Managing drug withdrawal in the newborn infant

Transcription

1 Seminars in Fetal & Neonatal Medicine (2007) 12, 127e133 available at journal homepage: Managing drug withdrawal in the newborn infant Carl Kuschel* Auckland District Health Board, Private Bag , Auckland, New Zealand KEYWORDS Neonatal abstinence syndrome; Opioids; Substance use Summary The management of the infant exposed to drugs in utero poses significant challenges. Symptoms and signs of neonatal abstinence syndrome (NAS) are non-specific but most commonly associated with withdrawal from maternal opioids. A high index of suspicion is required when presented with an infant who could be manifesting symptoms of NAS. In the absence of a reliable history of maternal drug exposure, analysis of neonatal meconium or urine may be indicated. Approximately 90% of infants exposed to opioids will exhibit signs of NAS, although a smaller proportion will require pharmacological treatment. Although few studies have evaluated the advantages of different therapeutic agents and strategies, opioid withdrawal is best treated initially with opioid medication. Supportive care of the infant should include assessment of the adequacy of feeding, evaluation of social circumstances (particularly child protection issues) and surveillance for transmission of viral infection. ª 2007 Elsevier Ltd. All rights reserved. Introduction Neonatal drug withdrawal is a common problem in populations where there is ready availability to drugs taken for therapeutic, recreational or addiction purposes by pregnant women. The National Household Survey on Drug Abuse in the United States found that 6.4% of non-pregnant women of child-bearing age and 2.8% of pregnant women reported using illicit drugs. 1 A more recent study, primarily evaluating methamphetamine use in a non-selected population, reported that 10.7% of mothers had used illicit drugs during pregnancy. 2 The clinical picture of infants withdrawing from in-utero substance exposure has been termed neonatal abstinence syndrome (NAS). The assessment and management of NAS * Tel.: þ ; fax: þ address: carlk@adhb.govt.nz pose difficulties for staff and families, and have been hampered by a lack of prospective studies and by few research studies specifically assessing the merits of one management approach over another. Reports of the management of NAS have predominantly described experience with infants who have been exposed to opioids such as heroin, morphine and methadone. Therefore, the emphasis in this review will largely focus on opioids, and methadone in particular. Definition and assessment of the infant It is difficult to determine the incidence of NAS in newborn infants exposed to maternal drugs. The incidence and severity of withdrawal symptoms vary with the type of drug used, and polydrug use in pregnancy is common. 3e5 Undoubtedly, because of maternal under-reporting and the non-recognition of subtle neonatal symptoms, the incidence of NAS is higher than reported X/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved. doi: /j.siny

2 128 C. Kuschel The number of infants who display signs of NAS is difficult to predict from antenatal maternal demographic features. Maternal dose of methadone has been reported to have no relationship, 6e9 a positive relationship, or a negative relationship 14 to the incidence of severe NAS. Neonatal methadone levels might have a role in identifying infants most at risk of displaying NAS severe enough to require treatment 14 but do not negate a period of observation in the first few days after birth. There are no clear data to indicate that the route of maternal drug ingestiondoral versus intravenous versus inhalationald has any modifying effect on the presentation in infants. However, other pharmacokinetic properties, such as the half-life of the drug and the timing of use prior to delivery, can influence the severity and onset NAS. Infants exposed to methadone have delayed but more severe NAS than infants exposed to shorter-acting opioids such as heroin. 15,16 Infants whose mothers are using methadone for pain control rather than addiction may be less at risk of NAS. 17 In addition, symptoms in newborn infants are nonspecific. Perhaps the most widely used system of assessing the severity of NAS is the Finnegan scoring system, in both its original and modified forms. 18 The Finnegan scoring system assesses at regular intervals the symptoms and signs of withdrawal and grades severity with a weighted score (Table 1). 19 Despite the number of items that can be scored, it is nevertheless a relatively easy and reliable system to use once staff have been adequately trained. 19 However, there is potential for bias and subjectivity to affect the scores, and the thresholds for treatment reported in the literature vary. Infants have been reported to receive treatment at thresholds of a score greater than 7, 20 three scores more than 8, 4,21 a score above 9, 13 a score above 10, 4 or a score greater than The decision to commence treatment can depend on factors other than this score alone, including the reported exposure, the age of the infant, consideration of co-morbidities that might influence the score, whether an inpatient or outpatient strategy is used and the experience of the clinician making treatment decisions. Although the Finnegan score is in common use, other scoring tools have been used clinically. 