neonatal abstinence syndrome author:...

17
Neonatal Abstinence Syndrome abstract Neonatal abstinence syndrome (NAS) is a result of the sudden discon- tinuation of fetal exposure to substances that were used or abused by the mother during pregnancy. Withdrawal from licit or illicit substan- ces is becoming more common among neonates in both developed and developing countries. NAS continues to be an important clinical entity throughout much of the world. NAS leads to a constellation of signs and symptoms involving multiple systems. The pathophysiology of NAS is not completely understood. Urine or meconium conrmation 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 be helpful for initiating, monitoring, and terminating treatment in neo- nates. Nonpharmacological care is the initial treatment option, and pharmacological treatment is required if an improvement is not ob- served after nonpharmacological measures or if the infant develops severe withdrawal. Morphine is the most commonly used drug in the treatment of NAS secondary to opioids. An algorithmic approach to the management of infants with NAS is suggested. Breastfeeding is not contraindicated in NAS, unless the mother is taking street drugs, is involved in polydrug abuse, or is infected with HIV. Future studies are required 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 Fareri Childrens Hospital at New York Medical College, Valhalla, New York KEY WORDS benzodiazepines, breastfeeding, buprenorphine, Finnegan scores, inhalants, methadone, methamphetamine, morphine, neonatal abstinence syndrome, opioid abuse, opioid receptors, prescription opioids, selective serotonin reuptake inhibitor, withdrawal ABBREVIATIONS NASneonatal abstinence syndrome SNRIselective norepinephrine reuptake inhibitor SSRIselective serotonin reuptake inhibitor TCAtricyclic 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, Elaine Kaplan NICU, St Lukes Cornwall Hospital, 70 Dubois St, Newburgh, NY 12550. E-mail: [email protected] 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 no nancial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The author has indicated he has no potential conicts of interest to disclose. PEDIATRICS Volume 134, Number 2, August 2014 e547 STATE-OF-THE-ART REVIEW ARTICLE by guest on May 25, 2018 http://pediatrics.aappublications.org/ Downloaded from

Upload: haduong

Post on 28-Mar-2018

258 views

Category:

Documents


0 download

TRANSCRIPT

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:e547–e561

AUTHOR: Prabhakar Kocherlakota, MD

Division of Neonatology, Department of Pediatrics, Maria FareriChildren’s 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

ABBREVIATIONSNAS—neonatal abstinence syndromeSNRI—selective norepinephrine reuptake inhibitorSSRI—selective serotonin reuptake inhibitorTCA—tricyclic 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: [email protected]

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

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from

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 until∼1903, 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 children’s 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.32–37

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

e548 KOCHERLAKOTA

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from

alternative to methadone for opioiddependency during pregnancy.38–40

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).41–48 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.52–55 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.58–60

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 NAS.61,64

Women with mental health disordersare also at increased risk of substanceabuse.

As of 2012, .4% of pregnant womenhave used nonopioid illicit substancesduring pregnancy as compared with,3% in 2002.65 Although the use ofmethamphetamines and inhalants de-creased during the same period inNorth America and Europe, the use of

methamphetamines and inhalants isan increasing concern in developingcountries.66–68 Both of these substancesalso are associated with NAS.69,70

The spectrum of NAS has changed overtime. Before 1970, NAS was generallysecondary to eithermorphine or heroinuse. Today, NASmay be secondary to theuse of morphine, heroin, methadonebuprenorphine, prescription opioid an-algesics, antidepressants, anxiolytics,and/or other substances. This spec-trum of causes has worsened, not onlybecause of an increase in the use ofopioids but also because of the simul-taneous use of multiple opioids, whichis further complicated by the concur-rent use of multiple other licit and illicitsubstances. Accordingly, NAS has be-comemore common andmore complex,imposing additional social, economic,and health care costs on society.18,60

PATHOPHYSIOLOGY

The pathophysiological mechanism ofopioid withdrawal in neonates is notknown. Several factors can affect the

FIGURE 1Time line of NAS. FDA, Food and Drug Administration.

STATE-OF-THE-ART REVIEW ARTICLE

PEDIATRICS Volume 134, Number 2, August 2014 e549

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from

accumulation of opioids in the fetus.Opiate drugs have low molecularweights, are water soluble, and are li-pophilic substances; hence, they areeasily transferable across the placentato the fetus. The transmission of opioidsacross the placenta increases as ges-tation increases.71 Synthetic opiatescross the placenta more easily com-pared with semisynthetic opiates.72

The combination of cocaine or heroinwith methadone further increases thepermeability of methadone across theplacenta.73 Together, the ease withwhich these drugs can cross the blood-brain barrier of the fetus, and theprolonged half-life of these drugs in thefetus,74 may worsen the withdrawal ininfants. Neonatal abstinence syndromeis the end result of the sudden dis-continuation of prolonged fetal expo-sure to opioids.

Opioid withdrawal is a complex bio-logical phenomenon. The cellular andmolecular mechanisms of this processare poorly understood even in adults.The pathophysiology of opioid with-drawal is more complex in neonates asa result of immature neurologic devel-opment, impaired neurologic process-ing, and complex materno-feto-placentalpharmacokinetics.

Opioids mostly act through opioid re-ceptors (G protein–coupled receptors,m, k, and d), which are extensivelydistributed across the central nervoussystem and are also located within theperipheral nervous system, gastroin-testinal system, and various othersystems.75 The density and affinity ofm-receptors in neonates are as good asthose in adults; however, evidencefailed to show similar development ofk- and d-receptors, as well as otherreceptors, in the neonatal brain.76 Alack of opioids in a chronically stimu-lated state increases activity in theopioid receptors, leading to increasedadenyl cyclase activity, and cellularionic imbalance. Ultimately, this results

in the increased production of variousneurotransmitters through a cascadeof enzymatic activities (Fig 2).77

The most important center of activity inopioid withdrawal is the locus coeru-leus of the pons. This is the principalnoradrenergic nucleus of the brain andis extremely sensitive to opioid status.78

A lack of opioids causes increasedproduction of norepinephrine,79 whichis responsible for most of the signs ofNAS. The ventral tegmental area of themidbrain, the storage center of dopa-mine, releases decreased dopamineduring opioid withdrawal.80,81 Opioidwithdrawal also causes decreased se-rotonin expression in the dorsal raphenucleus,82,83 causing sleep distur-bances in neonates undergoing opioidwithdrawal. Opioid deficits also affectthe functioning of the autonomic andperipheral nervous systems, as wellas the gastrointestinal system. Opioiddeficits cause increased production ofmultiple neurotransmitters, such asacetylcholine, during withdrawal phase.84

Opioid withdrawal may activate thehypothalamic-pituitary-adrenocorticalaxis, leading to increased corticotrophinrelease.85 Further, opioid withdrawalmay be associated with hyperalgesia.86

It also may affect gene expressionwithin various body systems (Fig 2).87

The incidence and severity of with-drawal is less extensive in pretermneonates.88 Various factors explain thedecreased incidence in preterm neo-nates, including decreased cumulativeexposure,88 decreased transmissionacross the placenta during early ges-tation,71 decreased morphine clear-ance,89 decreased excretion because ofimmaturity of the kidneys and liver,decreased fatty tissues in preterminfants (methadone is accumulated infatty tissue), decreased receptor de-velopment, and decreased receptorsensitivity.76,90

Withdrawal symptomsamongneonateswhose mothers took an SSRI or SNRI

may result from excess serotonin andnoradrenaline. Neonatal withdrawalfrom TCA is a cholinergic rebound phe-nomenon. Neonatal withdrawal withbenzodiazepines probably results fromthe increased release of g-amino bu-tyric acid.91 Methamphetamine with-drawal may be secondary to a decreasein dopamine, serotonin, and other mono-amines.92 Inhalant withdrawal involvesthe dopamine, glutamate, and g-aminobutyric acid pathways.68

CLINICAL PRESENTATION

NAS continues to be an important clin-ical entity and leads to a constellation ofsigns and symptoms that involve mul-tiple systems. At presentation, signs ofNASusually include tremors, irritability,excessive crying, and diarrhea. Occa-sionally, seizures also are present.Central nervoussystemsigns, includingirritability, jitteriness, tremors, andexcessive crying, usually appearfirst. Hyperirritability, which is ahallmark of this syndrome, can lead toagitation, difficulty sleeping, and in-consolable crying. The high-pitched,uncontrollable excessive crying isoften striking, and requires immedi-ate attention.

