Skip to main content

A Retrospective Cohort Study of Birth Outcomes in Neonates Exposed to Naltrexone in Utero: A Comparison with Methadone-, Buprenorphine- and Non-opioid-Exposed Neonates



Naltrexone may provide a suitable alternative to methadone and buprenorphine in the treatment of pregnant opioid-dependent women; however, little is known about its effects on neonatal morbidity and mortality.


The aim was to evaluate the health of neonates exposed to naltrexone in utero, and compare it with outcomes in neonates exposed to methadone or buprenorphine and a non-exposed control group.


Sequential cohorts of Western Australian (WA) opioid-dependent women treated with implant naltrexone, oral methadone or sublingual buprenorphine were identified via records from a drug and alcohol clinic (Subiaco, WA) for naltrexone and state prescribing records for methadone and buprenorphine. A control cohort of non-opioid-dependent women was obtained from the WA electoral roll. Identifying information and treatment records for these women were linked against the Midwife Notification System records to identify exposed offspring born between 2001 and 2011. Birth characteristics, congenital anomalies and perinatal mortality for all neonates were extracted from state records.


The birth characteristics of naltrexone-exposed neonates (n = 68) were superior to methadone-exposed neonates (n = 199) in terms of birth size (birth weight, head circumference and length), hospital length of stay (5.5 vs. 11.3 days), and rates of neonatal abstinence syndrome (NAS) (7.5 vs. 51.5%). Naltrexone-exposed neonates were generally not significantly different to buprenorphine-exposed neonates (n = 124), with the exception of significantly lower rates of NAS (7.5 vs. 41.8%) and shorter hospital length of stay (5.5 vs. 8.0 days) in naltrexone-exposed neonates. Compared with the control group of neonates (n = 569), naltrexone-exposed neonates were not significantly different in terms of overall rates of congenital anomalies, stillbirths and neonatal mortality; however, they were significantly smaller (3137.1 vs. 3378.0 g), spent more time in hospital following birth (5.5 vs. 4.3 days) and had higher rates of NAS (7.5 vs. 0.2%). Exposure of neonates to prenatal methadone was associated with a high incidence of neonatal mortality (2.0 vs. 0.2 per 100 live births) and congenital anomalies (10.6 vs. 4.4 per 100 births) compared with the control group. Rates of neonatal mortality and congenital abnormalities in buprenorphine-exposed neonates were not significantly different to the control group.


The use of implant naltrexone during pregnancy was not associated with higher rates of negative birth outcomes compared with methadone- and buprenorphine-exposed neonates. Significantly, naltrexone and buprenorphine were not associated with the high rates of neonatal mortality or congenital anomalies seen in methadone-exposed neonates.

This is a preview of subscription content, access via your institution.


  1. 1.

    Center for substance abuse treatment. Medication-assisted treatment for opioid addiction in in Opioid treatment programs. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 2005, (Treatment Improvement Protocol (TIP) Series, No. 43). Medication-assisted treatment for Opioid addiction during pregnancy.

  2. 2.

    Finnegan L. Treatment issues for opioid dependent women during the perinatal period. J Psychoact Drugs. 1991;23(2):191–201.

    CAS  Article  Google Scholar 

  3. 3.

    WHO. Guidelines for the identification and management of substance use and substance use disorders in pregnancy. Geneva: World Health Organisation; 2014.

    Google Scholar 

  4. 4.

    Binder T, Vavrinkova B. Prospective randomised comparative study of the effect of buprenorphine, methadone and heroin on the course of pregnancy, birthweight of newborns, early postpartum adaptation and course of the neonatal abstinence syndrome (NAS) in women followed up in the outpatient department. Neuro Endocrinol Lett. 2008;29(1):80–6.

    CAS  PubMed  Google Scholar 

  5. 5.

    Patrick S, Schumacher R, Benneyworth B, Krans E, McAllister J, Davis M. Neonatal abstinence syndrome and associated health care expenditures: United States, 2000–2009. JAMA. 2012;307(18):1934–40.

  6. 6.

    Jones HE, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010;363(24):2320–31.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Kocherlakota P. Neonatal abstinence syndrome. Pediatrics. 2014;134(2):e547–61.

    Article  PubMed  Google Scholar 

  8. 8.

    Hulse GK, O’Neill G. A possible role for implantable naltrexone in the management of the high-risk pregnant heroin user. Aust N Z J Obstet Gynaecol. 2002;42(1):104–5.

    Article  Google Scholar 

  9. 9.

    Hulse GK, O’Neil G, Arnold-Reed DE. Methadone maintenance vs. implantable naltrexone treatment in the pregnant heroin user. Int J Gynaecol Obstet. 2004;85(2):170–1.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Hulse GK, et al. Naltrexone implant and blood naltrexone levels over pregnancy. Aust N Z J Obstet Gynaecol. 2003;43(5):386–8.

    Article  PubMed  Google Scholar 

  11. 11.

    Hulse GK, O’Neil G. Using naltrexone implants in the management of the pregnant heroin user. Aust N Z J Obstet Gynaecol. 2002;42(5):102–6.

    Article  Google Scholar 

  12. 12.

