Neonatal Abstinence Syndrome

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 in newborns that are remarkably similar despite marked differences in the properties of the causative agent. ^[1] Two major types of NAS are recognized: NAS due to prenatal or maternal use of substances that result in withdrawal symptoms in the newborn and postnatal NAS secondary to discontinuation of medications such as fentanyl or morphine used for pain therapy in newborns admitted to the neonatal intensive care unit (NICU). ^[2] Chronic opioid exposure in the most common source of NAS. ^[1]

Postnatal NAS 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. ^{[3, 4]} This article focuses on prenatal or maternal use of licit or illicit drugs, although symptoms and therapy for postnatal NAS are similar.

Maternal substance abuse, the cause of prenatal NAS, 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. An estimated average of 5.4% of pregnant women aged 15-44 years used illicit drugs in 2012-2013, with the highest rate seen in those aged 15-17 years (14.6%), followed by women aged 18-25 years (8.6%), and those aged 26-44 years (3.2%). ^[5] From 2000-2009, the annual rate of NAS diagnosis among newborns in the United States increased almost 3-fold. ^[6]

Drugs frequently associated with neonatal problems are listed below.

Opiates and narcotics include the following:

• Codeine

• Fentanyl

• Heroin

• Methadone

• Meperidine (Demerol)

• Oxycodone

• Morphine

• Hydromorphone (Dilaudid)

• Butorphanol (Stadol)

• Pentazocine

• Propoxyphene (Darvon)

• Chlordiazepoxide

• Buprenorphine ^[7]

Other drugs include the following:

• Barbiturates

• Caffeine

• Cocaine

• Selective serotonin reuptake inhibitors (SSRIs)

• Antihistamines (Diphenhydramine, Hydroxyzine)

• Ethanol

• Marijuana

• Nicotine

• Phencyclidine

• Meprobamate

• Glutethimide

• Ethchlorvynol

• Diazepam and lorazepam

Most illicit drugs cause an addiction in the mother and dependence in the infant. Dependence 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 central nervous system (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 (NAS) is often a multisystem disorder that frequently involves the CNS, gastrointestinal (GI) system, autonomic system, and respiratory system. Manifestations of NAS 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 NAS 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 NAS in the infant.

It has been suggested that brain-derived neurotrophic factor (BDNF) may have a neuromodulatory role during withdrawal after in utero opiate exposure. A study of 67 infants with NAS (n = 34) and without NAS (n = 33) noted significantly elevated levels of plasma BDNF in infants with NAS during the first 48 hours of birth compared to those without NAS. ^[8]

The specific effects of illicit substances are complex and depend on the type of substance, the frequency and duration of use, the dose, the route of substance intake, and the timing of substance exposure with respect to gestational period.

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-dependent pregnant women since the late 1960s. This is currently the recommended treatment for opioid-dependent pregnant women; when properly used, methadone is considered relatively safe for the fetus. 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. ^[9] However, maternal methadone use is also associated with NAS, 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 late 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 NAS is controversial, and the available data are conflicting. Several studies have shown 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 NAS indicates more significant withdrawal symptoms. ^{[9, 10, 11]} However, a more recent study showed that the incidence and duration of the NAS is not associated with maternal methadone dose. ^[12]

Buprenorphine is a semi-synthetic opioid approved for treating opioid addiction and dependence. A review suggested that buprenorphine and methadone have comparable maternal efficacy. Although methadone seems superior in terms of retaining patients in treatment, infants who had prenatal exposure to buprenorphine required significantly less morphine for the treatment of NAS, a significantly shorter period of NAS treatment, and a significantly shorter hospital stay than did infants with prenatal exposure to methadone. ^{[13, 14]}

The relationship between maternal buprenorphine dose and either NAS incidence or severity has been inconsistent. Secondary analysis study of data from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study failed to support any relationship between maternal buprenorphine dose at delivery and NAS severity, total amount of morphine needed to treat NAS, duration of treatment, or duration of hospital stay. ^[15] A more recent study indicated that polysubstance exposure was the most potent predictor of NAS severity in a group of buprenorphine-exposed neonates; there was a positive association between maternal buprenorphine dose and lower infant birth weight and length. ^[16] In another study, preliminary findings suggest that although marijuana exposure in the third trimester does not appear to complicate the pregnancy or the delivery process, such exposure may impact the severity of NAS, particularly the likelihood of needing pharmacologic therapy for NAS and the duration of hospital stay. ^[17]