Tremors, exaggerated Moro reflex, hy-pertonia, andmyoclonic jerks aremorecommonduringmethadonewithdrawal.93

These can mimic seizures, and an EEGmay be required for confirmation. Sei-zures are observed in 2% to 11% ofneonates with NAS, are a serious man-ifestation of withdrawal, and should betreated immediately.94 The exact causeof withdrawal-related seizure is un-known, although the threshold for sei-zure activity may be decreased due toupregulation of sodium channels as aresult of receptor instability.75 Heartrate, respiratory rate, muscle tone, andother physiologic responses to stimuliare impaired in these neonates withNAS as a result of the dysregulationand instability of the autonomic nervous

e550 KOCHERLAKOTA

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from

system.95 Other autonomic nervoussystem signs include temperature in-stability, sweating, sneezing, and mot-tling. These may persist for months,or even longer, especially in casesinvolving maternal buprenorphineuse.93 A chemical odor is common inneonates born to mothers who abuseinhalants.70

Tachypnea, nasal flaring, and nasalstuffiness may be misinterpreted asrespiratory distress in newborns. Hy-perthermia, although rarely higherthan 102°F, can result in misdiagnosis

as sepsis. Poor feeding, excessive mo-tor activity, regurgitation, vomiting, anddiarrheamay lead to poorweight gain inthese infants. Severe diarrhea, leadingto dehydration and electrolyte imbal-ance, is more commonly observed inheroin withdrawal. Perianal skin exco-riation secondary to excessive loosestools further increases irritability andagitation. Similarly, irritability and agi-tation may be increased by unattendedskin excoriation over the face and body,which are secondary to excessive motormovements. Hyperphagia is widely rec-

ognized in infants with NAS, who mayrequire intake of more than 150 caloriesper kilogram per day.96

The onset, duration, and severity of NASdepend on several characteristics ofthe drugs abused by the mother, in-cluding their types, amounts, half-lives,receptor-binding capacities, receptoraffinities, placental transferability, andother pharmacological properties. Ad-ditionally, NAS may be affected by thetime of the last dose, the duration ofexposure, the total accumulation of theexposure, and the multiplicity of the

FIGURE 2A schematic illustration of themechanism of opioid withdrawal in neonates. Lack of opiates in a chronically stimulated state leads to the upregulation of cyclicadenosine monophosphate, which leads to increased production and release of various neurotransmitters through complex mechanisms. Withdrawal is theresult of increased production of noradrenaline, acetyl choline, corticotrophin, and other substances, as well as the decreased production of serotonin anddopamine. These mechanisms may be able to explain most of the signs that are characteristically seen in neonates with abstinence syndrome.

STATE-OF-THE-ART REVIEW ARTICLE

PEDIATRICS Volume 134, Number 2, August 2014 e551

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from

substances that the neonate was ex-posed to.97–99

Of the opioids, heroin exposure causesearlierand shorterwithdrawal,whereasmethadone and buprenorphine expo-sure lead to later onset and longerwithdrawal. Of the nonopioids, meth-amphetamines cause immediate with-drawal,psychotropicmedicationsusuallyinduce transitional and self-limitingwithdrawal, and the results are inde-terminate for benzodizepines.96–100 Ta-ble 1 summarizes the onset, duration,and frequency of NAS caused by varioussubstances.

Onset may be delayed with buprenorphine,especially in higher doses.102,103 De-layed onset also is noted when opioidsare used along with barbiturates orbenzodiazepines.104 In general, infantsborn at term, infants with good birthweight, polydrug-exposed neonates,and infants with delayed drug metab-olism are more prone to severe andprolonged withdrawal. Additional riskfactors for increased NAS may includematernal smoking, methadone usage,and male gender. Increased lengthof hospital stays and an increasedneed for pharmacotherapy in NAShave recently been observed amongneonates with the m-opioid receptor(OPRM1) gene and the catechol-O-methyltransferase (COMT) gene. How-ever, these results need to be exploredfurther for clinical application.105

Risk factors associated with severityand intensity are summarized inTable 2.

NAS may involve an initial phase that isshort but intense, consisting of tremors,seizures, irritability, feeding problems,vomiting, diarrhea, hyperthermia, andother systemic signs (lasting for 1 to 2weeks). This initial phase may be fol-lowed by a long chronic and relapsingcourse that includes hyperirritability,sleep disturbances, hyperphagia, andother neurologic and autonomic signs(lasting fora fewweekstoa fewmonths).

TOXICOLOGY CONFIRMATION

Although NAS is a clinical diagnosis,toxicological confirmation is necessaryto identify the exact type of substancethat the mother was using or abusingand to confirm or rule out the use ofother licit or illicit substances duringpregnancy. Analysis of the urine ormeconium,which is thematrixof choicefor detecting in-utero drug exposure,is a noninvasive, inexpensive, repro-ducible,and fullyautomatedprocedure;specimen collection also is relativelyeasy in neonates. The analysis can beperformed by using the immunoassaytechnique in hospital clinical labora-tories, by using specific lower cutoffconcentrations for each drug.116 Be-cause these are merely screeningtests, confirmation is required fromsecondary testing with mass spec-trometry after the chromatographicmethod, especially if quantitative ordefinitive results are needed. However,these tests are expensive and time-consuming, and require significantexpertise.

Meconium testing is more sensitivethan urine testing, and has a longerwindow of detection (from 20 weeks ofgestational age); however, the extrac-tion of the drug depends on the solvent.Urine testing is more popular. It hasa shorter window for detection (a fewdays), but extraction is efficient (Ta-ble 3).116,117 Detection of the abuseddrug depends on the amount and theduration of drug exposure, the methodof maternal administration, and theindividual metabolism and clearanceof the drug in the mother and her fetus.Although natural opioids are easilydetectable in urine and meconium,semisynthetic and synthetic opioiddrugs are not.118,119 Synthetic cannabi-noids, synthetic cathinones, and otherdesigner drugs cannot be detectedwith regular laboratory tests and mayrequire more selective methods.121,122

False-positive results are often seenwith amphetamines. False-positive re-sults are observed when meconium iscontaminatedwithurine,andalsowhensoap or alcohol has been used forcleaning before collection.116 False-negative results can occur with urinebecause of delays in collection. Addi-tionally, urine is relatively dilute atbirth in neonates. Meconium analysismay yield false-negative results formarijuana.117 Improper storage ofmeconium may interfere with analysisbecause meconium is light-sensitiveand temperature-sensitive. A combi-nation of maternal urine and neonatalmeconium usually yields the bestresults. Peripartum use of opioids formaternal analgesia may interfere withneonatal toxicology results. Hair andumbilical cord analyses may help de-tect even minor and remote exposures;however, such tests require referencelaboratories. Early detection of sub-stance exposure leads to early as-sessment and management of theaffected neonate.124 Inaccurate anddelayed detection may not only delay

TABLE 1 Onset, Duration, and Frequency of NAS Caused by Various Substances

Drug Onset, h Frequency, % Duration, d

OpioidsHeroin 24‒48 40‒8027 8‒10Methadone 48‒72 13‒9437 Up to 30 or moreBuprenorphine 36‒60 22‒6746,48 Up to 28 or morePrescription opioid medications 36‒72 5‒2056,60 10‒30

NonopioidsSSRIs 24‒48 20‒3064 2‒6TCAs 24‒48 20‒5064 2‒6Methamphetamines 24 2‒49101 7‒10Inhalants 24‒48 4870 2‒7

e552 KOCHERLAKOTA

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from

treatment, but also may create con-flicts with and within the family.

MANAGEMENT

Many scoring systems allow cliniciansto assess the severity of NAS, but noscoring system is perfect and all thesystems are subject to a strong in-terobserver variability. At present, themodified Finnegan scores remains themost common tool that is used.126,127

The Finnegan scoring system is usedfor opioid and nonopioid withdrawalassessment.70,96 Shortened or simpli-fied versions of these scores have metwith little success.128,129 Quantifying theseverity of NAS assists in determining if

and when pharmacological interventionwill be needed. Scoring also assists inmonitoring, titrating, and terminatingtherapy.130 Scoring should be perfor-med after feeds, at 3- to 4-hour intervals,when the infant is awake. The scoreshould represent the status of the infantboth at the time of assessment, andduring the preceding time period. Thesescoring systems are generally useful forterm neonates, but not for preterminfants.

NONPHARMACOLOGICAL CARE

Management of the neonate includesboth pharmacological and nonphar-macological care. Nonpharmacological

therapy is the first option in all cases,and may suffice in cases of mild with-drawal. Nonpharmacological therapy iseasily acceptable, less expensive, andless controversial. Nonpharmacologi-cal therapy can be attempted in allinfants before initiating pharmacolog-ical therapy. Successful managementcomprises gentle handling, demandfeeding, and careful avoidance ofwaking the sleeping infant. Swaddlinglessens stimulation, decreases cryingtimes, and promotes sleep that is moresustained.131,132 Continuous minimalstimulation practices with dim lightand low noise must be implementedin all neonates. Frequent feeds, high-calorie formula, and thickened feedsmay meet nutritional and metabolicdemands. Kangaroo care and pacifiersmay help to calm infants. Water bedsalso may help but not rocking beds.133

Music therapy and massage therapymay soothe some infants.134 Non-insertive acupuncture also has beenattempted.135 Holding, cuddling, andmanual rocking also can help. Allinfants need to be monitored for feed-ing, weight gain, and good sleep.96 Todate, no studies have compared theeffectiveness of any of these measuresin neonates with NAS. To control theseverity of withdrawal, it may be es-pecially important to stay alert early tosigns of the newborn’s irritability. Ifparents, volunteers, and cuddlers areimmediately available, they can calmand soothe these infants before thecycle of irritability, excessive crying,poor feeding, and lack of sleep setsin. Rooming-in of mother and infantalso decreases the severity of with-drawal.136,137 A caring, nonjudgmentalapproach may encourage maternalparticipation. Active maternal partici-pation is the best nonpharmacologiccare. Continuous excellent supportivecare can help to avoid pharmacologicalintervention, and also may lead toearlier discharge from hospital.

