Neonatal withdrawal syndrome, generically termed neonatal abstinence syndrome (NAS), is a complex disorder. It is defined as a constellation of behavioral and physiological signs and symptoms that are remarkably similar despite marked differences in the properties of the causative agent. Two major types of neonatal abstinence syndrome are recognized: neonatal abstinence syndrome due to prenatal or maternal use of substances that result in withdrawal symptoms in the newborn and postnatal neonatal abstinence syndrome secondary to discontinuation of medications such as fentanyl or morphine used for pain therapy in the newborn.
Postnatal neonatal abstinence syndrome results when an abrupt discontinuation of opioid analgesia occurs, usually after prolonged drug exposure. Fentanyl is the most commonly used analgesic drug in the neonatal intensive care unit (NICU). It is a potent, rapid-acting, synthetic opioid with a relative lack of hemodynamic side effects. Clinical studies have found that continuous infusions of fentanyl and morphine produce a high rate of opioid withdrawal when administered to critically ill infants. Tolerance and physical dependence are thought to develop more rapidly with shorter acting drugs and after continuous infusions rather than with intermittent administration. Tolerance and withdrawal symptoms may occur after 5 or more days of continuous infusion of fentanyl. This occurs more often with fentanyl than morphine.[1, 2] This article focuses on prenatal or maternal use of illicit drugs, although symptoms and therapy for postnatal neonatal abstinence syndrome are similar.
Maternal substance abuse, the cause of prenatal neonatal abstinence syndrome, is a leading preventable cause of mental, physical, and psychological problems in infants and children. Substance use by pregnant women has both medical and developmental consequences for the newborn, in addition to the legal, health, and economic consequences for the mother.
Drug abuse in pregnancy and neonatal psychomotor behavior consistent with withdrawal from opiate and polydrug withdrawal is currently a significant clinical and social problem. Approximately 3% of the 4.1 million women of child-bearing age who abuse drugs are believed to continue drug use during pregnancy.
Drugs frequently associated with neonatal problems include the following:
- Opiates and narcotics
- Meperidine (Demerol)
- Hydromorphone (Dilaudid)
- Butorphanol (Stadol)
- Propoxyphene (Darvon)
- Other drugs
- Selective serotonin reuptake inhibitors (SSRIs)
- Antihistaminics (Diphenhydramine, Hydroxyzine)
- Diazepam and lorazepam
Most illicit drugs cause an addiction in both the mother and the infant. Addiction or tolerance in the latter is due to passage of the drugs across the placental barrier; this occurs in varying degrees, depending on the pharmacokinetic properties of the individual drugs. Substances that act on the CNS are usually highly lipophilic and have relatively low molecular weight. These characteristics facilitate crossing from maternal to fetal circulation, with rapid equilibration of free drug between mother and fetus. Once drugs cross the placenta, they tend to accumulate in the fetus because of the immaturity of the renal function and the enzymes used for metabolism. Disruption of the transplacental passage of drugs at birth results in the development of a withdrawal syndrome.Neonatal abstinence syndrome is often a multisystem disorder that frequently involves the CNS, GI system, autonomic system, and respiratory system. Manifestations of neonatal abstinence syndrome depend on various factors, including the drug used, its dose, frequency of use, and the infant's own metabolism and excretion of the active compound or compounds. In addition, prenatal neonatal abstinence syndrome depends on the infant's last intrauterine drug exposure and the mother's drug metabolism and excretion. Withdrawal is generally a function of the drug's half-life; the longer the half-life, the later the onset of withdrawal. A longer half-life is also associated with a decreased likelihood of neonatal abstinence syndrome in the infant.Opiates produce the most dramatic effects on both the mother and fetus. Aside from the withdrawal symptoms, common findings in infants exposed to opiates include low birth weight, prematurity, and intrauterine growth retardation (IUGR). Because of its short half-life, heroin withdrawal may start as early as 24 hours after birth and usually peaks within 48-72 hours in 50-80% of infants born to mothers who are dependent on heroin. Some delayed withdrawal may occur as long as 6 days after birth. Sedative-hypnotics such as benzodiazepines and barbiturates have an even longer half-life, and withdrawal may not start until after the infant has been discharged from hospital (age 2 wk).Methadone maintenance has been an acceptable form of therapy for opiate-addicted pregnant women since the late 1960s. Methadone has been shown to decrease illicit behaviors, improve prenatal care and obstetric outcomes, and prevent acute maternal withdrawal that is associated with fetal death.However, maternal methadone use is also associated with neonatal abstinence syndrome, and its effects on the fetus are similar to the effects of heroin. Methadone's half-life is longer than 24 hours, and acute withdrawal may occur within the first 48 hours after birth and as long as 7-14 days later. The withdrawal may even be delayed for as long as 4 weeks after birth, with subacute signs developing as long as 6 months after birth. Neonates face an increased risk of fetal distress and demise, impaired fetal growth, and an increased risk of sudden infant death syndrome (SIDS). Thrombocytosis may occur in the second week of life and may continue until age 4 months.The relationship between maternal methadone dosage and neonatal abstinence syndrome is controversial, and the available data are conflicting. However, articles have showed that higher maternal doses are associated with an increase in the risk of preterm birth, the risk of symmetrically smaller infants, and longer hospital stays; the need for treatment for neonatal abstinence syndrome indicates more significant withdrawal symptoms.