Opioid dependence and pregnancy: minimizing stress on the fetal brain

Published:October 08, 2016DOI:
      Increase in the number of opioid-dependent pregnant women delivering babies at risk for neonatal abstinence syndrome prompted a US Government Accountability Office report documenting deficits in research and provider knowledge about care of the maternal/fetal unit and the neonate. There are 3 general sources of dependence: untreated opioid use disorder, pain management, and medication-assisted treatment with methadone or buprenorphine. A survey of methadone patients’ experiences when telling a physician of their pregnancy and opioid dependence demonstrated physician confusion about proper care, frequent negative interactions with the mother, and failures to provide appropriate referral. Patients in pain management were discharged without referral when the physician was told of the pregnancy. Methadone and buprenorphine were frequently seen negatively because they “caused” neonatal abstinence syndrome. Most mothers surveyed had to find opioid treatment on their own. How dependence is managed medically is a critical determinant of the level of stress on both mother and fetus, and therefore another determinant of neonatal health. The effects of both opioid withdrawal stress and maternal emotional stress on neonatal and developmental outcomes are reviewed. Currently, there have been efforts to criminalize maternal opioid dependence and to encourage or coerce pregnant women to undergo withdrawal. This practice poses both acute risks of fetal hypoxia and long-term risks of adverse epigenetic programming related to catecholamine and corticosteroid surges during withdrawal. Contemporary studies of the effects of withdrawal stress on the developing fetal brain are urgently needed to elucidate and quantify the risks of such practices. At birth, inconsistencies in the hospital management of neonates at risk for neonatal abstinence syndrome have been observed. Neglect of the critical role of maternal comforting in neonatal abstinence syndrome management is an iatrogenic and preventable cause of poor outcomes and long hospitalizations. Rooming-in allows for continuous care of the baby and maternal/neonatal attachment, often unwittingly disrupted by the neonatal intensive care unit environment. Recommendations are made for further research into physician/patient interactions and into optimal dosing of methadone and buprenorphine to minimize maternal/fetal withdrawal.

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      1. US Government Accountability Office. Prenatal drug use and newborn health: federal efforts need better planning and coordination. Available at: Accessed December 2, 2016.

        • Maeda A.
        • Bateman B.T.
        • Clancy C.R.
        • Creanga A.A.
        • Leffert L.R.
        Opioid abuse and dependence during pregnancy: temporal trends and obstetrical outcomes.
        Anesthesiology. 2014; 121: 1158-1165
        • Whiteman V.E.
        • Salemi J.L.
        • Mogos M.F.
        • Cain M.A.
        • Alyiu M.H.
        • Salihu H.M.
        Maternal opioid use during pregnancy and its impact on perinatal morbidity, mortality, and the cost of medical care in the United States.
        J Pregnancy. 2014; 2014: 906723
        • Patrick S.W.
        • Schumacher R.E.
        • Benneyworth B.D.
        • Krans E.E.
        • McAllister J.M.
        • Davis M.M.
        Neonatal abstinence syndrome and associated health care expenditures: United States, 2000-2009.
        JAMA. 2012; 307: 1934-1940
        • McCarthy J.J.
        • Leamon M.H.
        • Willits N.H.
        • Salo R.
        The effects of methadone dose regimen on neonatal abstinence syndrome.
        J Addict Med. 2015; 9: 105-110
      2. Rewire News. Tennessee Fetal Assault Law (SB 1391). Available at: Accessed October 26, 2016.