TABLE 2 Risk Factors for Increasing Severity and/or Intensity of NAS

Definite Probable

Term97,98,108 Male gender112,113

Good birth weight97,109 Methadone45,46

Polydrug abuse106,107, 110 Smoking97,109,114

Combination with benzodiazepines97,111 Combination with SSRIs97,109,115

m-opioid receptor (OPRM1 118 AA) positive105

Catechol-O-methyltransferase (COMT 158 AA) positive105

TABLE 3 Urinary Screening for Various Drugs and Approximate Duration of Detection in theNeonate116,118–120

Substance Compound/Metabolite/Usage Duration of Detectability

Alcohol123 Ethanol Few hFatty acid ethyl esters Up to 5 dEthyl glucuronide Up to 30 hEthyl sulfate

Amphetamines Amphetamine 1‒2 dMethamphetamine 1‒2 d

Barbiturate Short acting ,2 dLong acting 1‒7 d

Benzodiazepines Short acting 1‒7 dLong acting Up to 30 d

Cocaine Cocaine 6‒8 hMetabolites 2‒5 d

(up to 10‒22 d with heavy use)Marijuana Single use 1‒3 d

Moderate use 5‒7 dHeavy up to 10 dChronic heavy use up to 30 d

Opiates Heroin, morphine, codeine 1‒2 dHydromorphone, oxycodone 2‒4 dMethadone 2‒3 dMethadone metabolite Up to 6 dBuprenorphine125 2‒3 dBuprenorphine 2‒3 dNorbuprenorphine

Phencyclidine 1 to 8 d

STATE-OF-THE-ART REVIEW ARTICLE

PEDIATRICS Volume 134, Number 2, August 2014 e553

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from

PHARMACOLOGICAL CARE

Medical intervention to control with-drawal symptoms is required in 27% to91% of neonates with NAS.138,139 How-ever, because of the complex nature ofwithdrawal and the unknown effectsof various licit and illicit drugs, thereare currently no uniformly acceptedpharmacological interventions or stan-dardized regimens for the managementof NAS.96 Many available medicationscan facilitate short-term ameliorationof the withdrawal symptoms; however,no large-scale studies have comparedthese medications because the spec-trum of withdrawal varies for differentdrugs, doses, weights, and gestationalperiods. Medications are required onlywhen (1) supportive therapy fails tocontrol the signs and symptoms; (2)withdrawal scores remain high; (3)serious signs are observed, such asseizures; or (4) withdrawal is associ-ated with severe dehydration becauseof diarrhea and/or vomiting. Delaysin the administration of pharmaco-logical therapy are associated withhigher morbidity and longer hospitalstays.140

Manymedications are available to treatthese signs, but no single medication issuitable for every patient and no singleregimen is acceptable to every patient.The pharmacological management ofNAS has been a subject of recentreviews.141–143 Opioid antagonists, suchas naloxone, are contraindicated be-cause they may precipitate seizures inneonates. Older medications, such asparegoric or tincture of opium, are nolonger used or available because theyhave toxic ingredients and high alcoholcontent. Sedatives, such as diazepamand chlorpromazine, are not usefulbecause of their prolonged half-livesand associated complications.144 Themechanisms of action, doses, advan-tages, and risks of commonly usedmedications for NAS are included inTable 4.

Morphine is the most commonly pre-ferred medication.127,145 Morphine de-creases the incidence of seizures,improves feeding, eliminates diarrhea,decreases agitation, and can controlsevere symptoms.146 However, mor-phine treatment also prolongs thelength of hospital stay.147 Incrementalincrease or decrease of the dose ofmorphine depending on the severity ofwithdrawal is often a common prac-tice.46,143 Because morphine has shorthalf-life, it must be provided every 3 to4 hours. Morphine solution is stableand easy to administer.148 Additionally,morphine treatment is relatively saferand more suitable for NAS manage-ment.149 Morphine dose can be esca-lated rapidly for higher scores; however,weaning has to be gradual. When anoptimal response is not attained withthe maximal dose, additional medi-cations may be considered. An algo-rithmic approach (Fig 3) for themanagement of NAS is not only usefulfor consistent management, but isespecially beneficial for communityhospital settings, where most casesof NAS are managed.22

Methadone is an alternative to morphinefor the treatment of NAS. Methadone ismore frequently used in the UnitedStates than in other countries.130,150

Methadone can be administered onlytwice per day; however, because ofthe long half-life of methadone, it maybe difficult to titrate the methadonedose. The methadone dose also can beincreased or decreased depending onthe severity score. Caution must beexercised when methadone is usedalong with other medications, such asphenobarbital or antiretroviral medi-cations.151 Buprenorphine is a new op-tion for the treatment of NAS and mustbe given sublingually; however, nolarge-scale studies are available tosupport the use of this medication.152 Ide-ally, both methadone and buprenorphineare logical choices, if the mothers

were receiving these medicationsprenatally.

Phenobarbital is a drug of choice fornonopiate NAS.134,150 Although it is oc-casionally used as a single therapeuticagent for opioid NAS, phenobarbital ismore often used as an adjunct tomorphine or methadone.130,144 Pheno-barbital does not prevent seizures atthe dosage administered for withdrawal,nor does it improve gastrointestinalsymptoms. However, phenobarbital isadvantageous because it can be usedas an adjuvant, especially in infantssuffering withdrawal from polydrugabuse,145 which is generally severeand prolonged. Clonidine, a centrallyacting a-adrenergic receptor agonist,has been studied as a single replace-ment therapy or adjunct therapy,although the theoretical risk of hypo-tension and bradycardia may alwaysprohibit increasing its dose. No large-scale studies have proven the efficacyof clonidine for NAS.153,154 Clonidineand phenobarbital levels can bemonitored, and both are beneficialfor decreasing the duration of treat-ment as well as for curtailing theuse of higher doses of morphine ormethadone.138,155

BREASTFEEDING

In 2001, the American Academy of Pe-diatrics removed the restrictions onbreastfeeding for mothers on anydosage of methadone.156 This positionwas further reaffirmed in 2013.157

Multiple studies have validated thefinding that breast milk contains onlyminimal quantities of methadone andbuprenorphine.158–160 Obstetricians andlactation specialists also have en-dorsed breastfeeding among opioid-addicted mothers.161,162 Subsequentto these recommendations, some im-provements in breastfeeding practiceshave been noted.127,163 The amount ofmethadone or buprenorphine in breastmilk is too small to treat NAS, and the

e554 KOCHERLAKOTA

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from

sudden discontinuation of breastmilk isnot associated with the worsening ofNAS164,165; however, gradual weaningfrom breastfeeding is advised.166 Be-cause of the high concentrations ofhydrocodone and oxycodone in breastmilk aswell as the reduced clearance ofsome of these medications in someneonates, mothers taking these pre-scription opioids should be alerted tothe problem of sedation among infantswhen breastfeeding.167–169 Breastfeed-ing increases mother-infant bonding,enhances maternal confidence, andencourages active maternal participa-tion in the management of the infant.Breastfeeding may decrease the in-cidence of NAS,170 the need for phar-macological treatment,99,171 and thelength of the hospital stay.111,172 Breast-feeding is not contraindicated by psy-chotropic medications.61 Breastfeedingis contraindicated only if the mother istaking illicit drugs, has polydrug abuse,or is infected with HIV.