[6, 5, 7]Cocaine and amphetamines are stimulants with potent vasoconstrictor effects that stimulate the release and block the reuptake of the neurotransmitters dopamine, epinephrine, norepinephrine, and serotonin. Cocaine is a potent CNS stimulant that alters the major neurotransmitters and rapidly crosses the placenta. Early studies suggested that neonates exposed to cocaine exhibited a hyperactive Moro reflex, jitteriness, and excessive sucking. More recent studies do not support that neonates who have been exposed to cocaine differ behaviorally from unexposed infants. The unresolved question is whether or not cocaine acts to limit head growth or disrupt brain development. A synergistic effect between cocaine and other CNS toxins is still possible.Methylxanthine accumulates in the blood of breastfed infants whose mothers regularly consume caffeine substances. Nicotine is transferred through the placenta and may reach concentrations 15% higher than maternal levels. In utero exposure impairs neonatal habituation, orientation, autonomic regulation, and orientation to sound. Exposure also affects the infant's ability to be comforted and is associated with exaggerated startle reflex and tremor.No evidence suggests neonatal withdrawal problems associated with maternal use of marijuana during pregnancy. Fetal exposure to marijuana has been associated with hypoglycemia, hypocalcemia, sepsis, hypoxic encephalopathy, intracranial hemorrhage, and jitteriness. Effects on the fetus depend on the dose, with evidence of IUGR noted in cases of heavier usage.Neonates exposed to marijuana while in utero may also exhibit signs of nicotine toxicity, such as tachycardia, poor perfusion, irritability, and poor feeding. Growth inhibition is pronounced at birth and affects weight, length, and head circumference. Catch-up growth occurs within the first year in each growth category. Cognitive effects may persist to school age. However, withdrawal symptoms are generally not noted in infants in the newborn period. Extended follow-up does not show any effect in children aged 5-6 years.Several studies have demonstrated that maternal cigarette smoking during pregnancy increases the risk of having a low birth weight infant. Neonates born to mothers who smoke during pregnancy weigh an average of 150-250 g less at birth than neonates born to mothers who do not smoke during pregnancy. Research findings also suggest that infants of mothers who smoke during pregnancy may develop nicotine withdrawal in a pattern that is related to the magnitude of in utero exposure. Infants who have been exposed to tobacco have been found to be more excitable and hypertonic and demonstrate more stress and abstinence signs.Neonates who are exposed to antidepressant medications during gestation are at increased risk of neonatal abstinence syndrome. SSRIs (eg, fluoxetine, paroxetine, sertraline, citalopram) are used to treat depression and a wide spectrum of other mood and behavioral disorders. Infants exposed to SSRIs during the last trimester of pregnancy may exhibit neonatal adaptation syndrome. This is primarily manifested as CNS (eg, irritability), motor (eg, agitation, tremors), respiratory (eg, increased respiratory rate, nasal congestion), and GI signs (eg, emesis, diarrhea). These manifestations are self-limiting and usually disappear by age 2 weeks. Symptoms are more commonly reported with fluoxetine and paroxetine exposure.A prospective study showed no statistically significant differences between tricyclic antidepressants and SSRIs. It also revealed that women using antidepressants often use other medications as well during pregnancy, making the interpretation of antidepressant withdrawal symptoms difficult. A decrease in maternal SSRI and tricyclic antidepressant use during the third trimester may lower the neonatal risk of developing withdrawal syndrome; however, this needs to be balanced against the harmful effects of depression during pregnancy.EPIDEMIOLOGY
United StatesNeonatal drug withdrawal is a common problem in populations in which drugs taken for therapeutic, recreational, or addiction purposes are readily available to pregnant women. However, the incidence is difficult to determine because of unreliable histories of maternal drug abuse and limited health provider skills in eliciting drug histories and diagnosing nonopiate drug exposure in the newborn period. In addition, maternal use of more than one drug makes ascribing a given effect on the neonate to a specific drug difficult.In the United States, substance use among pregnant and postpartum women is a public health issue. In 2002-2003, the National Survey on Drug Use and Health (NSDUH) in the United States found that 4.3% of pregnant women aged 15-44 years reported using illicit drugs, compared with 10.4% of nonpregnant women in this age group. The rate of illicit drug use among pregnant women aged 15-25 years was 8%. The rate for nonpregnant women of the same age was 16.8%. A later report , primarily evaluating methamphetamine use in a nonselected population, reported that 10.7% of mothers had used illicit drugs during pregnancy.A more recent NSDUH report examined past month use of alcohol, cigarettes, and marijuana among pregnant and parenting women aged 18-44. Combined 2002-2007 data showed that past-month alcohol use among women aged 18-44 was highest for those who were not pregnant and who did not have children living in the household (63%). The rate was comparatively low for those in the first trimester of pregnancy (19%) and even lower for those in the second (7.8%) or third (6.2%) trimester. Similar patterns were noted across these 4 subgroups of women for past-month binge alcohol use, cigarette use, and marijuana use.Data from the 2009 NSDUH report provide indirect evidence of dramatic increases in the prevalence of substance use following childbirth. Marijuana use was higher for recent mothers with children younger than 3 months in the household (3.8%) than for women in the third trimester of pregnancy (1.4%), suggesting resumption of use among mothers in the first 3 months after childbirth.Overall the incidence of drug-exposed newborns is reportedly 3-50%, depending on the specific patient population, with urban centers usually reporting higher rates. An estimated 10–11% of the 4.1 million live births (in 2005) involved prenatal exposure to alcohol or illegal drugs. When tobacco data are included more than one million children are affected by prenatal exposure. Among offspring exposed to opioids or heroin in utero, withdrawal signs develop in 55-94%.
