. PubMed

Fischer G., Ortner R., Rohrmeister K., Jagsch R., Baewert A., Langer M. et al Methadone versus buprenorphine in pregnant addicts: a double‐blind, double‐dummy comparison study. Addiction 2006; 101: 275–281. PubMed

Lund I. O., Fischer G., Welle‐Strand G. K., O'Grady K. E., Debelak K., Morrone W. R. et al A comparison of buprenorphine + naloxone to buprenorphine and methadone in the treatment of opioid dependence during pregnancy: maternal and neonatal outcomes. Subst Abuse 2013; 7: 61–74. PubMed PMC

Peles E., Sason A., Schreiber S., Adelson M. Newborn birth‐weight of pregnant women on methadone or buprenorphine maintenance treatment: a national contingency management approach trial. Am J Addict 2017; 26: 167–175. PubMed

Meyer M., Phillips J. Caring for pregnant opioid abusers in Vermont: a potential model for non‐urban areas. Prev Med 2015; 80: 18–22. PubMed PMC

Gabrhelik R., Nechanska B., Mravcik V., Skurtveit S., Lund I. O., Handal M. A unique opportunity to study short and long term consequences in children prenatally exposed to illicit drugs and opioid maintenance treatment using Czech and Scandinavian registers. Cent Eur J Public Health 2016; 24: 248–251. PubMed

Popov P. Metadonová substituční léčba v České republice [Methadone substitution treatment in the Czech Republic]. Adiktologie 2002; 2: 25–31.

Mravčík V., Pešek R., Škařupová K., Orlíková B., Škrdlantová E., Šťastná L. et al Annual Report on the Czech Republic 2008 Drug Situation. Prague: Office of the Government of the Czech Republic, National Monitoring Centre For Drugs And Drug Addiction; 2009.

Zábranský T., Csémy L., Gajdošíková H., Korčišová B., Kuda A., Miovský M. et al Výroční zpráva o stavu a vývoji ve věcech drog v České republice za rok 2001 [Annual Report of The Czech Republic 2001 Drug Situation]. Prague: Úřad vlády ČR; 2002.

Nechanská B. Údaje v Národním registru uživatelů lékařsky indikovaných substitučních látek—rok 2012. Aktuální informace č. 01/2013 [Data in the Natonal Register of Users of Medically Indicated Substitution Substances—2012. Current Information no. 01/2013]. Prague: ÚZIS ČR; 2013.

Mravčík V., Orlíková B. Překryv klientů mezi jednotlivými nízkoprahovými programy a zneužívání buprenorfinu v Praze [The overlap of clients among low‐threshold programmes in Prague and the assessment of current drug situation in Prague with emphasis on buprenorphine misuse]. Adiktologie 2007; 7: 13–20.

Norwegian Directorate of Public Health (MHaSA) . National Guidelines for Opioid Maintenance Treatment of opioid Dependency [Nasjonal retningslinje for legemiddelassistert rehabilitering ved opioidavhengighet]. Oslo, Norway: Norwegian Institute of Public Health; 2010.

Lund I. O., Skurtveit S., Engeland A., Furu K., Ravndal E., Handal M. Prescription drug use among pregnant women in opioid maintenance treatment. Addiction 2013; 108: 367–376. PubMed

Welle‐Strand G. K., Skurtveit S., Jones H. E., Waal H., Bakstad B., Bjarko L. 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: 200–206. PubMed

Lov 1999, nr 61, Sosialtjenesteloven § 6‐2a.Tilbakeholdelse av gravide rusmisbrukere [Social Services Act § 6‐2a Retention of substance dependent pregnant women in institutions], Norway; 2010.

Nechanská B., Mravčík V., Sopko B., Velebil P. Rodičky užívající alkohol, tabák a nelegální drogy [Pregnant women and mothers using alcohol, tobacco and illegal drugs]. Ceska Gynekol 2012; 77: 457–469. PubMed

Nechanská B., Mravčík V., Popov P. Máme se bát národního registru léčby uživatelů drog? [Should we worry about the national registry of drug treatment?]. Česká Slov Psychiatr 2015; 111: 117–118.

Nechanská B., Mravčík V., Popov P. Národní registr léčby uživatelů drog [The National Register of Drug Users in Treatment]. Adiktologie 2014; 14: 364–365.

World Health Organization (WHO) . WHO Collaborating Centre for Drug Statistics Methodology. ATC Classification Index with DDDs 2010. Oslo, Norway: Norwegian Institute of Public Health; 2010.

Marsal K., Persson P. H., Larsen T., Lilja H., Selbing A., Sultan B. Intrauterine growth curves based on ultrasonically estimated foetal weights. Acta Paediatr 1996; 85: 843–848. PubMed

Vollset S. E. Confidence intervals for a binomial proportion. Stat Med 1993; 12: 809–824. PubMed

Haug K., Irgens L. M., Skjaerven R., Markestad T., Baste V., Schreuder P. Maternal smoking and birthweight: effect modification of period, maternal age and paternal smoking. Acta Obstet Gynecol Scand 2000; 79: 485–489. PubMed

Lacroix I., Berrebi A., Garipuy D., Schmitt L., Hammou Y., Chaumerliac C. et al Buprenorphine versus methadone in pregnant opioid‐dependent women: a prospective multicenter study. Eur J Clin Pharmacol 2011; 67: 1053–1059. PubMed

Norgaard M., Nielsson M. S., Heide‐Jorgensen U. Birth and neonatal outcomes following opioid use in pregnancy: a Danish population‐based study. Subst Abuse 2015; 9: 5–11. PubMed PMC

Jones H. E., Kaltenbach K., Heil S. H., Stine S. M., Coyle M. G., Arria A. M. et al Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med 2010; 363: 2320–2331. PubMed PMC

Brogly S. B., Hahn K. A., Diaz S. H., Werler M. Confounding of the comparative safety of prenatal opioid agonist therapy. J Addict Res Ther 2015; 6: 252. PubMed PMC

Opioid maintenance treatment in the Czech Republic, Norway and Denmark: a study protocol of a comparative registry linkage study

Prenatal exposure to opioid maintenance treatment and neonatal outcomes: Nationwide registry studies from the Czech Republic and Norway

Hospitalization of children after prenatal exposure to opioid maintenance therapy during pregnancy: a national registry study from the Czech Republic