DISCHARGE AND FOLLOW-UP

When theneonateshowsnomajorsignsof withdrawal and the infant is feeding

well, sleeping well, gaining weight, andmaintaining stable withdrawal scoreswith minimal medication support, theinfant can be discharged with theparents (provided that the home envi-ronment is safe and stable) or toa foster home (if necessary). A multi-disciplinary approach that includesparental participation is extremelyhelpful in the management of theseneonates, not only during the hospitalstay but also after discharge from thehospital. Indeed, these infants aremoreprone to both short-termand long-termproblems.173,174 Whether prenatal opi-oid exposure or postnatal opioid treat-ment has any long-term effects on thenewborn brain is largely unknown. In-deed, no longitudinal follow-up studieshave extended beyond the first fewyears of life.175 Animal experimentshave neither proven nor disproven theeffects of chronic maternal opioid ad-ministration on dendritic growth anddevelopment in the fetus.176,177 Recentobservations of delayed or altered mat-uration of neuronal connective tractsand smaller neuroanatomic volumes ininfants born to opioid-addicted moth-ers178,179 have established an urgent

need for studies of long-term out-comes in these children. No signifi-cant adverse long-term outcomeswere reported among neonates whowere exposed in utero to SSRIs, SNRIs,TCAs, benzodiazepines, or methamphet-amines.180–182

During follow-up, infants with NASparticularly require (1) neurodevelop-mental assessments to identify motordeficits, cognitive delays, or relativemicrocephaly174,183; (2) psycho-behavioralassessments to identify hyperactivity,impulsivity, and attention-deficit inpreschool-aged children, as well asschool absence, school failure, andother behavioral problems in school-aged children184; (3) ophthalmologicassessment to identify nystagmus, stra-bismus, refractive errors, and othervisual defects185–187; (4) growth andnutritional assessment to identify fail-ure to thrive and short stature174; and(5) family support assessments to ex-clude continuous maternal substanceabuse and child abuse. Parents needto be educated about sudden infantdeaths as well as complications dueto perinatal infections. The complexityand challenging nature of the home

TABLE 4 Pharmacological Treatment Options for NAS

Medication Mechanism of Action Dose Advantages Disadvantages

Morphine Natural m-receptor agonist 0.05‒0.2 mg/kg/dose q 3‒4 h No alcohol SedationIncrease by 0.05 mg/kg Short half-life (9 h) ApneaMaximum dose: 1.3 mg/kg/day141 Constipation

Frequent dosingMethadone Synthetic complete 0.05‒0.1 mg/kg/dose q 12 h, increase

by 0.05 mg/kg q 48 hLong half-life (26 h) Longer duration of treatment

m-receptor agonist Alcohol 8%N-methyl-d-aspartate antagonist Maximum dose: 1 mg/kg/d21 12 hourly doses Frequent follow-up needed

(Variable half-life)Phenobarbital g-amino butyric acid agonist Loading dose: 16 mg/kg Long half-life (45‒100 h) Possible hyperactivity

Maintenance dose: 1‒4 mg/kg/dose q12 h150 High treatment failureMonitor level Alcohol 15%

Drug-drug interactionsSedation

Clonidine a-adrenergic receptor agonist Initial dose: 0.5‒1 mg/kg, followed by0.5‒1.25 mg/kg per dose q 4‒6 h153

Nonnarcotic antagonist HypotensionNo sedation Abrupt discontinuation may

cause rapid rise of bloodpressure and heart rate

No alcoholLong half-life (44‒72 h)Monitor level

Buprenorphine Semi-synthetic partial m-receptoragonist, k-receptor antagonist

Dose: 4‒5 mg/kg/dose q 8 h Sublingual route Alcohol 30%Maximum dose: 60 mg/kg/d152 Half-life (12 h) Adjuvant medications required

q, every.

STATE-OF-THE-ART REVIEW ARTICLE

PEDIATRICS Volume 134, Number 2, August 2014 e555

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from

atmosphere should never be underes-timated in these situations. The impor-tance of an optimal home environment

for the global development of thesechildren should be emphasized to allparents.

ACKNOWLEDGMENT

I thank Vasudev Kamath, MD, MPH, forcriticallyreviewingthemanuscriptdraft.

REFERENCES

1. Heroin timeline. Heroin addiction. Avail-able at: www.heroinaddiction.com/heroin_timeline.html. Accessed October 12, 2013

2. Merry J. A social history of heroin ad-diction. Br J Addict Alcohol Other Drugs.1975;70(3):307–310

3. Courtwright D. Dark Paradise: Opiate Ad-diction in America Before 1940. Cam-bridge, MA: Harvard University Press; 1982

4. Menninger-Lerchenthal E. Die morphinkranheit der neugeborenen morphine

stischer mutter Monatsschr. F Kinderh.1934;60:182–193

5. Happel TJ. Morphinism in its relation tothe sexual functions and appetite and itseffects on the offspring of the users ofthe drug. Tr M Soc Tennessee. 1892;162–179

6. Earle FB. Maternal opium habit and infantmortality. M Standard (Chicago). 1888;3:2

7. OD. Fetal morphine addiction, queries andminor notes. JAMA. 1903;40:1092

8. Perlstein MA. Congenital morphinism;a rare cause of convulsions in thenewborn. J Am Med Assoc. 1947;135(10):633

9. Goodfriend MJ, Shey IA, Klein MD. Theeffects of maternal narcotic addiction onthe newborn. Am J Obstet Gynecol. 1956;71(1):29–36

10. Cobrinik RW, Hood RT Jr, Chusid E. Theeffect of maternal narcotic addiction onthe newborn infant; review of literature

FIGURE 3Amanagement plan forNAS in neonates.Medications are to be initiated, increased, decreased, ordiscontinueddepending on the Finnegan score.Morphine canbe initiated at a higher dose if scores are high; for example, if the scores are 17 to 20, morphine can be started at 0.12 mg per dose, and if the scores are$25,morphine can be initiated at 0.20 mg per dose.49 Morphine dose can also be escalated by .10% for higher scores.21 Methadone can be substituted formorphine for opioid withdrawal. Cardiopulmonary monitoring of the infant is preferred during the acute stage.

e556 KOCHERLAKOTA

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from

and report of 22 cases. Pediatrics. 1959;24(2):288–304

11. National Consensus Development Panel onEffective Medical Treatment of Opiate Ad-diction. Effective medical treatment of opi-ate addiction. JAMA. 1998;280(22):1936–1943

12. Reddy AM, Harper RG, Stern G. Observa-tions on heroin and methadone with-drawal in the newborn. Pediatrics. 1971;48(3):353–358

13. Auriacombe M, Fatséas M, Dubernet J,Daulouède JP, Tignol J. French field expe-rience with buprenorphine. Am J Addict.2004;13(suppl 1):S17–S28

14. Center for Substance Abuse Treatment. Clin-ical guidelines for the use of buprenorphinein the treatment of opioid addiction. Treat-ment Improvement Protocol (TIP) series 40.Rockville, MD: Substance Abuse and MentalHealth Administration; 2004. DHHS publica-tion (SMA) 04-3939

15. Marquet P, Chevrel J, Lavignasse P, MerleL, Lachâtre G. Buprenorphine withdrawalsyndrome in a newborn. Clin PharmacolTher. 1997;62(5):569–571

16. Kayemba-Kay’s S, Laclyde JP. Buprenorphinewithdrawal syndrome in newborns: a re-port of 13 cases. Addiction. 2003;98(11):1599–1604

17. Rao R, Desai NS. OxyContin and neonatalabstinence syndrome. J Perinatol. 2002;22(4):324–325

18. Patrick SW, Schumacher RE, BenneyworthBD, Krans EE, McAllister JM, Davis MM.Neonatal abstinence syndrome and asso-ciated health care expenditures: UnitedStates, 2000-2009. JAMA. 2012;307(18):1934–1940

19. O’Donnell M, Nassar N, Leonard H, et al.Increasing prevalence of neonatal with-drawal syndrome: population study ofmaternal factors and child protection in-volvement. Pediatrics. 2009;123(4). Avail-able at: www.pediatrics.org/cgi/content/full/123/4/e614

20. SAMHSA. Center for Behavioral HealthStatistics and Quality, National Survey onDrug Use and Health, 2008-2011. Avail-able at: www.samhsa.gov/data/NSDUH/2011SummNatFindDetTables/NSDUH-DetTabsPDFWHTML2011/2k11DetailedTabs/Web/HTML/NSDUH-DetTabsSect6peTabs55to107-2011.htm#Tab6.72A. Accessed February 25,2013

21. Napolitano A, Theophilopoulos D, Seng SK,Calhoun DA. Pharmacologic managementof neonatal abstinence syndrome ina community hospital. Clin Obstet Gynecol.2013;56(1):193–201

22. Patrick SW, Benneyworth BD, SchumacherR, Davis MM. Variation in hospital type in

treatment of neonatal abstinence syn-drome in the United States. Paper pre-sented at Pediatric Academic SocietiesAnnual Meeting; May 4–7, 2013; Wash-ington, DC. Abstract 2922

23. Tetstall E, Liu AJ, An EI, Canalese J, NananR. Pregnancy and neonatal characteristicsof opioid-dependent Indigenous Australians:a rural and metropolitan comparison.Aust N Z J Obstet Gynaecol. 2009;49(3):279–284

24. Substance Abuse and Mental Health Ad-ministration. Report TEDS. Injection drugabuse admission to substance abusetreatment, 1999 to 2009. Available at:www.samhsa.gov/data/2k11/WEB_TEDS_012/WEB_TEDS_012.htm. Accessed February 25,2013

25. Carrieri MP, Amass L, Lucas GM, Vlahov D,Wodak A, Woody GE. Buprenorphine use:the international experience. Clin InfectDis. 2006;43(suppl 4):S197–S215

26. Shainker SA, Saia K, Lee-Parritz A. Opioidaddiction in pregnancy. Obstet GynecolSurv. 2012;67(12):817–825

27. Cunningham FG, Leveno KJ, Bloom SL,Hauth JC, Rouse DJ, Spong CJ, eds. Tera-tology and medications that affect thefetus. In: Williams Obstetrics. 23rd ed.New York, NY: McGraw Hill; 2010:328