InternationalNo accurate data are available concerning worldwide incidence. Data from the UK Advisory Council on the Misuse of Drugs suggests 6,000 babies are born to mothers who abuse drugs each year (1% of all UK deliveries).[11, 12] In the past, heroin was the most commonly abused drug. Women are now more likely to use cocaine, methadone, or more than one illicit drug.In Europe, each year as many as 30,000 pregnant women use opioids, and the number of pregnant women using drugs other than opioids may be equally as high.
Mortality/MorbidityDeath is rarely associated with withdrawal alone but occurs as a consequence of prematurity, infection, and severe perinatal asphyxia.Long-term mortality rate is likely to be extremely low, although the risk for SIDS is significantly higher among infants who are exposed to opiates. Infants exposed to methadone have a 3.7-fold higher risk of SIDS compared with controls. Infants exposed to cocaine have a 2.3-fold higher risk for SIDS compared with infants with no exposure. This increased risk is related to a complex interplay of factors; the compromised home environment associated with a mother who is drug addicted is an important variable.
RacePregnant white women and Hispanic women had lower rates of illicit drug use (4.4% and 3%, respectively) than black women (8%). Among women aged 15-44 years, the rate of cigarette use is higher among pregnant white women than among pregnant black or pregnant Hispanic women.
AgeRates of substance use among pregnant women vary by age group, with past-month illicit drug and alcohol use highest among teenagers. Pregnant women aged 15-25 years (8%) are more likely to use illicit drugs than pregnant women aged 26-44 years (1.6%). The NSDUH report on 2003-2004 annual averages of substance use by pregnant women showed that 16% of pregnant teens aged 15-17 years reported past month illicit drug use compared with 7.8% of those aged 18-25 years and 2.1% of pregnant women aged 26-44 years.
HISTORYWhen assessing potential neonatal abstinence syndrome (NAS), 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.The amount of information obtained from the mother about prenatal drug exposure widely varies and may not be reliable. How the mother is questioned and the specificity of the questions are the most important factors. Maternal interviews have been reported to be the least sensitive method of identifying drug use in pregnancy when compared with maternal hair and meconium drug testing. Maternal self-report was found to underestimate in utero drug exposure by as much as 44% when compared with data from meconium analyses.Despite concerted efforts by health care professionals to promote prenatal care, the mother may not have received such care and the delivery hospitalization may be the only opportunity to elicit information on the nature and extent of the infant's in utero exposure to drugs and alcohol. The mother's concern for her infant's health may encourage valid responses; conversely, fear of legal reprisals or loss of custody of the infant may cause the mother to deny drug use.The Committee on Substance Abuse of the American Academy of Pediatrics recommends obtaining a comprehensive medical and psychological history that includes specific information regarding maternal drug use as part of every newborn evaluation.The relationship between maternal cocaine use and placental abruption is well established. Therefore, a perinatal history of abruption should alert the medical caretaker that prenatal exposure to cocaine is a possibility.
PHYSICALA thorough physical examination of the neonate should include accurate assessment of weight, length, and head circumference and a standardized assessment of gestational age. Special attention should be paid to signs of intrauterine growth retardation (IUGR), microcephaly, prematurity, congenital infection, and major and minor congenital malformations.Infants are suspected of having neonatal abstinence syndrome if they exhibit any of the following signs:
The timing of onset of the symptoms gives an indication of the maternal drug abuse. Withdrawal from high levels of maternal alcohol can occur within a day or 2 of birth. Heroin has a short half-life and withdrawal also occurs within 48–72 h of birth, whereas methadone withdrawal occurs at 7–14 days.Different scoring systems have been developed for assessing the severity of neonatal abstinence syndrome, such as those by Finnegan, Ostrea, Lipsitz, Rivers, and the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS).[17, 18, 19] These are based on opiate withdrawal and may not be entirely appropriate for the infant exposed to cocaine or other drugs.The most widely used system is the Finnegan scoring system, in both its original and modified forms. A neonatal abstinence syndrome scoring form is shown below.Neonatal abstinence syndrome scoring form.The Finnegan scale assesses 21 of the most common signs of neonatal drug withdrawal syndrome and is scored on the basis of pathological significance and severity of the adverse symptoms, which sometimes requires pharmacological treatment. 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. However, the potential for bias and subjectivity may affect the scores, and the thresholds for treatment reported in the literature vary. This scale can also be used to assess the resolution of signs and symptoms after initiating treatment.To obtain a daily average score, measurements are performed every 4 hours until the patient is stable. If 3 consecutive scores are equal to or greater than 8, treatment for withdrawal is started. 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 comorbidities that might influence the score, whether an inpatient or outpatient strategy is used, and the experience of the clinician making treatment decisions.The infant is best cared for in a unit with experienced personnel who can recognize problems, perform constant evaluations, and institute the necessary interventions.