22 The Lipsitz scoring system is used less widely but scores fewer items 23 ;itis Table 1 A modified Finnegan scoring system for assessment of neonatal abstinence syndrome (as used in the author s institution) System Signs and symptoms Score Date and time Central nervous system disturbances Metabolic, vasomotor, respiratory disturbances Gastrointestinal disturbances Consider treatment if scores are >8. High-pitched cry Continuous high-pitched cry Sleeps <1 h after feeding Sleeps <2 h after feeding Sleeps <3 h after feeding Mild tremors when disturbed Moderateesevere tremors when disturbed Mild tremorsdundisturbed Moderateesevere tremorsdundisturbed Increased muscle tone Excoriation (specify area) Myoclonic jerks Generalized convulsions Sweating Fever (37.5e38.3 C) Fever (38.4 C and higher) Frequent yawning (>3e4 times) Nasal stuffiness Sneezing (>3e4 times) Nasal flaring Respiratory rate >60/min Respiratory rate >60/min with retractions Excessive sucking Poor feeding Regurgitation Projectile vomiting Loose stools Watery stools Total score Scorer s initials

3 Managing drug withdrawal in the newborn infant 129 therefore less time consuming and more user friendly. Another tool used to assess the severity of NAS is the NICU Network Neurobehavioural Scale (NNNS), 24 which has a specific scale for neonatal stress/abstinence based on the Finnegan scoring system. However, the NNNS is not intended as a tool for determining treatment thresholds or the response to treatment. 25 Although scoring tools are designed to be objective, a degree of subjectivity is invariably introduced. This has led some researchers to evaluate physiological parameters in drug-exposed infants. Quantification of movement using an actigraph has demonstrated that infants undergoing NAS severe enough to require treatment have significantly more movement than unexposed infants or those already stable on treatment. 21 Prospective evaluation of the clinical applicability of this technique is still required to determine if it is useful in the assessment of NAS and whether it can define treatment thresholds. Accepting that there is a considerable body of literature on the neonatal effects of opioid exposure, it is also important to appreciate that other drugsdillicit or prescribedd can cause abnormal behaviour in infants. The scoring systems in current use have not been specifically validated for non-opioid drug exposure. Drugs reported to cause neonatal withdrawal syndromes include selective serotonin release inhibitors, 26,27 benzodiazepines, 28 cocaine, 29 barbiturates, 30 alcohol, 31 caffeine, 32 valproate 33 and solvents. 34 As many infants exhibiting signs of NAS have been exposed to more than one drug, it is frequently difficult to isolate symptoms to one particular compound. It is also important to consider that infants with signs and symptoms of NAS may have other conditions leading to abnormal behaviour. The non-specific nature of the clinical features of NAS mean that some drug-exposed infants may have exaggerated scores when they are hungry, or may have other conditions such as neonatal sepsis, hypoglycaemia, hypocalcaemia or hyperthyroidism. For that reason, it is important to assess the infant and consider if symptoms are solely due to NAS and whether other investigations are warranted. Detection of drug use The most reliable method of determining the extent of drug use in pregnancy is maternal history as part of routine antenatal assessment, with a structured interview providing a greater yield than an informal interview. 35 The role of routine toxicology assessment of drug-using women and their infants is debatable. Even in those women who admit to illicit substance use, under-reporting is common when compared with analysis of maternal hair 36 or neonatal meconium. 29,36,37 However, caregivers need to be mindful of potentially disrupting their relationship with the mother by requesting toxicology samples without clear reason to suspect ongoing and unreported illicit use. Neonatal samples have variable utility. Blood samples are of limited value as there is a narrow window of detection due to the rapid effects of metabolism and the low concentrations of drugs present in blood. 38 Urine samples are relatively easy to obtain, require minimal preparation (provided they are not contaminated by meconium or faeces), and can be analysed by a number of laboratory techniques. 38 Whereas urine samples generally contain a higher drug concentration than serum samples, the detection of compounds depends on obtaining an appropriate sample as close as possible to birth, and on the timing of maternal drug ingestion prior to delivery. Meconium analysis is currently considered the best method for detecting drug exposure in pregnancy. Although meconium is more complicated to analyse than urine (because it requires some preliminary processing to provide a sample suitable for analysis), various laboratory techniques can be used for drug detection. 