28. Kandall SR, Doberczak TM, Jantunen M,Stein J. The methadone-maintained preg-nancy. Clin Perinatol. 1999;26(1):173–183

29. Kaltenbach K, Berghella V, Finnegan L.Opioid dependence during pregnancy.Effects and management. Obstet GynecolClin North Am. 1998;25(1):139–151

30. Pond SM, Kreek MJ, Tong TG, Raghunath J,Benowitz NL. Altered methadone pharma-cokinetics in methadone-maintained preg-nant women. J Pharmacol Exp Ther. 1985;233(1):1–6

31. Jarvis MA, Wu-Pong S, Kniseley JS, SchnollSH. Alterations in methadone metabolismduring late pregnancy. J Addict Dis. 1999;18(4):51–61

32. Seligman NS, Almario CV, Hayes EJ, DysartKC, Berghella V, Baxter JK. Relationshipbetween maternal methadone dose atdelivery and neonatal abstinence syn-drome. J Pediatr. 2010;157(3):428–433, e1

33. Lim S, Prasad MR, Samuels P, Gardner DK,Cordero L. High-dose methadone in preg-nant women and its effect on neonatalabstinence syndrome. Am J Obstet Gynecol.2009;200:70.e1–70.e5

34. Pizarro D, Habli M, Grier M, Bombrys A,Sibai B, Livingston J. Higher maternaldoses of methadone does not increaseneonatal abstinence syndrome. J SubstAbuse Treat. 2011;40(3):295–298

35. Dashe J, Sheffield JS, Olscher DA, Todd SJ,Jackson GL, Wendel GD. Relationship be-tween maternal methadone dosage andneonatal withdrawal. Obstet Gynecol.2002;100:1244–1258

36. McCarthy JJ, Leamon MH, Parr MS, AnaniaB. High-dose methadone maintenance inpregnancy: maternal and neonatal out-comes. Am J Obstet Gynecol. 2005;193(3 pt1):606–610

37. Cleary BJ, Donnelly J, Strawbridge J, et al.Methadone dose and neonatal abstinencesyndrome-systematic review and meta-analysis. Addiction. 2010;105(12):2071–2084

38. Riksheim M, Gossop M, Clausen T. Frommethadone to buprenorphine: changesduring a 10 year period within a nationalopioid maintenance treatment programme.J Subst Abuse Treat. 2014;46:291–294

39. Soyka M. Buprenorphine use in pregnantopioid users: a critical review. CNS Drugs.2013;27(8):653–662

40. Jones HE, Heil SH, Baewert A, et al.Buprenorphine treatment of opioid-dependent pregnant women: a compre-hensive review. Addiction. 2012;107(suppl1):5–27

41. Jones HE, Johnson RE, Jasinski DR, et al.Buprenorphine versus methadone in thetreatment of pregnant opioid-dependentpatients: effects on the neonatal absti-nence syndrome. Drug Alcohol Depend.2005;79(1):1–10

42. Lejeune C, Simmat-Durand L, Gourarier L,Aubisson S; Groupe d’Etudes Grossesse etAddictions (GEGA). Prospective multicen-ter observational study of 260 infantsborn to 259 opiate-dependent mothers onmethadone or high-dose buprenophinesubstitution. Drug Alcohol Depend. 2006;82(3):250–257

43. Fischer G, Ortner R, Rohrmeister K, et al.Methadone versus buprenorphine inpregnant addicts: a double-blind, double-dummy comparison study. Addiction.2006;101(2):275–281

44. Kakko J, Heilig M, Sarman I. Buprenorphineand methadone treatment of opiate de-pendence during pregnancy: comparisonof fetal growth and neonatal outcomes intwo consecutive case series. Drug AlcoholDepend. 2008;96(1-2):69–78

45. Bakstad B, Sarfi M, Welle-strand G, RavndalE. Opioid maintenance treatment duringpregnancy: occurrence and severity ofneonatal abstinence syndrome. A nationalprospective study. Eur Addict Res. 2009;15(3):128–134

46. Lacroix I, Berrebi A, Garipuy D, et al.Buprenorphine versus methadone in preg-nant opioid-dependent women: a prospective

STATE-OF-THE-ART REVIEW ARTICLE

PEDIATRICS Volume 134, Number 2, August 2014 e557

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from

multicenter study. Eur J Clin Pharmacol.2011;67:1053–1059

47. Welle-Strand GK, Skurtveit S, Jones HE,et al. Neonatal outcomes following in uteroexposure to methadone or buprenorphine:a National Cohort Study of opioid-agonisttreatment of Pregnant Women in Norwayfrom 1996 to 2009. Drug Alcohol Depend.2013;127(1-3):200–206

48. Patel P, Abdel-Latif ME, Hazelton B, et al. Peri-natal outcomes of Australian buprenorphine-exposed mothers and their newborn infants.J Paediatr Child Health. 2013;49(9):746–753

49. Jones HE, Kaltenbach K, Heil SH, et al.Neonatal abstinence syndrome aftermethadone or buprenorphine exposure. NEngl J Med. 2010;363(24):2320–2331

50. Minozzi S, Amato L, Bellisario C, Ferri M,Davoli M. Maintenance agonist treatmentsfor opiate-dependent pregnant women.Cochrane Database Syst Rev. 2013;(12):CD006318

51. Jones HE, Dengler E, Garrison A, et al.Neonatal outcomes and their relationshipto maternal buprenorphine dose duringpregnancy. Drug Alcohol Depend. 2014;134:414–417

52. Epstein RA, Bobo WV, Martin PR, et al. In-creasing pregnancy-related use of pre-scribed opioid analgesics. Ann Epidemiol.2013;23(8):498–503

53. Buchi KF, Suarez C, Varner MW. The prev-alence of prenatal opioid and other druguse in Utah. Am J Perinatol. 2013;30(3):241–244

54. Handal M, Engeland A, Rønning M, SkurtveitS, Furu K. Use of prescribed opioid anal-gesics and co-medication with benzodi-azepines in women before, during, andafter pregnancy: a population-based co-hort study. Eur J Clin Pharmacol. 2011;67(9):953–960

55. Committee on Health Care for Un-derserved Women, The American Collegeof Obstetricians and Gynecologists. Com-mittee opinion no. 538: nonmedical use ofprescription drugs. Obstet Gynecol. 2012;120(4):977–982

56. Kellogg A, Rose CH, Harms RH, Watson WJ.Current trends in narcotic use in preg-nancy and neonatal outcomes. Am JObstet Gynecol. 2011;204:259.e1–e4

57. Kelly L, Dooley J, Cromarty H, et al.Narcotic-exposed neonates in a FirstNations population in northwesternOntario: incidence and implications. CanFam Physician. 2011;57(11):e441–e447

58. Winchester PD, Miller K, Proctor C, SinghalA, Ying J, Ellis G. Neonatal abstinence andopiate prescriptions. Paper presented at

Pediatric Academic Societies AnnualMeeting; April 28–May 1, 2012; Boston, MA.Abstract

59. Brown MS, Hayes MJ, LaBrie S. Breast-feeding is associated with decreased riskand length of treatment for neonatal ab-stinence syndrome in methadone andbuprenorphine exposed infants. Paperpresented at Pediatric Academic Socie-ties; May 1–4, 2011; Vancouver, BC, Can-ada. Abstract

60. Kocherlakota P. Changing spectrum ofneonatal abstinence syndrome. Paperpresented at Pediatric Academic Socie-ties; April 28–May 1, 2012; Boston, MA.Abstract

61. ACOG Committee on Practice Bulletins;Obstetrics. ACOG Practice Bulletin: Clinicalmanagement guidelines for obstetrician-gynecologists number 92, April 2008(replaces practice bulletin number 87,November 2007). Use of psychiatric med-ications during pregnancy and lactation.Obstet Gynecol. 2008;111(4):1001–1020

62. Fenger-Gron J, Thomsen M, Andersen KS,Nielsen G. Pediatric outcomes followingintrauterine exposure to serotonin reup-take inhibitors: a systemic review. DanMed Bul. 2011;58:A4303

63. Stephansson O, Kieler H, Haglund B, et al.Selective serotonin reuptake inhibitorsduring pregnancy and risk of stillbirthand infant mortality. JAMA. 2013;309(1):48–54

64. Kieviet N, Dolman KM, Honig A. The use ofpsychotropic medication during preg-nancy: how about the newborn? Neuro-psychiatr Dis Treat. 2013;9:1257–1266

65. Substance Abuse and Mental HealthServices Administration. Center for Be-havioral Health Statistics and Quality.Results from the 2012 National Survey onDrug Use and Health: summary of nationalfindings. Available at: www.samhsa.gov/data/NSDUH/2012SummNatFindDetTables/NationalFindings/NSDUHresults2012.pdf.Accessed January 14, 2014

66. United Nations Office on Drugs and Crime.Global smart update 2012. Volume 8.Available at: www.unodc.org/documents/scientific/Global_SMART_Update_8_E_web.pdf. Accessed January 24, 2014