- CNS dysfunction
- High-pitched cry
- Restlessness, with sleep duration less than 1-3 hours after feeding
- Hyperactive reflexes
- Myoclonic jerks
- Generalized convulsions
- Metabolic, vasomotor, and respiratory disturbances
- Frequent yawning
- Sneezing (>3 times per interval)
- Nasal flaring
- Respiratory rate greater than 60 breaths per minute without retractions
- GI dysfunction
- Excessive (frantic) sucking or rooting
- Poor feeding
- Hyperphagia, usually associated with poor weight gain
- Regurgitation or projectile vomiting
- Loose or watery stools
- Alcohol-specific symptoms
- Withdrawal that presents within the first 24 hours of life is reported among infants with the dysmorphic features of fetal alcohol syndrome.
- Neonates also exhibit irritability, tremors, seizures, opisthotonus, and abdominal distention.
- Lysergic acid (LSD) symptoms
- The effect of LSD on the fetus is clouded by the high incidence of polydrug abuse.
- Withdrawal symptoms manifest as hypertonia, tremors, poor feeding, and abnormal feeding patterns.
- Other symptoms
- Nicotine may produce withdrawal symptoms in infants, including increased excitability and hypertonicity.
- Caffeine withdrawal includes feeding difficulties, vomiting, excessive crying, irritability, and poor sleep patterns. Onset of symptoms may occur as long as 5 days after birth and persist for weeks or months.
CAUSESCurrent resurgence in heroin use is associated with the introduction of a cheap, smokeable form that is comparable to crack cocaine, only more potent. Cocaine's current popularity is related to increased availability and the presence of newer, cheaper forms.Depression is common in reproductive age women, and continued pharmacologic treatment of depression during pregnancy may be necessary to prevent relapse. Neonates who are exposed to antidepressant medications during gestation are at increased risk to have neonatal abstinence syndrome.
LABORATORY STUDIESHealth care professionals, hospitals, and clinics have an obligation to assess newborns who exhibit signs and symptoms of drug exposure, whose mothers have been identified as probable substance users, or whose mothers have signs and symptoms of drug use.Clear evidence suggests that recognizing the substance exposed infant and implementing early intervention services for the child and mother are keys to minimizing the acute and long-term effects of prenatal substance exposure. Thus, even if the infant exhibits no clinically significant difficulties in the neonatal period, identification of the substance exposed infant can improve the long-term outcome.Specific clinical conditions for which urine or meconium toxicology testing is indicated are noted. Commonly accepted indications for toxicology analysis include no prenatal care, intrauterine growth retardation (IUGR), preterm delivery, abruptio placentae, or cardiovascular accidents in mother or child, especially in those cases in which no other reasons for poor outcome are noted.The following studies may be necessary to prevent or diagnose cases of neonatal abstinence syndrome (NAS):
- Radioimmunoassay and enzyme immunoassay
- These are the most commonly used drug screens. Both are semiquantitative and highly sensitive, but enzyme immunoassay takes less time to perform and is less expensive.
- These tests inform the clinician about the presence or absence of substance abuse, rather than quantifying the drug level, as in toxicology screens.
- Blood tests: The usefulness of neonatal blood samples varies. Blood samples are of limited value because the window of detection is narrow because of the rapid effects of metabolism and the low concentrations of drugs present in blood.
- Urine toxicology assays
- Urine was traditionally the specimen of choice for neonatal drug testing, although collection is difficult. The adhesive for the collection bag causes skin irritation and frequently fails to adhere. Another disadvantage is the short detection window; urine provides maternal drug use data only for a few days prior to delivery.
- Urine toxicology screening is useful for clinical and research purposes. Urinary excretion of metabolites may be detectable only for a few days (eg, benzoylecgonine) to a few weeks (eg, cannabinoids). One cannot expect to ascertain early pregnancy use or even relatively recent use if the metabolite concentration does not reach the detection threshold.
- Urine is relatively easy to obtain, requires minimal preparation (provided samples are not contaminated by meconium or feces), and can be analyzed using numerous laboratory techniques. Although 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 also depends on the timing of maternal drug ingestion prior to delivery.
- These tests detect recent use of cocaine and its metabolites, amphetamines, marijuana, barbiturates, and opiates. Cocaine can be detected in urine 6-8 hours after use in the mother and as long as 48-72 hours after use in the newborn.
- Detection of drugs depends on many variables, including individual drug metabolism, hydration status of the subject, route of administration, and frequency of ingestion.
- No drugs are known to crossreact with the immunoassays for cocaine and marijuana. Several over-the-counter remedies and herbal preparations may contain ephedrine and phenylpropanolamine (recalled from US market), which can produce false-positive enzyme immunoassay test results for amphetamines. Therefore, confirmatory testing is required.
- Immunoassay for opiates does not distinguish between codeine, morphine, or their glucuronide conjugates.
- Meconium analysis
- Meconium analysis is currently considered the best method for detecting drug exposure in pregnancy. It provides a wider window of detection of gestational exposure, presumably as remote as the second trimester, when drugs begin to accumulate in meconium (by direct deposition from the biliary tree or when the fetus ingests amniotic fluid).
- 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.
- Meconium can be contaminated by infant urine, although only cocaine or opiate use within approximately 72 hours of birth is reflected.
- False positive results occur if meconium is contaminated with urine, reflecting antepartum and perinatal exposure. Theoretically, lidocaine can cause a positive result, but a large amount is required.
- When a meconium sample is stored at room temperature, it decreases cocaine and cannabinoid levels by 25% per day.
- Hair analysis
- Neonatal hair testing can also identify prenatal drug exposure. Hair begins to form at approximately 6 months' gestation; a positive result indicates use during the last trimester. Hair testing is advantageous because the specimen can be collected at any point during the first 3 months of life, after which time infant hair replaces neonatal hair.
