Neonatal Abstinence Syndrome AUTHOR: Abstinence Syndrome abstract Neonatal abstinence syndrome (NAS) is a result of the sudden discon-tinuation of fetal exposure to substances that

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  • Neonatal Abstinence Syndrome

    abstractNeonatal abstinence syndrome (NAS) is a result of the sudden discon-tinuation of fetal exposure to substances that were used or abused bythe mother during pregnancy. Withdrawal from licit or illicit substan-ces is becoming more common among neonates in both developed anddeveloping countries. NAS continues to be an important clinical entitythroughout much of the world. NAS leads to a constellation of signs andsymptoms involving multiple systems. The pathophysiology of NAS isnot completely understood. Urine or meconium confirmation may as-sist the diagnosis and management of NAS. The Finnegan scoring sys-tem is commonly used to assess the severity of NAS; scoring can behelpful for initiating, monitoring, and terminating treatment in neo-nates. Nonpharmacological care is the initial treatment option, andpharmacological treatment is required if an improvement is not ob-served after nonpharmacological measures or if the infant developssevere withdrawal. Morphine is the most commonly used drug inthe treatment of NAS secondary to opioids. An algorithmic approachto the management of infants with NAS is suggested. Breastfeeding isnot contraindicated in NAS, unless the mother is taking street drugs, isinvolved in polydrug abuse, or is infected with HIV. Future studies arerequired to assess the long-term effects of NAS on children after pre-natal exposure. Pediatrics 2014;134:e547e561

    AUTHOR: Prabhakar Kocherlakota, MD

    Division of Neonatology, Department of Pediatrics, Maria FareriChildrens Hospital at New York Medical College, Valhalla, NewYork

    KEY WORDSbenzodiazepines, breastfeeding, buprenorphine, Finnegan scores,inhalants, methadone, methamphetamine, morphine, neonatalabstinence syndrome, opioid abuse, opioid receptors,prescription opioids, selective serotonin reuptake inhibitor,withdrawal

    ABBREVIATIONSNASneonatal abstinence syndromeSNRIselective norepinephrine reuptake inhibitorSSRIselective serotonin reuptake inhibitorTCAtricyclic antidepressant

    www.pediatrics.org/cgi/doi/10.1542/peds.2013-3524

    doi:10.1542/peds.2013-3524

    Accepted for publication Mar 7, 2014

    Address correspondence to Prabhakar Kocherlakota, MD, ElaineKaplan NICU, St Lukes Cornwall Hospital, 70 Dubois St, Newburgh,NY 12550. E-mail: pkocherlaj@aol.com

    PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

    Copyright 2014 by the American Academy of Pediatrics

    FINANCIAL DISCLOSURE: The author has indicated he has nofinancial relationships relevant to this article to disclose.

    FUNDING: No external funding.

    POTENTIAL CONFLICT OF INTEREST: The author has indicated hehas no potential conflicts of interest to disclose.

    PEDIATRICS Volume 134, Number 2, August 2014 e547

    STATE-OF-THE-ART REVIEW ARTICLE

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  • Neonatal abstinence syndrome (NAS) isa clinical diagnosis, and a consequenceof the abrupt discontinuation of chronicfetal exposure to substances that wereused or abused by the mother duringpregnancy. NAS is a generalized multi-system disorder, which predominantlyinvolves the central and autonomicnervous systems, as well as the gas-trointestinal tract. Neonatalwithdrawaldue to prolonged maternal opioid usemay be severe and intense. AlthoughNAS is rarely fatal, it can cause signif-icant illness and often results in pro-longed hospital stays. This reviewprovides a summary of the history,epidemiology, pathophysiology, clinicalpresentation, toxicology confirmation,and treatment of NAS. Implications forbreastfeeding and follow-up are dis-cussed.

    HISTORICAL BACKGROUND

    Although opium use dates back to theancient civilizations of Mesopotamia(3400 BCE), the first surviving re-cords of opium addiction date from theend of the 18th century.1 Morphine wasisolated in 1804, heroin was synthe-sized in 1874, and addiction to theseopioids became more common aftertheir commercial production.2 An in-crease in the incidence of morphineand heroin addiction among womenwas noted as early as the 19th century3;however, infants were not thought tobe affected because it was believedthat morphine use among women wasassociated with sterility and a loss ofsexual desire. That fallacy was cor-rected after the first reported case ina neonate (1875),4 who manifestedsigns of opioid withdrawal at birth,diagnosed with congenital morphin-ism. Subsequently, there was a surgeof similar reports.5 However, most ofthe involved infants died and no spe-cific treatment was offered,6 until1903, when a report appeared inmedical literature that described the

    survival of a neonate after morphinetreatment.7 Congenital morphinism re-mained a medical curiosity until 1947,when the successful treatment ofseizures in an infant with congenitalmorphinismwas reported.8 Thereafter,increased reports of congenital mor-phinism (and related morbidity andmortality) resulted in significant at-tention from obstetricians as well aspediatricians.9,10 Congenital morphin-ism was subsequently renamed asabstinence syndrome in neonates.