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, a potent CNS stimulant, alters the major neurotransmitters and rapidly crosses the placenta. Neurobehavioral abnormalities frequently occur in neonates with intrauterine cocaine exposure, most frequently on day 2-3 postnatally. Because cocaine or its metabolites may be detected in neonatal urine up to 7 days after delivery, ^[18] observed abnormalities in exposed infants may reflect drug effect rather than withdrawal. Early studies suggested neonates exposed to cocaine exhibited a hyperactive Moro reflex, jitteriness, and excessive sucking. Studies do not support that neonates exposed to cocaine differ behaviorally from unexposed infants. The unresolved question is whether 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 intrauterine growth retardation (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. ^[19] 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 exposed to antidepressant medications during gestation are at increased risk of NAS. Selective serotonin reuptake inhibitors (SSRIs) (eg, fluoxetine, paroxetine, sertraline, citalopram, escitalopram, and fluvoxamine) are now the most frequently used drugs to treat depression both in the general population and in pregnant women, and they are also used to treat 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 signs (eg, irritability, seizure), motor signs (eg, agitation, tremors, hypertonia), respiratory (eg, increased respiratory rate, nasal congestion), and GI signs (eg, emesis, diarrhea, feeding difficulty), fever, and hypoglycemia. ^[20] The onset of these signs ranges from several hours to several days after birth, and they are self-limiting, 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.

A case has been reported in which maternal tianeptine (atypical antidepressant) dependence during pregnancy appeared to induce a type of NAS that mimics opiate NAS. ^[21]

The current 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.

United States data

Neonatal 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 it is not uniformly tracked, ^[1] because of unreliable histories of maternal drug abuse, and because of 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. One reported estimate was 3.39 per 1,000 hospital births (13,500 newborns). ^[1]

In the United States, substance use among pregnant and postpartum women is a public health issue. An estimated one third of childbearing women take prescription opioids. ^[22] A pooled analysis of data from the 2009-2013 National Survey on Drug Use and Health (NSDUH) revealed 0.9% of pregnant women met criteria for opioid analgesics, and 0.2% met the criteria for heroin. ^[1]

Between 2004 and 2013, neonatal abstinence syndrome (NAS) quadrupled and hospital length of stay increased from 13 days to 19 days, resulting in 7-fold increases neonatal intensive care unit stays for NAS. ^[22]

In 2011-2012, the NSDUH in the United States found that 5.9% of pregnant women aged 15-44 years reported using illicit drugs, compared with 10.7% of nonpregnant women in this age group. ^[23] The rate of illicit drug use among pregnant women aged 15-17 years was 18.3%, 9% among pregnant women aged 18-25 years, and 3.4% among pregnant women aged 26-44 years. ^[23]

In the 2013 report, among pregnant women aged 15-44 years, an estimated 8.5% reported current alcohol use, 2.7% reported binge drinking, and 0.3% reported heavy drinking. These rates were lower than the rates for nonpregnant women in the same age group (55.5, 24.7, and 5.2%, respectively). ^[23] In the same report, first trimester consumption was 17.9%, compared with significantly lower reporting during the second (4.2%) and third (3.7%) trimesters.

According to data from the Treatment Episode Data Set (TEDS), the proportion of female substance abuse treatment admissions aged 15 to 44 who were pregnant at treatment entry remained relatively stable between 2000 and 2010 (4.4 and 4.8 percent). However, there were shifts in the types of substances reported by these treatment admissions. The percentage of pregnant admissions reporting alcohol abuse (with or without drug abuse) decreased from 46.6 percent in 2000 to 34.8 percent in 2010, and the percentage reporting drug abuse but not alcohol abuse increased from 51.1 percent in 2000 to 63.8 percent in 2010. ^[24]

About 1 in 6 pregnant women aged 15-44 years had smoked cigarettes in the past month, based on combined data for 2011 and 2012. The rate of past-month cigarette use was lower among those who were pregnant (15.9%) than it was among those who were not pregnant (24.6%). This pattern was also evident among women aged 18-25 years (20.9 vs. 28.2 for pregnant and nonpregnant women, respectively) and among women aged 26-44 years (12.5 vs. 25.2, respectively). However, among those aged 15-17 years, the rate of cigarette smoking was higher for pregnant women than nonpregnant women (22.7% vs 13.4%). ^[23]

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. ^[25]

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%.