        • McCarthy J.J.
        • Terplan M.
        Detoxification from opiates during pregnancy: stressing the fetal brain.
        Am J Obstet Gynecol. 2016; 215: 670.e1-670.e2
        • Kaltenbach K.
        • Finnegan L.P.
        Developmental outcomes of children born to methadone maintained women: a review of longitudinal studies.
        Neurobehav Toxicol Teratol. 1984; 6: 271-275
        • ACOG Committee on Health Care for Underserved Women; American Society of Addiction Medicine
        Opioid abuse, dependence, and addiction in pregnancy. Committee opinion no. 524.
        Obstet Gynecol. 2012; 119: 1070-1076
        • McCarthy J.
        Intrauterine abstinence syndrome (IAS) during buprenorphine inductions and methadone tapers: can we assure the safety of the fetus?.
        J Matern Fetal Neonatal Med. 2012; 25: 109-112
        • Macedo T.R.
        • Relvas J.
        • Fontes Ribeiro C.A.
        • et al.
        Plasma catecholamines during an ultrarapid heroin detoxification.
        Ann N Y Acad Sci. 2000; 914: 303-310
        • Stevenson D.K.
        • Sunshine P.
        • Benitz W.E.
        Fetal and neonatal brain injury.
        3rd ed. Cambridge University Press, Cambridge, UK2005: 287
        • Zuspan F.P.
        • Gumpel J.A.
        • Mejia-Zelaya A.
        • Madden J.
        • Davis R.
        Fetal stress from methadone withdrawal.
        Am J Obstet Gynecol. 1975; 122: 43-46
        • Dashe J.S.
        • Jackson G.L.
        • Olsher D.A.
        • Zane E.H.
        • Wendel G.D.
        Opiate detoxification in pregnancy.
        Obstet Gynecol. 1998; 92: 854-858
        • Terplan M.
        The obstetrical and neonatal impact of maternal opioid detoxification in pregnancy.
        Am J Obstet Gynecol. 2014; 210: 375-376
        • Maymon E.L.
        • Chaim W.
        • Furman B.
        • Ghezzi F.
        • Shoham Vardi I.
        Meconium stained amniotic fluid in very low risk pregnancies at term gestation.
        Eur J Obstet Gynecol Reprod Biol. 1998; 80: 169-173
        • Bell J.
        • Towers C.V.
        • Hennessy M.D.
        • Heitzman C.
        • Smith B.
        • Chattin K.
        Detoxification from opiate drugs during pregnancy.
        Am J Obstet Gynecol. 2016; 215: 374.e1-374.e6
        • Kapoor A.
        • Dunn E.
        • Kostaki A.
        • Andrews M.H.
        • Matthews S.G.
        Fetal programming of hypothalamo-pituitary-adrenal function: prenatal stress and glucocorticoids.
        J Physiol. 2006; 572: 31-44
        • Mulder E.J.
        • Robles de Medina P.G.
        • Huizink A.C.
        • Van den Bergh B.R.
        • Buitelaar J.K.
        • Visser G.H.
        Prenatal maternal stress: effects on pregnancy and the (unborn) child.
        Early Hum Dev. 2002; 70: 3-14
        • Zhang G.F.
        • Ren Y.P.
        • Sheng L.X.
        • et al.
        Dysfunction of the hypothalamic-pituitary-adrenal axis in opioid dependent subjects: effects of acute and protracted abstinence.
        Am J Drug Alcohol Abuse. 2008; 34: 760-768
        • Gowland R.L.
        Entangled lives: implications of the developmental origins of health and disease hypothesis for bioarchaeology and the life course.
        Am J Phys Anthropol. 2015; 158: 530-540
        • Nijhuis J.G.
        Fetal behavior.
        Neurobiol Aging. 2003; 24: S41-S47
        • Tolia V.N.
        • Patrick S.W.
        • Bennett M.M.
        • et al.
        Increasing incidence of the neonatal abstinence syndrome in US neonatal ICUs.
        N Engl J Med. 2015; 372: 2118-2126
        • Sharpe C.
        • Kuschel C.
        Outcomes of infants born to mothers receiving methadone for pain management in pregnancy.
        Arch Dis Child Fetal Neonatal Ed. 2004; 89: 33-36
        • Bogen D.L.
        • Perel J.M.
        • Helsel J.C.
        • et al.
        Pharmacologic evidence to support clinical decision making for peripartum methadone treatment.
        Psychopharmacology. 2013; 225: 441-451
      3. Center for Substance Abuse Treatment. Medication-assisted treatment for opioid addiction in opioid treatment programs. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 2005. (Treatment Improvement Protocol [TIP] Series, no. 43.) Chapter 13. Medication-assisted treatment for opioid addiction during pregnancy. Available at: Accessed December 2, 2016.