38 Thus, meconium analysis is reliable for detecting opioid and cocaine exposure after the first trimester and can be used to detect a range of other illicit and prescribed medications. 39 Neonatal hair can also be used to detect antenatal drug exposure but this technique is limited by the procedures required to quantify the very small amounts of drug present. There can be difficulties in obtaining an adequate sample and recent exposure might not be detected, as hair growth is slow. 38 A recent report has suggested that detecting drug exposure from umbilical cord tissue has similar sensitivity and specificity to meconium samples, but has some advantages over collection of meconium. 40 Term and preterm infants Few comparative data have evaluated the symptoms and severity of NAS in term and preterm infants. Preterm infants exposed to methadone have been shown to exhibit later and less severe symptoms and are less likely to require treatment than term infants. 41 This is postulated to be due in part to the relative immaturity of the central nervous system, with a decreased ability to manifest signs that will score with the traditional assessment methods used. Although modulation of symptoms in preterm infants might also be due to a shorter duration of drug exposure, 65% of the preterm infants in this report were born between 34 and 36 weeks gestation and thus subjected to only a marginally shorter duration of drug exposure. Preterm infants exposed to cocaine and other drugs (predominantly alcohol, tobacco and cannabis) are reported to have more irritability. 3 Scoring in preterm infants needs to consider carefully whether the symptoms exhibited are due to the prematurity alone or to manifestations of drug withdrawal. It may be prudent to consider carefully symptomsdsuch as irritability, diarrhoea, sneezing and yawningdthat are more specific to NAS and to place less importance on symptoms such as respiratory distress, tremulous movements and poor feeding. Care of the newborn infant Between 30% 42 and 91% 20 of infants exhibiting signs of NAS will receive pharmacological treatment. Onset of symptoms is usually within the first 48e72 h, but can be delayedd particularly in breast-fed infantsdfor several days. 4 Withdrawal is delayed with exposure to barbiturates 30 and long-acting benzodiazepines. Not all infants with NAS will require pharmacological treatment, with many exhibiting

4 130 C. Kuschel only mild symptoms that can be controlled by nonpharmacological means. As infants can be difficult to settle and are easily overstimulated, strategies such as reducing the degree of ambient light exposure, minimizing excessive noise and avoiding unnecessary handling are frequently employed. Infants frequently require swaddling for settling, which can be intensive for caregivers. There is no clear evidence that tactile stimulation, such as a rocking bed, reduces the severity of symptoms. 43 Many pharmacological agents have been used to treat NAS. A recent survey in the USA showed that opioid medications are the most commonly used medications for the treatment of both opioid and polydrug withdrawal. 18 Diluted tincture of opium (DTO) is recommended by the American Academy of Pediatrics for the treatment of NAS due to opioid withdrawal. 44 Many neonatal units use proprietary oral or intravenous morphine solutions, and methadone is also employed. 18 Paregoric, which is a relatively impure compound containing opium, camphor and alcohol, was prominent in early reports of the treatment of NAS in opioid-exposed infants but is now rarely used. 22 Phenobarbitone is frequently used to treat NAS resulting from polydrug use and as a second-line agent for opioid withdrawal. 18 There is a paucity of controlled trial data supporting the efficacy of any one preparation or treatment regimen over another. Evidence is hampered by the methodological quality of the available published trials. 22,45,46 However, it is recommended that opioid withdrawal is best treated with opioids. 44,45,47 This recommendation is supported by a recent double-blind randomized trial of morphine versus phenobarbitone, in which infants treated with morphine had reduced admission to the neonatal unit, a shorter duration of treatment and reduced need for second-line agents. 48 Methadone is also a common first choice for the treatment of opioid withdrawal. 18 Although no randomized trials have specifically evaluated methadone against other opioid preparations, a retrospective report comparing outcomes of infants with NAS who were treated with either methadone or oral morphine did not demonstrate any significant differences in clinical outcomes. 49 Using a combination of treatment agents might also improve outcomes of NAS. Reports comparing a combination of DTO with phenobarbitone against DTO alone have demonstrated a significant reduction in hospital stay and cost of treatment, 20 and improvements in the symptoms of NAS. 50 However, the authors are careful to emphasize that only a small number of infants are included in the reported series and that larger studies addressing long-term follow-up are required. Of other sedatives used for the treatment of NAS, diazepam has a higher treatment failure rate than opioids and phenobarbitone. 