Patrick et al reported that from 2000-2009, the rate of newborns diagnosed with NAS increased from 1.20 (95% CI, 1.04-1.37) to 3.39 (95% CI, 3.12-3.67) per 1000 hospital births per year. During the same period, total hospital charges for NAS are estimated to have increased from $190 million (95% CI, $160-$230 million) to $720 million (95% CI, $640-$800 million), adjusted for inflation. In 2009, the estimated number of newborns with NAS was 13,539 (95% CI, 12 441-14 635) or approximately 1 infant born per hour in the United States with signs of drug withdrawal. ^[6]

International data

No 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). ^{[26, 27]} 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. ^[28]

In Canada, 3 of every 1,000 babies born from 2009–2010 had NAS. ^[29]

In Australia, the incidence of NAS as a discharge diagnosis decreased from 5.07 per 1000 live births in 2002, to 3.18 in 2011. ^[30]

Race- and age-related demographics

Pregnant white women and Hispanic women had lower rates of illicit drug use (4.4% and 3%, respectively) than black women (8%). ^[31] 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. ^[31]

Rates of substance use among pregnant women vary by age group, with past-month illicit drug and alcohol use highest among teenagers. The rate of illicit drug use among pregnant women aged 15-17 years was 16.2%, was 7.4% among pregnant women aged 18-25 years, and was 1.9% among pregnant women aged 26-44 years. ^[23]

Infants born to mothers who are chemically dependent face not only the experience of sudden withdrawal from poly intoxicants but also other medical and social challenges. Prognosis widely varies and depends on the family, socioeconomic variables, and whether either or both parents continue to use illicit drugs. A home environment with an addicted mother is a compromising variable.

Irner et al showed that children of mothers ceasing or decreasing their use of substances up to time of the birth delivered healthier babies than the mothers who continued to use substances. In addition, their results indicated that early intervention, including treatment of addiction during pregnancy, prenatal care, and psychosocial support, can help to prevent some developmental defects of newborn children of substance-using mothers. ^[32]

Long-term problems of children exposed to illicit drugs in utero include adverse neurodevelopmental outcomes. Lower intelligence quotient scores have been reported in children with in utero exposure to cocaine or methadone. Speech, perceptual, and cognitive disturbances have been reported in toddlers who were exposed to opiates. Difficulties with expressive language articulation have been reported in children of mothers who abused cocaine. Behavioral problems are also reported in children of mothers who have taken illicit substances in pregnancy. These include lower levels of learning and adapting to new situations; higher sensitivity to their environment resulting in irritability, agitation, aggression, poor social skills; and a lack of imitative play and late emergence of symbolic play.

In utero opioid exposure may have the potential to also affect gastrointestinal tract and the gut biome, which, in turn, may impair immunity and protection against pathogens, thereby affecting health over the long term. ^[33]

Prenatal exposure to marijuana has been associated with increased levels of depression during childhood. ^[34] Another study showed increased hyperactivity, impulsivity, inattention symptoms, and delinquency has been associated with prenatal marijuana use. ^[35]

The severity of withdrawal signs, including seizures, has not been proven to be associated with differences in long-term outcome after intrauterine drug exposure. Furthermore, treatment of drug withdrawal may not alter the long-term outcome.

Morbidity/mortality

Death 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.

Prenatal opioid exposures may cause birth defects, altered brain development and neonatal abstinence syndrome. ^{[2, 22]}

Complications

Narcotics may have a direct effect on the development of the respiratory center in the brain stem, but an adverse effect of opiates on long-term postnatal growth is not evident. In longitudinal studies, developmental sequelae have not been proven. Problems with habituation, visual and auditory responsiveness, and interactive patterns have been observed in the first months of life.