67. Oei JL, Kingsbury A, Dhawan A, et al.Amphetamines, the pregnant woman andher children: a review. J Perinatol. 2012;32(10):737–747

68. Jones HE, Balster RL. Inhalant abuse inpregnancy. Obstet Gynecol Clin North Am.1998;25(1):153–167

69. Behnke M, Smith VC; Committee on Sub-stance Abuse and Committee on Fetus

and Newborn. Prenatal substance abuse:short- and long-term effects on the ex-posed fetus. Pediatrics. 2013;131(3).Available at: www.pediatrics.org/cgi/con-tent/full/131/3/e1009

70. Tenenbein M, Casiro OG, Seshia MM, DebooyVD. Neonatal withdrawal from maternalvolatile substance abuse. Arch Dis ChildFetal Neonatal Ed. 1996;74(3):F204–F207

71. Nanovskaya TN, Nekhayeva, Hankins GDV,Ahmed MS. Transfer of methadone acrossthe dually perfused preterm human pla-cental lobule. Am J Obstet Gynecol. 2008:198:126.e1–e4

72. Szeto HH. Kinetics of drug transfer to thefetus. Clin Obstet Gynecol. 1993;36(2):246–254

73. Malek A, Obrist C, Wenzinger S, von MandachU. The impact of cocaine and heroin on theplacental transfer of methadone. ReprodBiol Endocrinol. 2009;7:61

74. Scott CS, Riggs KW, Ling EW, et al. Morphinepharmacokinetics and pain assessment inpremature newborns. J Pediatr. 1999;135(4):423–429

75. Feng Y, He X, Yang Y, Chao D, Lazarus LH,Xia Y. Current research on opioid receptorfunction. Curr Drug Targets. 2012;13(2):230–246

76. Barr GA, McPhie-Lalmansingh A, Perez J,Riley M. Changing mechanisms of opiatetolerance and withdrawal during earlydevelopment: animal models of the hu-man experience. ILAR J. 2011;52:329–341

77. Rehni AK, Jaggi AS, Singh N. Opioid with-drawal syndrome: emerging concepts andnovel therapeutic targets. CNS NeurolDisord Drug Targets. 2013;12(1):112–125

78. Scavone JL, Sterling RC, Van BockstaeleEJ. Cannabinoid and opioid interactions:implications for opiate dependence andwithdrawal. Neuroscience. 2013;248:637–654

79. Little PJ, Price RR, Hinton RK, Kuhn CM.Role of noradrenergic hyperactivity inneonatal opiate abstinence. Drug AlcoholDepend. 1996;41(1):47–54

80. Spiga S, Puddu MC, Pisano M, Diana M.Morphine withdrawal-induced morpho-logical changes in the nucleus accumbens.Eur J Neurosci. 2005;22(9):2332–2340

81. Radke AK, Rothwell PE, Gewirtz JC. Ananatomical basis for opponent processmechanisms of opiate withdrawal. JNeurosci. 2011;31(20):7533–7539

82. Lutz PE, Kieffer BL. Opioid receptors: dis-tinct roles in mood disorders. TrendsNeurosci. 2013;36(3):195–206

83. Lauden J, Kerby LG. Opiate exposure andwithdrawal dynamically regulate mRNAexpression in the serotonergic dorsalraphe nucleus. Neuroscience. 2013;254:160–172

e558 KOCHERLAKOTA

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from

84. Capasso A, Gallo C. Molecules acting onCB1 receptor and their effects on mor-phine withdrawal in vitro. Open BiochemJ. 2009;3:78–84

85. Nunez C, Földes A, Laorden ML, MilanesMV, Kovács KJ. Activation of stress-relatedhypothalamic neuropeptide gene expres-sion during morphine withdrawal. J Neu-rochem. 2007;101(4):1060–1071

86. Pasero C, McCaffery M. Opioid-inducedhyperalgesia. J Perianesth Nurs. 2012;27(1):46–50

87. Juul SE, Beyer RP, Bammler TK, Farin FM,Gleason CA. Effects of neonatal stress andmorphine on murine hippocampal geneexpression. Pediatr Res. 2011;69(4):285–292

88. Doberczak TM, Kandall SR, Wilets I. Neo-natal opiate abstinence syndrome in termand preterm infants. J Pediatr. 1991;118(6):933–937

89. Anand KJS, Anderson BJ, Holford NHG,et al; NEOPAIN Trial Investigators Group.Morphine pharmacokinetics and pharma-codynamics in preterm and term neo-nates: secondary results from the NEOPAINtrial. Br J Anaesth. 2008;101(5):680–689

90. Dysart K, Hsieh HC, Kaltenbach K, GreenspanJS. Sequela of preterm versus term infantsborn to mothers on a methadone mainte-nance program: differential course of neo-natal abstinence syndrome. J Perinat Med.2007;35(4):344–346

91. Sanj EJ, De-las-Cuevas C, Kiuru A, Bate A,Edwards R. Selective serotonin inhibitorsin pregnant women and neonatal with-drawal syndrome: a database analysis.Lancet. 2005;365(9458):482–487

92. Chiu VM, Schenk JO. Mechanism of actionof methamphetamine within the cate-cholamine and serotonin areas of thecentral nervous system. Curr Drug AbuseRev. 2012;5(3):227–242

93. Gaalema DE, Scott TL, Heil SH, et al. Differ-ences in the profile of neonatal abstinencesyndrome signs in methadone- versusbuprenorphine-exposed neonates. Addic-tion. 2012;107(suppl 1):53–62

94. Herzlinger RA, Kandall SR, Vaughan HG Jr.Neonatal seizures associated with nar-cotic withdrawal. J Pediatr. 1977;91(4):638–641

95. Jansson LM, Dipietro JA, Elko A, Velez M.Infant autonomic functioning and neo-natal abstinence syndrome. Drug AlcoholDepend. 2010;109(1-3):198–204

96. Hudak ML, Tan RC; Committee on Drugs;Committee on Fetus and NewbornAmericanAcademy of Pediatrics Clinical Report.Neonatal drug withdrawal. Pediatrics. 2012;129(2). Available at: www.pediatrics.org/cgi/content/full/129/2/e540

97. Seligman NS, Salva N, Hayes EJ, Dysart KC,Pequignot EC, Baxter JK. Predicting lengthof treatment for neonatal abstinence syn-drome in methadone exposed neonates. AmJ Obstet Gynecol. 2008;199:396.e1–396.e7

98. Liu AJW, Jones MP, Murray H, Cook CM,Nanan R. Perinatal risk factors for theneonatal abstinence syndrome in infantsborn to women on methadone mainte-nance therapy. Aust N Z J Obstet Gynaecol.2010;50(3):253–258

99. Dryden C, Young D, Hepburn M, Mactier H.Maternal methadone use in pregnancy:factors associated with the developmentof neonatal abstinence syndrome andimplications for healthcare resources.BJOG. 2009;116(5):665–671

100. Sie SD, Wennink JM, van Driel JJ, et al.Maternal use of SSRIs, SNRIs and NaSSAs:practical recommendations during preg-nancy and lactation. Arch Dis Child FetalNeonatal Ed. 2012;97(6):F472–F476

101. Chomchai C, Manaboriboon B. Stimulantmethamphetamine and dextromethorphanuse among Thai adolescents: implicationsfor health of women and children. J MedToxicol. 2012;8(3):291–294

102. Gaalema DE, Heil SH, Badger GJ, MetayerJS, Johnston AM. Time to initiation oftreatment for neonatal abstinence syn-drome in neonates exposed in utero tobuprenorphine or methadone. Drug Alco-hol Depend. 2013;133(1):266–269

103. Oei J, Lui K. Management of the newborninfant affected by maternal opiates andother drugs of dependency. J PaediatrChild Health. 2007;43(1–2):9–18

104. Cleary BJ, Eogan M, O’Connell MP, et al.Methadone and perinatal outcomes:a prospective cohort study. Addiction.2012;107(8):1482–1492

105. Wachman EM, Hayes MJ, Brown MS, et al.Association of OPRM1 and COMT single-nucleotide polymorphisms with hospitallength of stay and treatment of neonatalabstinence syndrome. JAMA. 2013;309(17):1821–1827

106. Jansson LM, Di Pietro JA, Elko A, WilliamsEL, Milio L, Velez M. Pregnancies exposedto methadone, methadone and other illicitsubstances, and poly-drugs withoutmethadone: a comparison of fetal neuro-behaviors and infant outcomes. Drug Al-cohol Depend. 2012;122(3):213–219

107. Johnson K, Greenough A, Gerada C. Ma-ternal drug use and length of neonatalunit stay. Addiction. 2003;98(6):785–789

108. Dabek MT, Porschl J, Englert S, Ruef P.Treatment of neonatal abstinence syn-drome in preterm and term neonates. KlinPadiatr. 2013;225(5):252–256

109. Kaltenbach K, Holbrook AM, Coyle MG,et al. Predicting treatment for neonatalabstinence syndrome in infants born towomen maintained on opioid agonistmedication. Addiction. 2012;107(suppl 1):45–52