    Hulse GK, et al. Obstetric and neonatal outcomes associated with maternal naltrexone exposure. Aust N Z J Obstet Gynaecol. 2001;41(4):424–8.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Farid WO, et al. Maternally administered sustained-released naltrexone in rats affects offpsring neurochemistry and behaviour in adulthood. PLoS One. 2012;7(12):e52812.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    White J. Blocking endogenous opioids during development-do we understand the consequences? Addiction. 2013;108(2):251–2.

    Article  PubMed  Google Scholar 

  15. 15.

    Jones HE, et al. Naltrexone in the treatment of opioid-dependent pregnant women: the case for a considered and measured approach to research. Addiction. 2013;108(2):233–47.

    Article  PubMed  Google Scholar 

  16. 16.

    Keshet GI, Weinstock M. Maternal naltrexone prevents morphological and behavioral alterations induced in rats by prenatal stress. Pharmacol Biochem Behav. 1995;50(3):413–9.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Zagon IS, et al. Opioid receptor blockade throughout prenatal life confers long-term insensitivity to morphine and alters mu opioid receptors. Pharmacol Biochem Behav. 1998;59(1):201–7.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    McLaughlin PJ, et al. Opioid receptor blockade during prenatal life modifies postnatal behavioral development. Pharmacol Biochem Behav. 1997;58(4):1075–82.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Farid WO, et al. The effects of maternally administered methadone, buprenorphine and naltrexone on offspring: review of human and animal data. Curr Neuropharmacol. 2008;6(2):125–50.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Ngo HTT, et al. Blood naltrexone levels over time following naltrexone implant. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(1):23–8.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Bower C, et al., Report of the Western Australian register of developmental anomolies: 1980–2011. 2012. King Edward Memorial Hospital.

  22. 22.

    WHO, CDC, ICBDSR. Birth defects surveillance: a manual for programme managers. Geneva: World Health Organisation; 2014.

    Google Scholar 

  23. 23.

    Roberts CL, Lancaster PAL. Australian national birthweight percentiles by gestational age. Med J Aust. 1999;170:114–8.

    CAS  PubMed  Google Scholar 

  24. 24.

    Fajemirokun-Odudeyi O, et al. Pregnancy outcome in women who use opiates. Eur J Obstet Gynecol Reprod Biol. 2006;126(2):170–5.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Burns L, Conroy E, Mattick RP. Infant mortality among women on a methadone program during pregnancy. Drug Alcohol Rev. 2010;29(5):551–6.

    Article  PubMed  Google Scholar 

  26. 26.

    Kandall SR, et al. The narcotic-dependent mother: fetal and neonatal consequences. Early Hum Dev. 1977;1(2):159–69.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Dryden C, et al. Maternal methadone use in pregnancy: factors associated with the development of neonatal abstinence syndrome and implications for healthcare resources. BJOG. 2009;116(5):665–71.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Stimmel B, et al. Fetal outcome in narcotic-dependent women: the importance of the type of maternal narcotic used. Am J Drug Alcohol Abuse. 1982;9(4):383–95.

    Article  PubMed  Google Scholar 

  29. 29.

    Zelson C, Lee SJ, Casalino M. Neonatal narcotic addiction. N Engl J Med. 1973;289(23):1216–20.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Zedler BK, 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.

  31. 31.

    Meyer MC, et al. Methadone and buprenorphine for opioid dependence during pregnancy: a retrospective cohort study. J Addict Med. 2015;9(2):81–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Jumah NA, et al. Observational study of the safety of buprenorphine + naloxone in pregnancy in a rural and remote population. BMJ Open. 2016;6(10):e011774.

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Wurst KE, et al. A Swedish population-based study of adverse birth outcomes among pregnant women treated with buprenorphine or methadone: preliminary findings. Subst Abuse. 2016;10:89–97.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    McLaughlin PJ, et al. Chronic exposure to the opioid antagonist naltrexone during pregnancy: maternal and offspring effects. Physiol Behav. 1997;62(3):501–8.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Kramer MS. Determinants of low birth weight: methodological assessment and meta-analysis. Bull World Health Organ. 1987;65(5):663–737.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Glass L, Rajegowda BK, Evans HE. Absence of respiratory distress syndrome in premature infants of heroin-addicted mothers. Lancet. 1971;2(7726):685–6.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Blandthorn J, Forster DA, Love V. Neonatal and maternal outcomes following maternal use of buprenorphine or methadone during pregnancy: findings of a retrospective audit. Women Birth. 2011;24(1):32–9.

    Article  PubMed  Google Scholar 

  38. 38.

    Bower C, et al. Age at diagnosis of birth defects. Birth Defects Res A Clin Mol Teratol. 2010;88(4):251–5.

    CAS  PubMed  Google Scholar 

Download references


The research team would like to acknowledge the support of the Data Linkage Branch and the data custodians for linking the data, and the Western Australian Department of Health data custodians for providing the data.

Author information



Corresponding author

Correspondence to Erin Kelty.

Ethics declarations

Conflict of interest

Erin Kelty has no interests to declare; Prof. Gary Hulse has no interests to declare.


Funding for this study was provided by the State Health Research Advisory Council (SHRAC) via a Research Translation Project Grant and a Telethon Institute for Child Health Research Grant.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kelty, E., Hulse, G. A Retrospective Cohort Study of Birth Outcomes in Neonates Exposed to Naltrexone in Utero: A Comparison with Methadone-, Buprenorphine- and Non-opioid-Exposed Neonates. Drugs 77, 1211–1219 (2017).

Download citation