- This method is useful in detecting narcotics, marijuana, cocaine, and cocaine-alcohol metabolites, but the technique is expensive, is not widely available, and is limited by the procedures required to quantify the very small amounts of drug present. Obtaining an adequate sample may be difficult, and recent exposure might not be detected because hair growth is slow.
- Analysis of 1.5 cm of maternal hair reveals the maternal drug use pattern during the previous 3 months. Drug metabolites can be detected in infant hair for 2-3 months after birth
IMAGING STUDIESCranial ultrasonography is not routinely recommended, but literature is suggestive of CNS abnormalities, including hemorrhagic ischemic lesions in some drug-exposed infants.Evidence is insufficient to support a mandate for cranial ultrasonography in all cocaine-exposed infants. Smit et al studied 154 neonates exposed to cocaine in utero and found that none of the infants had severe abnormalities on cranial ultrasonography. Also, the detected abnormalities were not correlated with the duration or maximum amount of cocaine use. Given these findings, they recommended that routine cranial ultrasonography in this population is not warranted. However, special consideration should be given to specific neuroimaging of cocaine-exposed preterm infants, infants whose head circumference falls below the 10th percentile on standardized fetal growth curves, and infants with abnormal neurologic signs, neurobehavioral dysfunction, or seizure activity.
OTHER TESTA recent report has suggested that detecting drug exposure from umbilical cord tissue has similar sensitivity and specificity to meconium samples and may have some advantages over collection of meconium. Testing umbilical cord tissue enables analysis to occur immediately after birth, compared with meconium testing, which is delayed as long as 3 days prior to specimen availability. Umbilical cord is easily and noninvasively collected and may reflect a long window of drug detection; however, because few studies have examined cord tissue analysis to date, interpreting results is difficult.Drug-exposed infants are at increased risk of acquiring infections transmitted from mothers whose lifestyles include unsafe sexual practices or intravenous drug abuse. Assessment of the mother who abuse drugs and their infants forhepatitis B and hepatitis C and sexually transmitted diseases including human immunodeficiency virus (HIV) should be incorporated into the prenatal care setting and delivery hospitalization.
MEDICAL CAREThe large number of infants who suffer from neonatal abstinence syndrome (NAS) and the associated long-term morbidity mandate that affected infants be accurately identified and their treatment and support should be optimized.
- The assessment and management of neonatal abstinence syndrome pose difficulties for staff and families and have been hampered by a lack of prospective studies and by few research studies that specifically assess the merits of one management approach over another.
- Vomiting and diarrhea leading to dehydration and poor weight gain, in the absence of other diagnoses, are indications for treatment, even in the absence of a high drug-withdrawal score.
- In the delivery room, naloxone use is contraindicated in infants whose mothers are known to be dependent on opioids because of the risk of neonatal seizures from abrupt drug withdrawal. However, in the absence of a specific history of opioid abuse in a mother who has recently received narcotics, naloxone treatment remains a reasonable option in the delivery room management of a depressed infant if the infant continues to demonstrate respiratory depression after positive pressure ventilation has restored normal heart rate and color.
- Primary treatment of neonatal symptoms related to prenatal substance exposure should be supportive because pharmacologic therapy can prolong hospitalization and exposes the infant to additional agents that are often not necessary. The treatment for morphine administration has been reported to last 8-79 days. This length of hospitalization interferes with maternal bonding, has potential for nosocomial infection, and is a major use of resources.
- Pharmacotherapy for infants with more severe expression of neonatal abstinence syndrome is necessary to allow them to feed, sleep, gain weight, and interact with care givers. Approximately 30-91% of infants who exhibit signs of neonatal abstinence syndrome receive pharmacological treatment.
Nonpharmacologic approaches include the following:
- Assess daily for signs of withdrawal, including sleeping habits, feeding patterns, and weight gain.
- Reduce the degree of ambient light exposure, minimize excessive noise, avoid unnecessary handling, and provide swaddling for settling.
- Provide frequent small feeds of hypercaloric formula
Medications used in patients with neonatal abstinence syndrome (NAS) should be considered when supportive measures fail to ameliorate the infant's withdrawal. This may be manifested early on as difficulty with feeding, extreme irritability, and poor sleeping. If a scoring system is used, pharmacological treatment is commonly started when the average of 3 scores is 8 or more on the Finnegan scale or 4 or more on the Lipsitz scale.
The optimal treatment for neonatal abstinence syndrome has not been established. This is reflected in the considerable heterogeneity in the pharmacologic treatment of neonatal abstinence syndrome among different institutions. Many pharmacological agents have been used to treat neonatal abstinence syndrome. However, few randomized trials have compared the efficacy of the various pharmacological treatments. For opioid related neonatal abstinence syndrome, morphine and methadone are given as substitutes. Nonmorphine treatments (eg, phenobarbital, chlorpromazine, diazepam, clonidine) provide symptomatic relief.
Agthe et al studied 80 infants who were exposed in utero to methadone or heroin and subsequently had neonatal abstinence syndrome to determine if oral clonidine would reduce the duration of opioid detoxification. Each infant received oral diluted tincture of opium (dosage according to standardized algorithm) and also either oral clonidine (1 mcg/kg every 4 h) or placebo. Duration of opioid therapy was measured. Median length of therapy was 27% shorter in the clonidine group (11 d) compared with placebo (15 d).