110. Irner TB, Teasdale TW, Nielsen T, Vedal S,Olofsson M. Substance use during preg-nancy and postnatal outcomes. J AddictDis. 2012;31(1):19–28

111. Pritham UA, Paul JA, Hayes MJ. Opioiddependency in pregnancy and length ofstay for neonatal abstinence syndrome. JObstet Gynecol Neonatal Nurs. 2102;41:180–190

112. O’Connor AB, O’Brien L, Alto WA. Are theregender related differences in neonatalabstinence syndrome following exposureto buprenorphine during pregnancy? JPerinat Med. 2013;41(5):621–623

113. Unger A, Jagsch R, Bäwert A, et al. Aremale neonates more vulnerable to neo-natal abstinence syndrome than femaleneonates? Gend Med. 2011;8(6):355–364

114. Jones HE, Heil SH, Tuten M, et al. Cigarettesmoking in opioid-dependent pregnantwomen: neonatal and maternal outcomes.Drug Alcohol Depend. 2013;131(3):271–277

115. Wachman EM, Newby PK, Vreeland J, et al.The relationship between maternal opioidagonists and psychiatric medications onlength of hospitalization for neonatal ab-stinence syndrome. J Addict Med. 2011;5(4):293–299

116. Cotten SW. Drug testing in the neonate.Clin Lab Med. 2012;32(3):449–466

117. Ostrea EM Jr, Knapp DK, Tannenbaum L,et al. Estimates of illicit drug use duringpregnancy by maternal interview, hairanalysis, and meconium analysis. JPediatr. 2001;138(3):344–348

118. Lozano J, García-Algar O, Vall O, de la TorreR, Scaravelli G, Pichini S. Biological ma-trices for the evaluation of in utero ex-posure to drugs of abuse. Ther DrugMonit. 2007;29(6):711–734

119. Gourlay DL, Heit HA, Caplan YH. Urine drugtesting in clinical practice: the art andscience of patient care. 5th ed. Baltimore,MD: Johns Hopkins University School ofMedicine; 2012

120. Cotten SW, Duncan DL, Burch EA, SeashoreCJ, Hammett-Stabler CA. Unexpected in-terference of baby wash products witha cannabinoid (THC) immunoassay. ClinBiochem. 2012;45(9):605–609

121. Wu AH, Gerona R, Armenian P, French D,Petrie M, Lynch KL. Role of liquidchromatography-high-resolution mass spec-trometry (LC-HR/MS) in clinical toxicology.Clin Toxicol (Phila). 2012;50(8):733–742

STATE-OF-THE-ART REVIEW ARTICLE

PEDIATRICS Volume 134, Number 2, August 2014 e559

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from

122. Kerrigan S, Mott A, Jatzlau B, et al. De-signer psychostimulants in urine by liquidchromatography-tandem mass spectrom-etry. J Forensic Sci. 2014;59(1):175–183

123. Ingall GB. Alcohol biomarkers. Clin LabMed. 2012;32(3):391–406

124. Murphy-Oikonen J, Montelpare WJ, SouthonS, Bertoldo L, Persichino N. Identifying in-fants at risk for neonatal abstinence syn-drome: a retrospective cohort comparisonstudy of 3 screening approaches. J PerinatNeonatal Nurs. 2010;24(4):366–372

125. Hytinantti T, Kahila H, Renlund M, JärvenpääAL, Halmesmäki E, Kivitie-Kallio S. Neonataloutcome of 58 infants exposed to maternalbuprenorphine in utero. Acta Paediatr.2008;97(8):1040–1044

126. Finnegan LP, Connaughton JF Jr, Kron RE,Emich JP. Neonatal abstinence syndrome:assessment and management. Addict Dis.1975;2(1–2):141–158

127. Mehta A, Forbes KD, Kuppala VS. Neonatalabstinence syndrome management fromprenatal counseling to a post dischargefollow-up care: results of a national sur-vey. Hosp Pediatr. 2013;3(4):317–323

128. Maguire D, Cline GJ, Parnell L, Tai CY. Val-idation of the Finnegan Neonatal Absti-nence Syndrome Tool-short form. AdvNeonatal Care. 2013;13(6):430–437

129. Zahorodny W, Rom C, Whitney W, et al. Theneonatal withdrawal inventory: a simpli-fied score of newborn withdrawal. J DevBehav Pediatr. 1998;19(2):89–93

130. Sarkar S, Donn SM. Management of neo-natal abstinence syndrome in neonatalintensive care units: a national survey.J Perinatol. 2006;26(1):15–17

131. van Sleuwen BE, Engelberts AC, Boere-Boonekamp MM, Kuis W, Schulpen TW,L’Hoir MP. Swaddling: a systematic review.Pediatrics. 2007;120(4). Available at: www.pediatrics.org/cgi/content/full/120/4/e1097

132. Caiola E. Swaddling young infants candecrease crying time. J Pediatr. 2007;150(3):320–321

133. D’Apolito K. Comparison of a rocking bedand standard bed for decreasing with-drawal symptoms in drug-exposed infants.MCN Am J Matern Child Nurs. 1999;24(3):138–144

134. American Academy of Pediatrics Commit-tee on Drugs. Neonatal drug withdrawal.Pediatrics. 1998;101(6):1079–1088

135. Filippelli AC, White LF, Spellman LW, et al.Non-insertive acupuncture and neonatalabstinence syndrome: a case series froman inner city safety net hospital. Glob AdvHealth Med. 2012;1(4):48–52

136. Hunseler C, Bruckle M, Roth B, Kribs A.Neonatal opiate withdrawal and rooming

in: a retrospective analysis of a singlecenter experience. Klin Padiatr. 2013;225(5):247–251

137. Hodgson ZG, Abrahams RR. A rooming-inprogram to mitigate the need to treat foropiate withdrawal in the newborn. JObstet Gynaecol Can. 2012;34(5):475–481

138. Kuschel C. Managing drug withdrawal inthe newborn infant. Semin Fetal NeonatalMed. 2007;12(2):127–133

139. Greig E, Ash A, Douiri A. Maternal andneonatal outcomes following methadonesubstitution during pregnancy. ArchGynecol Obstet. 2012;286(4):843–851

140. Finnegan L, Kaltenach K. Neonatal absti-nence syndrome. In: Hoekalman R, FriedmanS, Nelson N, Sidel H, eds. Primary PediatricCare. St Louis, MO: Mosby-Year Book; 1992:1367–1378

141. Kraft WK, van den Anker JN. Pharmaco-logic management of the opioid neonatalabstinence syndrome. Pediatr Clin NorthAm. 2012;59(5):1147–1165

142. Sublett J. Neonatal abstinence syndrome:therapeutic interventions. MCN Am JMatern Child Nurs. 2013;38(2):102–107,quiz 107–109

143. Grim K, Harrison TE, Wilder RT. Manage-ment of neonatal abstinence syndromefrom opioids. Clin Perinatol. 2013;40(3):509–524

144. Osborn DA, Jeffery HE, Cole MJ. Sedativesfor opiate withdrawal in newborn infants.Cochrane Database Syst Rev. 2010;(10):CD002053

145. O’Grady MJ, Hopewell J, White MJ. Man-agement of neonatal abstinence syn-drome: a national survey and review ofpractice. Arch Dis Child Fetal Neonatal Ed.2009;94(4):F249–F252

146. Jansson LM, Velez M, Harrow C. Theopioid-exposed newborn: assessment andpharmacologic management. J OpioidManag. 2009;5(1):47–55

147. Backes CH, Backes CR, Gardner D, NankervisCA, Giannone PJ, Cordero L. Neonatal absti-nence syndrome: transitioning methadone-treated infants from an inpatient to anoutpatient setting. J Perinatol. 2012;32(6):425–430

148. Sauberan J, Rossi S, Kim JH. Stability ofdilute oral morphine solution for neonatalabstinence syndrome. J Addict Med. 2013;7(2):113–115

149. Jackson L, Ting A, McKay S, Galea P, SkeochC. A randomised controlled trial of mor-phine versus phenobarbitone for neonatalabstinence syndrome. Arch Dis Child FetalNeonatal Ed. 2004;89(4):F300–F304

150. Bio LL, Siu A, Poon CY. Update on thepharmacologic management of neonatal

abstinence syndrome. J Perinatol. 2011;31(11):692–701

151. Kapur BM, Hutson JR, Chibber T, Luk A,Selby P. Methadone: a review of drug-drugand pathophysiological interactions. CritRev Clin Lab Sci. 2011;48(4):171–195

152. Kraft WK, Dysart K, Greenspan JS, GibsonE, Kaltenbach K, Ehrlich ME. Revised doseschema of sublingual buprenorphine inthe treatment of the neonatal opioid ab-stinence syndrome. Addiction. 2011;106(3):574–580

153. Leikin JB, Mackendrick WP, Maloney GE,et al. Use of clonidine in the preventionand management of neonatal abstinencesyndrome. Clin Toxicol (Phila). 2009;47(6):551–555