45,46 Although there are reports of the use of clonidine and chlorpromazine for the treatment of NAS, 22 neither drug has been evaluated in any published randomized trials and it is recommended that ongoing use of these medications should be in the context of clinical trials only. 46 Naloxone for the treatment of depression at birth has been reported to lead to acute convulsions from NAS in infants with longstanding exposure to maternal opioids. There is insufficient literature to support the use of naloxone as a method of rapid detoxification in newborn infants. 44 Inpatient or outpatient strategies Practice varies regarding the inpatient or outpatient management of infants with NAS. Both strategies have their potential advantages. An inpatient strategy allows for relatively rapid detoxification of the infant and close monitoring of parental input in the care of the infant. Inpatient management usually results in detoxification within 3 weeks in the majority of infants. 14,48 Direct treatment costs are easily accounted for in an inpatient stay, parental interaction can be observed closely and support can be given to encourage parenting abilities. Whether an infant is cared for in the neonatal unit (predominantly by unit staff) or in a postnatal ward (with the mother primarily rooming-in with the baby and managing infant cares) will depend on local facilities and staff resources. Our (unpublished) experience is that infants who are almost exclusively cared for on the postnatal ward by their mother (if appropriate) have a much shorter detoxification period, and therefore a shorter hospitalization, than infants admitted to the newborn unit. This might be because those infants admitted to the NICU are a particularly high-risk group with polydrug use, significant social issues and less breastfeeding. However, a potentially influencing factor leading to a shorter detoxification period with postnatal ward placement is that the mother is primarily responsible for settling the infant, can feed on demand and might be more open to dose reductions than staff in the newborn unit. A policy of outpatient management also holds some potential advantages. After an initial phase of stabilization in the neonatal unit or postnatal ward, infants are discharged and followed in a multidisciplinary clinic. Whereas hospital stay is reduced compared to inpatient strategies, the duration of neonatal treatment is prolonged. 51 Extended contact with the family may be beneficial to assess parenting abilities, provide support and ensure infant well-being. Ongoing involvement over an extended period clearly has implications for resource utilization, although these might not be as easily quantified as with an inpatient stay. Interaction with parents Interaction with parents can be challenging for staff, who may feel uncomfortable with the lifestyle choices of the parents; equally, the parents might feel threatened by staff attitudes. Mothers can have feelings of guilt, particularly if their infant has moderate or severe withdrawal, and parents are often concerned that the infant s case will be taken-up by local child protection services. It is not uncommon for extended family who are visiting to be unaware of parental drug use (and therefore the reason why the infant is remaining in hospital), and this can also create difficulties for both parents and staff. A prolonged hospitalization can expose parents to financial or other social pressures that interfere with their ability to interact positively with each other and with staff. It is particularly important for staff to treat parents in a non-judgemental manner. Staff are more likely to have

5 Managing drug withdrawal in the newborn infant 131 a positive experience with families and gain useful information if they show respect for the individuals, even though drug use itself cannot be condoned. Consistent approaches by experienced staff, particularly around assessments and treatment decisions, are invaluable. The involvement of social workers or support services should be mandatory, not least to determine if appropriate supports are in place for families and that child protection risks have been evaluated. 13 Other neonatal issues Poor feeding is a common early feature in infants with NAS. Infants often have excessive sucking behaviour yet, conversely, poor milk intake and regurgitation. Symptoms of hunger can artificially elevate NAS scores to treatment thresholds. It is therefore important to ensure that infants are adequately fed, which may necessitate temporary gastric tube feeding. Some infants display excessive weight loss from a combination of poor intake, diarrhoea and increased metabolic demand due to hyperactivity. Some infants, particularly once they have recovered from early symptoms of NAS, will voluntarily consume large quantities of feeds without apparent adverse gastrointestinal effects. 5,52 Breastfeeding is rarely contraindicated, unless there is ongoing use of drugs such as heroin, cocaine or amphetamines, 53 or if the mother is HIV positive. The earlier stance of the American Academy of Pediatricsdadvising against breastfeeding with methadone doses greater than 20 mg/daydhas been relaxed and methadone is now considered compatible with breastfeeding. 