Seven infants in the clonidine group required restarting opium after initial discontinuation, compared with none in the placebo group, although the total length of treatment was significantly less in the clonidine group. Higher opium doses were required by 40% of infants in the placebo group compared with 20% in the clonidine group. Treatment failures occurred in 12.5% of the infants in the placebo group compared with none in the clonidine group. The addition of clonidine to standard opioid therapy reduced the duration of pharmacotherapy for NAS.
A US survey reported that opioid medications are the most commonly used medications for the treatment of both opioid and polydrug withdrawal.Diluted tincture of opium is recommended by the American Academy of Pediatrics for the treatment of neonatal abstinence syndrome due to opioid withdrawal. Diluted tincture of opium is a 25-fold dilution of deodorized tincture of opium. Deodorized tincture of opium is equivalent to anhydrous morphine 10 mg/mL, whereas diluted tincture of opium is equivalent to anhydrous morphine 0.4 mg/mL. As a tincture, opium contains a high amount of alcohol. Diluted tincture of opium (Paregoric) contains 45% alcohol. The Institute for Safe Medication Practices considers this a high alert medication because of the confusion if abbreviated as DTO because the abbreviation could mean deodorized or diluted tincture of opium.
Many neonatal units use proprietary oral or intravenous morphine solutions, and methadone is also used. A recent study showed chlorpromazine to be efficacious, with no adverse effects in neonates with neonatal abstinence syndrome and shorter treatment time when compared with morphine. A large multicenter trial was recommended by the author to confirm the safety and efficacy of chlorpromazine.
Buprenorphine is the first prescription drug approved under the 2000 US Drug Addiction Treatment Act for office based treatment of addiction to narcotics. Buprenorphine has numerous characteristics that make it an attractive agent in the treatment of neonatal abstinence syndrome. Buprenorphine has a ceiling effect for respiratory depression. It does not have the cardiovascular liability associated with methadone and has an established safety profile in adults. Finally, abuse liability is limited, which makes consideration of outpatient treatment for neonatal abstinence syndrome a possibility for carefully screened caregivers. A pilot study showed that the treatment of neonatal abstinence syndrome with sublingual buprenorphine is feasible, has acceptable safety margin, and may represent a novel treatment.
Currently, many infants are exposed to polydrug abuse. Unfortunately, evidence from randomized studies is insufficient to determine the best management for these patients. In 2 randomized trials, phenobarbital (rather than diazepam or paregoric) was best at controlling symptoms in infants exposed to polydrugs. The results of another study suggested that the combination of phenobarbital with diluted tincture of opium may be more effective than diluted tincture of opium alone because the combination was associated with a shorter hospital stay.
hese drugs have a long half-life and can be orally administered, allowing for the neonate to be discharged and treated as an outpatient.
Disadvantages include lack of effect on GI symptoms and ineffectiveness in treating seizures secondary to withdrawal. In addition, antiepileptics contain 14-25% alcohol, and larger doses are required to achieve the desired effect.
Interferes with transmission of impulses from thalamus to cortex of brain. Used as a sedative. Irritability and insomnia are controlled. Available in PO and IV preparations.
These agents are the mainstay of treatment for opiate withdrawal, either alone or in combination with other medications. These agents are CNS depressants with advantages that include oral administration, mild sedation that improves the effectiveness of sucking, and effectiveness in treating seizures secondary to opiate withdrawal.
Morphine sulfate (Roxanol, Astramorph PF)
PO solutions are available in concentrations of 2 mg/mL, 4 mg/mL, and alcohol-free 20 mg/mL. Administered to neonates as diluted PO solution containing 0.4 mg/mL.
Bioavailability is 20-40% when administered orally. Elimination half-life is approximately 9 h. Recommended that Neonatal Abstinence Scoring System be used to guide treatment management of NAS.
Long-acting narcotic analgesic. PO bioavailability is 50%, with peak plasma levels obtained in 2-4 hours. Serum half-life ranges from 16-25 hours in neonates and is prolonged in patients with renal failure. Available as PO solutions in 1-mg/mL and 2-mg/mL concentrations containing 8% alcohol and 10-mg/mL alcohol-free solution.
- Franck LS, Vilardi J, Durand D, Powers R. Opioid withdrawal in neonates after continuous infusions of morphine or fentanyl during extracorporeal membrane oxygenation. Am J Crit Care. Sep 1998;7(5):364-9. [Medline].
- Substance Abuse and Mental Health Services Administration Office of Applied Studies. 2003 National Survey on Drug Use & Health: Results. US Department of Health and Human Services. Available athttp://www.drugabusestatistics.samhsa.gov/NHSDA/2k3NSDUH/2k3results.htm. Accessed December, 2007.
- Hytinantti T, Kahila H, Renlund M, Jarvenpaa AL, Halmesmaki E, Kivitie-Kallio S. Neonatal outcome of 58 infants exposed to maternal buprenorphine in utero. Acta Paediatr. Aug 2008;97(8):1040-4. [Medline].
- Lim S, Prasad MR, Samuels P, Gardner DK, Cordero L. High-dose methadone in pregnant women and its effect on duration of neonatal abstinence syndrome. Am J Obstet Gynecol. Jan 2009;200(1):70.e1-5. [Medline].
- Dryden C, Young D, Hepburn M, Mactier H. Maternal methadone use in pregnancy: factors associated with the development of neonatal abstinence syndrome and implications for healthcare resources. BJOG. Apr 2009;116(5):665-71. [Medline].