154. Esmaeili A, Keinhorst AK, Scuster T, BeskeF, Schosser R, Basanier C. Treatment ofneonatal abstinence syndrome with clo-nidine and chloral hydrate. Acta Paediatr.2010;99(2):209–214

155. Agthe AG, Kim GR, Mathias KB, et al. Clo-nidine as an adjunct therapy to opioidsfor neonatal abstinence syndrome: a ran-domized, controlled trial. Pediatrics. 2009;123(5). Available at: www.pediatrics.org/cgi/content/full/123/5/e849

156. American Academy of Pediatrics Commit-tee on Drugs. Transfer of drugs and otherchemicals into human milk. Pediatrics.2001;108(3):776–789

157. Sachs HC. Committee on Drugs. Thetransfer of drugs and therapeutics intohuman breast milk: an update on selectedtopics. Pediatrics. 2013;132(3): Available atwww.pediatrics.org/cgi/content/full/132/3/e796

158. Jansson LM, Choo R, Velez ML, et al.Methadone maintenance and breastfeed-ing in the neonatal period. Pediatrics.2008;121(1):106–114

159. McCarthy JJ, Posey BL. Methadone levelsin human milk. J Hum Lact. 2000;16(2):115–120

160. Ilett KF, Hackett LP, Gower S, Doherty DA,Hamilton D, Bartu AE. Estimated dose ex-posure of the neonate to buprenorphineand its metabolite norbuprenorphine viabreastmilk during maternal buprenorphinesubstitution treatment. Breastfeed Med.2012;7:269–274

161. ACOG Committee on Health Care for Un-derserved Women; American Society ofAddiction Medicine. ACOG Committee Opin-ion No. 524: Opioid abuse, dependence, andaddiction in pregnancy. Obstet Gynecol.2012;119(5):1070–1076

162. Jansson LM; Academy of BreastfeedingMedicine Protocol Committee. ABM clinicalprotocol #21: Guidelines for breastfeeding

e560 KOCHERLAKOTA

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from

and the drug-dependent woman. Breast-feed Med. 2009;4(4):225–228

163. O’Connor AB, Collett A, Alto WA, O’Brien LM.Breastfeeding rates and the relationshipbetween breastfeeding and neonatal ab-stinence syndrome in women maintainedon buprenorphine during pregnancy. JMidwifery Womens Health. 2013;58(4):383–388

164. Bogen DL, Perel JM, Helsel JC, Hanusa BH,Thompson M, Wisner KL. Estimated infantexposure to enantiomer-specific metha-done levels in breastmilk. BreastfeedMed. 2011;6(6):377–384

165. Lindemalm S, Nydert P, Svensson JO, StahleL, Sarman I. Transfer of buprenorphine intobreast milk and calculation of infant drugdose. J Hum Lact. 2009;25(2):199–205

166. Isemann B, Meinzen-Derr J, Akinbi H. Ma-ternal and neonatal factors impactingresponse to methadone therapy in infantstreated for neonatal abstinence syn-drome. J Perinatol. 2011;31(1):25–29

167. Sauberan JB, Anderson PO, Lane JR, et al.Breast milk hydrocodone and hydro-morphone levels in mothers usinghydrocodone for postpartum pain. ObstetGynecol. 2011;117(3):611–617

168. Seaton S, Reeves M, McLean S. Oxycodoneas a component of multimodal analgesiafor lactating mothers after Caesareansection: relationships between maternalplasma, breast milk and neonatal plasmalevels. Aust N Z J Obstet Gynaecol. 2007;47(3):181–185

169. Madadi P, Avard D, Koren G. Pharmacoge-netics of opioids for the treatment of acutematernal pain during pregnancy and lac-tation. Curr Drug Metab. 2012;13(6):721–727

170. Welle-Strand GK, Skurtveit S, Jansson LM,Bakstad B, Bjarkø L, Ravndal E. Breastfeeding

reduces the need for withdrawal treatmentin opioid-exposed infants. Acta Paediatr.2013;102(11):1060–1066

171. Abdel-Latif ME, Pinner J, Clews S, Cooke F,Lui K, Oei J. Effects of breast milk on theseverity and outcome of neonatal absti-nence syndrome among infants of drug-dependent mothers. Pediatrics. 2006;117(6). Available at: www.pediatrics.org/cgi/content/full/117/6/e1163

172. Wachman EM, Byrun J, Philip BL. Breastfeeding rates among mothers of infantswith neonatal abstinence syndrome. Paperpresented at Pediatric Academic SocietyMeeting; May 1–4, 2012; Boston, MA

173. Conradt E, Sheinkopf SJ, Lester BM, et al.Prenatal substance exposure: neurobio-logical organization at 1 month. J Pediatr.2013;163(4):989–994.ei

174. Hunt RW, Tzioumi D, Collins E, Jeffery HE.Adverse neurodevelopmental outcome ofinfants exposed to opiate in-utero. EarlyHum Dev. 2008;84(1):29–35

175. Lester BM, Lagasse LL. Children of addictedwomen. J Addict Dis. 2010;29(2):259–276

176. Mei B, Niu L, Cao B, Huang D, Zhou Y.Prenatal morphine exposure alters thelayer II/III pyramidal neurons morphologyin lateral secondary visual cortex of juve-nile rats. Synapse. 2009;63(12):1154–1161

177. Massa H, Lacoh CM, Vutskits L. Effects ofmorphine on the differentiation and sur-vival of developing pyramidal neuronsduring the brain growth spurt. Toxicol Sci.2012;130(1):168–179

178. Walhovd KB, Watts R, Amlien I, WoodwardLJ. Neural tract development of infantsborn to methadone-maintained mothers.Pediatr Neurol. 2012;47(1):1–6

179. Walhovd KB, Moe V, Slinning K, et al. Vol-umetric cerebral characteristics of chil-

dren exposed to opiates and othersubstances in utero. Neuroimage. 2007;36(4):1331–1344

180. Gentile S. Neurodevelopmental effects ofprenatal exposure to psychotropic medica-tions. Depress Anxiety. 2010;27(7):675–686

181. Hviid A, Melbye M, Pasternak B. Use ofselective serotonin reuptake inhibitorsduring pregnancy and risk of autism. NEngl J Med. 2013;369(25):2406–2415

182. Smith LM, LaGasse LL, Derauf C, et al.Motor and cognitive outcomes throughthree years of age in children exposed toprenatal methamphetamine. NeurotoxicolTeratol. 2011;33(1):176–184

183. Visconti K, Hennessy K, Towers C, HannessyM, Howard B. Opiate abuse/usage in preg-nancy and newborn head circumference.Am J Obstet Gynecol. 2013;208:S67–S68

184. Sundelin Wahlsten V, Sarman I. Neuro-behavioural development of preschool-agechildren born to addicted mothers givenopiate maintenance treatment withbuprenorphine during pregnancy. ActaPaediatr. 2013;102(5):544–549

185. Gill AC, Oei J, Lewis NL, Younan N, KennedyI, Lui K. Strabismus in infants of opiate-dependent mothers. Acta Paediatr. 2003;92(3):379–385

186. Spiteri Cornish K, Hrabovsky M, Scott NW,Myerscough E, Reddy AR. The short- andlong-term effects on the visual system ofchildren following exposure to maternalsubstance misuse in pregnancy. Am JOphthalmol. 2013;156(1):190–194

187. McGlone L, Hamilton R, McCulloch DL, et al.Neonatal visual evoked potentials ininfants born to mothers prescribedmethadone. Pediatrics. 2013;131(3). Avail-able at: www.pediatrics.org/cgi/content/full/131/3/e857

STATE-OF-THE-ART REVIEW ARTICLE

PEDIATRICS Volume 134, Number 2, August 2014 e561

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from

DOI: 10.1542/peds.2013-3524 originally published online July 28, 2014; 2014;134;e547Pediatrics 

Prabhakar KocherlakotaNeonatal Abstinence Syndrome

ServicesUpdated Information &

http://pediatrics.aappublications.org/content/134/2/e547including high resolution figures, can be found at:

Supplementary Material

013-3524.DCSupplementalhttp://pediatrics.aappublications.org/content/suppl/2014/07/23/peds.2Supplementary material can be found at:

References

1http://pediatrics.aappublications.org/content/134/2/e547.full#ref-list-This article cites 159 articles, 17 of which you can access for free at:

Permissions & Licensing

https://shop.aap.org/licensing-permissions/in its entirety can be found online at: Information about reproducing this article in parts (figures, tables) or

Reprintshttp://classic.pediatrics.aappublications.org/content/reprintsInformation about ordering reprints can be found online:

ISSN: . 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,has been published continuously since . Pediatrics is owned, published, and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from

DOI: 10.1542/peds.2013-3524 originally published online July 28, 2014; 2014;134;e547Pediatrics 

Prabhakar KocherlakotaNeonatal Abstinence Syndrome

http://pediatrics.aappublications.org/content/134/2/e547located on the World Wide Web at:

The online version of this article, along with updated information and services, is

ISSN: . 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,has been published continuously since . Pediatrics is owned, published, and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from