    Methadone was introduced as a re-placement treatment of opioid addic-tion in 1964.11 Methadone use duringpregnancy was at first believed to beunassociated with withdrawal in neo-nates; however, subsequent experiencecontradicted this initial misimpres-sion.12 Buprenorphine was approvedas an alternative to methadone foropioid addiction in both Europe (1996)and the United States (2002).13,14 Theuse of buprenorphine during preg-nancy has also resulted in NAS.15,16

    Neonatal withdrawal secondary to thematernal use of prescription painmedications is the latest additionaletiology in the history of neonatalwithdrawal (Fig 1).17,18

    INCIDENCE

    The incidence of NAS has been in-creasing in the United States18 andelsewhere.19 The Substance AbuseMental Health Services Administrationreported that 1.1% of pregnant womenabused opioids (0.9% used opioid painrelievers and 0.2% used heroin) in2011.20 In a recent national study, ma-ternal opioid use was shown to haveincreased from 1.2 mothers per 1000live births in 2000 to 5.6 mothers per1000 live births in 2009, and diagnosesof NAS correspondingly increased from1.2 to 3.4 per 1000 live births.18 Ina study from Florida, the number ofneonates who had NAS and were ad-mitted to the NICU increased by 10-fold

    from 2005 to 2011.21 Increases in theincidence of NAS have been reporteduniformly across community hospitals,teaching hospitals, and childrens hos-pitals.22 All communities and all eth-nicities have been affected.20,23

    GROWING EPIDEMIOLOGY

    Although heroin abuse has remainedrelatively constant in developed coun-tries, it has increased alarmingly indeveloping countries.24,25 Heroin abuseis more common among mothers whoare unmarried, unemployed, less edu-cated, and less insured. Pregnanciesamong heroin-abusing women areusually unplanned and with minimalprenatal care. Thesemothers generallylead risky lifestyles, and often havemultiple social, nutritional, physical,and mental health problems.26 Infantsborn to these mothers usually arepremature, usually have low birthweights, and are often growth re-stricted. Many of the infants born toheroin-abusing mothers develop NASimmediately after birth.27

    Methadone, a synthetic complete m-opioidreceptor agonist, has become thestandard of care for pregnant womenwith opioid addiction. Methadone main-tenance treatment during pregnancyoptimized obstetric care, decreasedillicit drug use, and improved fetaloutcomes.28 Nevertheless, methadonetreatment also has been related to theincreased incidence of NAS.12,29 Re-search on the pharmacokinetics ofmethadone during pregnancy has ledto the administration of higher meth-adone doses than were used 20 yearsago30,31; however, it is unclear if theseincreases in maternal methadone dosehave further increased the incidence ofNAS.3237

    Buprenorphine, a semisynthetic partialm-opioid receptor agonist and a com-plete k-opioid receptor antagonist, hasbeen found to be equally safe and effi-cacious and has become an effective

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  • alternative to methadone for opioiddependency during pregnancy.3840

    Multiple studies demonstrated thatbuprenorphine maintenance treatmentin pregnancy is either comparable orsuperior to methadone treatment withregard to NAS; however, these studieswere observational, retrospective, orsmall (Supplemental Table 5).4148 Alarger prospective randomized studyfavored buprenorphine over metha-done with regard to the doses anddurations of morphine treatment andlengths of hospital stays, but not theincidence nor the severity of NAS.49 Arecent meta-analysis did not favor oneover the other.50 No relationship hasbeen found between maternal opioiddose and NAS.51 Neither methadonenor buprenorphine were approved foruse in pregnancy.

    The abuse of prescription pain medi-cations has increased among pregnantwomen.5255 A recent study reportedthat 6% of mothers used opioids formore than a month during pregnancy.56

    Another study reported that the in-

    cidence of oxycodone abuse amongpregnant women doubled within the18-month study period.57 Multiple re-cent studies have noted increases inthe incidence of NAS secondary toprescription drug abuse.5860

    The use of psychotropic medications tocontrol depression and anxiety duringpregnancy has increased over thepast decade.61,62 Approximately 1.8% ofpregnant mothers use antidepressantsand 3.0% use benzodiazepines.63,64 Se-lective serotonin reuptake inhibitors(SSRIs), selective norepinephrine re-uptake inhibitors (SNRIs), tricyclicantidepressants (TCAs), and benzodiaz-epines are associated with NA