- Wouldes TA, Woodward LJ. Maternal methadone dose during pregnancy and infant clinical outcome. Neurotoxicol Teratol. Jan 25 2010;[Medline].
- Substance Use During Pregnancy: 2002 and 2003 Update. National survey on drug use and health; June 2, 2005. [Full Text].
- SAMHSA. Substance Use among Women During Pregnancy and Following Childbirth. Rockville, MD: Substance Abuse and Mental Health Services Administration; May 21, 2009. [Full Text].
- Cairns PA. Drug misuse: Conception into childhood. Current Paediatrics. December 2001;11(6):475-9.
- Prentice S. Substance misuse in pregnancy. Obstetrics, Gynaecology & Reproductive Med. September 2007;17:272-7.
- SAMHSA. Special issues during pregnancy. Rockford, MD: DHHS; May 21, 2009. [Full Text].
- Lester BM, ElSohly M, Wright LL, Smeriglio VL, Verter J, Bauer CR. The Maternal Lifestyle Study: drug use by meconium toxicology and maternal self-report. Pediatrics. Feb 2001;107(2):309-17. [Medline].
- [Guideline] American Academy of Pediatrics Committee on Substance Abuse. Drug-exposed infants. Pediatr. Aug 1995;96(2 Pt 1):364-7. [Medline].
- Finnegan LP. Neonatal abstinence syndrome: assessment and pharmacolotherapy. In: Neonatal therapy: An update. New York, NY: Excerpta Medica; 1986:122-46.
- Lester BM, Tronick EZ. History and description of the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Pediatrics. Mar 2004;113(3 Pt 2):634-40. [Medline].
- Chasnoff IJ. Prenatal substance exposure: maternal screening and neonatal identification and management. Neoreviews. 2003;4(9):e228-e235.
- Gray T, Huestis M. Bioanalytical procedures for monitoring in utero drug exposure. Anal Bioanal Chem. Aug 2007;388(7):1455-65.[Medline].
- van Huis M, van Kempen AA, Peelen M, Timmers M, Boer K, Smit BJ. Brain ultrasonography findings in neonates with exposure to cocaine during pregnancy. Pediatr Radiol. Mar 2009;39(3):232-8. [Medline].
- Kassima Z, Greenough A. Neonatal abstinence syndrome: Identification and management. Current Paediatrics. June 2006;16:172-5.
- 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. Oct 2005;5(5):265-72.[Medline].
- Kraft WK, Gibson E, Dysart K, et al. Sublingual buprenorphine for treatment of neonatal abstinence syndrome: a randomized trial.Pediatrics. Sep 2008;122(3):e601-7. [Medline].
- [Best Evidence] Agthe AG, Kim GR, Mathias KB, et al. Clonidine as an adjunct therapy to opioids for neonatal abstinence syndrome: a randomized, controlled trial. Pediatrics. May 2009;123(5):e849-56. [Medline].
- Sarkar S, Donn SM. Management of neonatal abstinence syndrome in neonatal intensive care units: a national survey. J Perinatol. Jan 1 2006;26(1):15-7. [Medline].
- [Guideline] American Academy of Pediatrics Committee on Drugs. Neonatal drug withdrawal. [published erratum appears in Pediatrics 1998 Sep;102(3 Pt 1):660]. Pediatrics. Jun 1998;101(6):1079-88. [Medline].
- Mazurier E, Cambonie G, Barbotte E, Grare A, Pinzani V, Picaud JC. Comparison of chlorpromazine versus morphine hydrochloride for treatment of neonatal abstinence syndrome. Acta Paediatr. Oct 2008;97(10):1358-61. [Medline].
- SAMHSA. The Drug Addiction Treatment Act of 2000 (DATA 2000). DHHS; 2000. [Full Text].
- Kraft WK, Gibson E, Dysart K, Damle VS, Larusso JL, Greenspan JS. Sublingual buprenorphine for treatment of neonatal abstinence syndrome: a randomized trial. Pediatrics. Sep 2008;122(3):e601-7. [Medline].
- [Guideline] Jansson LM, Choo R, Velez ML, Harrow C, Schroeder JR, Shakleya DM. Methadone maintenance and breastfeeding in the neonatal period. Pediatrics. Jan 2008;121(1):106-14. [Medline].
- [Guideline] AAP. Transfer of drugs and other chemicals into human milk. Pediatrics. Sep 2001;108(3):776-89. [Medline].
- Anthony BE, Bryan BL. Neonatal Abstinence Syndrome. NeoReviews. 2009;10(5):e222.
- Hale TW. Pharmacology review: drug therapy and breastfeeding: antidepressants, antipsychotics, antimanics, and sedatives.NeoReviews. May 2004;e451 –e456.
- Gray KA, Day NL, Leech S, Richardson GA. Prenatal marijuana exposure: effect on child depressive symptoms at ten years of age.Neurotoxicol Teratol. May-Jun 2005;27(3):439-48. [Medline].
- Goldschmidt L, Day NL, Richardson GA. Effects of prenatal marijuana exposure on child behavior problems at age 10. Neurotoxicol Teratol. May-Jun 2000;22(3):325-36. [Medline].
- Maternal Resource Center. Prenatal Substance Exposure. April 2008;Available from: National Abandoned Infants Assistance Resource Center. Accessed 2/20/2010. Available at http://aia.berkeley.edu/media/pdf/2008_perinatal_se.pdf.