53 Indeed, breastfeeding is associated with a reduced severity of NAS and reduced need for treatment. 4 Although it seems unlikely that there is sufficient transfer of methadone into breast milk such that breastfeeding alone will prevent treatment of NAS, some infants can experience NAS with sudden cessation of breastfeeding. 54 Transmission of viral infectious diseases is also relevant to the neonate. Whereas the prevalence of antihepatitis C virus (HCV) antibodies in pregnant women is estimated to be approximately 1%, 55 reports have indicated that a majority of women receiving methadone maintenance treatment test positive for anti-hcv antibodies. 4,14,51,56 The risk of HCV transmission to the infant is approximately 10% in HCV RNA positive mothers, but is halved in women who are only antibody positive. It is important to consider appropriate follow-up and referral if there is persistence of anti-hcv antibodies in the infant after 18 months of age. 55 Breast feeding is not contra-indicated solely because of maternal anti-hcv antibodies. Sudden infant death syndrome (SIDS) is reportedly more common in infants exposed to opioids in pregnancy. 57 Mothers should be encouraged to breastfeed and reduce modifiable risk factors, such as smoking. Caregivers should be educated about other preventive measures, such as sleep position and appropriate bedding. 57 In some infants, particularly very preterm infants or those with a previous sibling with SIDS, home monitoring may be considered for parental reassurance. Practice points Neonatal abstinence syndrome requiring treatment occurs in up to 90% of infants who are exposed to opioids. Withdrawal syndromes are less common with other drug use. Laboratory analysis of meconium provides the best opportunity to detect fetal drug exposure, with high sensitivity. However, routine analysis of meconium needs to be balanced with information gained from the mother and the relationship of trust developed during pregnancy. Management of the infant not only involves considering pharmacological treatment of the infant but also should incorporate assessment of parenting abilities, social supports and surveillance for transmission of viral infection. Research directions Prospective studies of cohorts of infants exposed to maternal drugs should be encouraged, particularly those studies evaluating long-term outcomes. There is a need for adequately powered and welldesigned trials evaluating different treatment preparations and regimens. References 1. Ebrahim SH, Gfroerer J. Pregnancy-related substance use in the United States during 1996e1998. Obstet Gynecol 2003; 101(2):374e9. 2. Arria AM, Derauf C, Lagasse LL, Grant P, Shah R, Smith L, et al. Methamphetamine and other substance use during pregnancy: preliminary estimates from the Infant Development, Environment, and Lifestyle (IDEAL) study. Matern Child Health J 2006;10(3):293e Brown JV, Bakeman R, Coles CD, Sexson WR, Demi AS. Maternal drug use during pregnancy: are preterm and full-term infants affected differently? Dev Psychol 1998;34(3):540e Abdel-Latif ME, Pinner J, Clews S, Cooke F, Lui K, Oei J. Effects of breast milk on the severity and outcome of neonatal abstinence syndrome among infants of drug-dependent mothers. Pediatrics 2006;117(6):e1163e9. 5. Martinez A, Kastner B, Taeusch HW. Hyperphagia in neonates withdrawing from methadone. Arch Dis Child Fetal Neonatal Ed 1999;80(3):F178e McCarthy J, Leamon MH, Parr MS, Anania B. High-dose methadone maintenance in pregnancy: maternal and neonatal outcomes. Am J Obstet Gynecol 2005;193(3 Pt 1):606e Rosen TS, Pippenger CE. Pharmacologic observations on the neonatal withdrawal syndrome. J Pediatr 1976;88(6):1044e8. 8. Mack G, Thomas D, Giles W, Buchanan N. Methadone levels and neonatal withdrawal. J Paediatr Child Health 1991;27(2): 96e100.

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7 Managing drug withdrawal in the newborn infant Lainwala S, Brown ER, Weinschenk NP, Blackwell MT, Hagadorn JI. A retrospective study of length of hospital stay in infants treated for neonatal abstinence syndrome with methadone versus oral morphine preparations. Adv Neonatal Care 2005;5(5):265e Coyle MG, Ferguson A, LaGasse L, Lui J, Lester B. Neurobehavioral effects of treatment for opiate withdrawal. Arch Dis Child Fetal Neonatal Ed 2005;90:73e Oei J, Feller JM, Lui K. Coordinated outpatient care of the narcotic-dependent infant. J Paediatr Child Health 2001;37(3): 266e Shephard R, Greenough A, Johnson K, Gerada C. Hyperphagia, weight gain and neonatal drug withdrawal. Acta Paediatr 2002; 91(9):951e American Academy of Pediatrics, Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108(3):776e Malpas TJ, Darlow BA. Neonatal abstinence syndrome following abrupt cessation of breastfeeding. N Z Med J 1999;112(1080): 12e Slowik MK, Jhaveri R. Hepatitis B and C viruses in infants and young children. Semin Pediatr Infect Dis 2005;16(4):296e Kashiwagi M, Arlettaz R, Lauper U, Zimmermann R, Hebisch G. Methadone maintenance program in a Swiss perinatal center: (I). Management and outcome of 89 pregnancies. Acta Obstet Gynecol Scand 2005;84(2):140e Hunt CE, Hauck FR. Sudden infant death syndrome. CMAJ 2006; 174(13):1861e9.