        • Whittmann B.K.
        • Segal S.
        A comparison of the effects of single- and split-dose methadone administration on the fetus: an ultrasound evaluation.
        Int J Addict. 1991; 26: 213-218
        • Jansson L.J.
        • DiPietro J.A.
        • Velez M.
        • et al.
        Maternal methadone dosing schedule and fetal neurobehavior.
        J Matern Fetal Neonatal Med. 2009; 22: 29-35
        • Hulse G.K.
        • Milne E.
        • English D.R.
        • Holman D.J.
        The relationship between maternal use of heroin and methadone and infant birth weight.
        Addiction. 1997; 92: 1571-1579
        • Johnson K.
        • Grenough A.
        • Gerada A.C.
        Maternal drug use and length of neonatal unit stay.
        Addiction. 2003; 98: 785-789
        • Cleary B.J.
        • Donnelly J.
        • Strawbridge J.
        • et al.
        Methadone dose and neonatal abstinence syndrome-systematic review and meta-analysis.
        Addiction. 2010; 105: 2071-2084
        • Jones H.E.
        • Jansson L.M.
        • O’Grady K.E.
        • Kaltenbach K.
        The relationship between maternal methadone dose at delivery and neonatal outcome: methodological and design considerations.
        Neurotoxicol Teratol. 2013; 39: 110-115
        • Bier J.B.
        • Finger A.S.
        • Bier B.A.
        • Johnson T.A.
        Growth and developmental outcome of infants with in-utero exposure to methadone vs buprenorphine.
        J Perinatol. 2015; 35: 656-659
        • Jones H.E.
        • Kaltenbach K.
        • Heil S.H.
        • et al.
        Neonatal abstinence syndrome after methadone or buprenorphine exposure.
        N Engl J Med. 2010; 363: 2320-2331
        • Meyer M.C.
        • Johnston A.M.
        • Crocker A.M.
        • Heil S.H.
        Methadone and buprenorphine for opioid dependence during pregnancy: a retrospective cohort study.
        J Addict Med. 2015; 9: 81-86
        • Brown S.M.
        • Holtzman M.
        • Kim T.
        • Kharasch E.D.
        Buprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active.
        Anesthesiology. 2011; 115: 1251-1260
        • Kacinko S.L.
        • Jones H.E.
        • Johnson R.E.
        • Choo R.E.
        • Concheiro-Guisan M.
        • Huestis M.A.
        Urinary excretion of buprenorphine, norbuprenorphine, buprenorphine-glucuronide, and norbuprenorphine-glucuronide in pregnant women receiving buprenorphine treatment.
        Clin Chem. 2009; 55: 1177-1187
        • Raffa R.B.
        • Ding Z.
        Examination of the preclinical antinociceptive efficacy of buprenorphine and its designation as a full or partial agonist.
        J Ac Pain. 2007; 9: 145-152
        • Hosseini S.M.
        • Biglan M.W.
        • Larkby C.
        • Brooks M.M.
        • Gorin M.B.
        • Day N.L.
        Trait anxiety in pregnant women predicts offspring birth outcomes.
        Paediatr Perinat Epidemiol. 2009; 23: 557-566
        • Cottrell E.C.
        • Seckl J.R.
        Prenatal stress, glucocorticoids and the programming of adult disease.
        Front Behav Neurosci. 2009; 3: 19
        • Patrick S.W.
        • Kaplan H.C.
        • Passarella M.
        • Davis M.M.
        • Lorch S.A.
        Variations in treatment of neonatal abstinence syndrome in US children's hospitals, 2004-2011.
        J Perinatol. 2014; 34: 867-872
        • Morgan B.E.
        • Horn A.R.
        • Bergman N.J.
        Should neonates sleep alone.
        Biol Psych. 2011; 70: 817-825
        • Holmes A.V.
        • Atwood E.C.
        • Whalen B.
        • et al.
        Rooming-in to treat neonatal abstinence syndrome: improved family-centered care at lower cost.
        Pediatrics. 2016; 137: e1-e9
        • Saiki T.
        • Lee S.
        • Hannam S.
        • Grenough A.
        Neonatal abstinence syndrome–postnatal ward versus neonatal unit management.
        Eur J Pediatr. 2010; 169: 95-98
        • Baewert A.
        • Jagsch R.
        • Winklbaur B.
        • et al.
        Influence of site differences between urban and rural American and Central European opioid-dependent women and neonatal outcome characteristics.
        Eur Addict Res. 2012; 18: 130-139
        • Finnegan L.P.
        • Kron R.E.
        • Connaughton J.F.
        • Emich J.P.
        A scoring system for evaluation and treatment of the neonatal abstinence syndrome: a clinical and research tool.
        in: Morselli P.L. Garattini S. Sereni F. Basic and therapeutic aspects of perinatal pharmacology. Raven Press, New York1975: 139-153
      4. D’Apolito K, Finnegan L. Assessing signs and symptoms of neonatal abstinence using the Finnegan scoring tool, an interobserver reliability program. Available at: Accessed December 2, 2016.

      5. Finnegan L. Substance abuse in Canada: licit and illicit drug use during pregnancy. Maternal, neonatal and early childhood consequences. Ottawa, Ontario. Canadian Center on Substance Abuse. Available at: Accessed December 2, 2016.

        • Weiner S.M.
        • Finnegan L.P.
        Drug withdrawal in the neonate.
        in: Carter B. Gardner S. Handbook of neonatal intensive care. 8th ed. Mosby-Year Book Inc, St. Louis, MO2015

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      • Opioid dependence and pregnancy: minimizing stress on the fetal brain
        American Journal of Obstetrics & GynecologyVol. 216Issue 4
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          The article by McCarthy et al1 is informative and thought-provoking. The authors indicated there are 3 general sources of opioid dependence: untreated opioid use disorder, pain management, and medication-assisted treatment with methadone or buprenorphine. The increase in the number of opioid-dependent pregnant women delivering babies at risk for neonatal abstinence syndrome prompted a General Accountability Office report documenting deficits in research and provider knowledge about care of the maternal/fetal unit and the neonate.
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