- Jaudes PK, Ekwo E, Van Voorhis J. Association of drug abuse and child abuse. Child Abuse Negl. Sep 1995;19(9):1065-75. [Medline].
- Smith DK, Johnson AB, Pears KC, Fisher PA, DeGarmo DS. Child maltreatment and foster care: unpacking the effects of prenatal and postnatal parental substance use. Child Maltreat. May 2007;12(2):150-60. [Medline].
- American Academy of Pediatrics. Pickering LK. The Red Book: 2006 Report of the Committee on Infectious Diseases. 27th. 2006.
- [Guideline] American Academy of Pediatrics Committee on Fetus and Newborn. The initiation or withdrawal of treatment for high-risk newborns. Pediatrics. Aug 1995;96(2 Pt 1):362-3. [Medline].
- Bahwere P, Haumont D, Delange F. Congenital hypothyroidism and neonatal withdrawal syndrome. Eur J Pediatr. Nov 1996;155(11):937-8. [Medline].
- Bauer CR. Perinatal effects of prenatal drug exposure. Neonatal aspects. Clin Perinatol. Mar 1999;26(1):87-106. [Medline].
- Boukydis CF, Lester BM. The NICU Network Neurobehavioral Scale. Clinical use with drug exposed infants and their mothers. Clin Perinatol. Mar 1999;26(1):213-30. [Medline].
- Buchi KF. The drug-exposed infant in the well-baby nursery. Clin Perinatol. Jun 1998;25(2):335-50. [Medline].
- Connolly WB Jr, Marshall AB. Drug addiction, pregnancy, and childbirth: legal issues for the medical and social services communities.Clin Perinatol. Mar 1991;18(1):147-86. [Medline].
- Frank L. Assessment and management of opioid withdrawal in ill neonates. Neonatal Network. 1995;14:39-48. [Medline].
- Heier LA, Carpanzano CR, Mast J, Brill PW, Winchester P, Deck MD. Maternal cocaine abuse: the spectrum of radiologic abnormalities in the neonatal CNS. AJNR Am J Neuroradiol. Sep-Oct 1991;12(5):951-6. [Medline].
- Johnson K, Gerada C, Greenough A. Treatment of neonatal abstinence syndrome. Arch Dis Child Fetal Neonatal Ed. Jan 2003;88(1):F2-5. [Medline].
- Kaltenbach K, Berghella V, Finnegan L. Opioid dependence during pregnancy. Effects and management. Obstet Gynecol Clin North Am. Mar 1998;25(1):139-51. [Medline].
- Kandall RS. Improving Treatment for Drug-Exposed Infants Treatment Improvement Protocol (TIP) Series 5. Available athttp://ncadi.samhsa.gov/govpubs/bkd110/default.aspx. Accessed February, 14 2010.
- Kandall SR. Treatment strategies for drug-exposed neonates. Clin Perinatol. Mar 1999;26(1):231-43. [Medline].
- Kuschel C. Managing drug withdrawal in the newborn infant. Semin Fetal Neonatal Med. Apr 2007;12(2):127-33. [Medline].
- McKim EM. Caffeine and its effects on pregnancy and the neonate. J Nurse Midwifery. Jul-Aug 1991;36(4):226-31. [Medline].
- [Best Evidence] Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA. May 18 2005;293(19):2372-83. [Medline].
- Oei J, Lui K. Management of the newborn infant affected by maternal opiates and other drugs of dependency. J Paediatr Child Health. Jan-Feb 2007;43(1-2):9-18. [Medline].
- Pierog S, Chandavasu O, Wexler I. Withdrawal symptoms in infants with the fetal alcohol syndrome. J Pediatr. Apr 1977;90(4):630-3.[Medline].
- Sanz EJ, De-las-Cuevas C, Kiuru A, et al. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet. Feb 5-11 2005;365(9458):482-7. [Medline].
- Ter Horst PG, Jansman FG, van Lingen RA, Smit JP, de Jong-van den Berg LT, Brouwers JR. Pharmacological aspects of neonatal antidepressant withdrawal. Obstet Gynecol Surv. Apr 2008;63(4):267-79. [Medline].
- Theis JG, Selby P, Ikizler Y, Koren G. Current management of the neonatal abstinence syndrome: a critical analysis of the evidence.Biol Neonate. 1997;71(6):345-56. [Medline].
- Umans JG, Szeto HH. Precipitated opiate abstinence in utero. Am J Obstet Gynecol. Feb 15 1985;151(4):441-4. [Medline].
- Vance JC, Chant DC, Tudehope DI, et al. Infants born to narcotic dependent mothers: physical growth patterns in the first 12 months of life. J Paediatr Child Health. Dec 1997;33(6):504-8. [Medline].
- Wagner CL, Katikaneni LD, Cox TH, Ryan RM. The impact of prenatal drug exposure on the neonate. Obstet Gynecol Clin North Am. Mar 1998;25(1):169-94. [Medline].
- Young T E, Mangum B. CNS Drugs. In: Thomson Reuters clinical editorial staff. Neofax: A manual of drugs used in neonatal care. 22nded. Montvale, New Jersey: Thomson Reuters healthcare; 2009:187-214.
- Zeskind PS, Stephens LE. Maternal selective serotonin reuptake inhibitor use during pregnancy and newborn neurobehavior.Pediatrics. Feb 2004;113(2):368-75. [Medline].