Neonatal withdrawal, neonatal abstinence syndrome (NAS) or neonatal opioid withdrawal syndrome (NOWS) is a drug withdrawal syndrome of infants, caused by the cessation of the administration of drugs which may or may not be licit. Tolerance, dependence, and withdrawal may occur as a result of repeated administration of drugs, or after short-term high-dose use—for example, during mechanical ventilation in intensive care units.
There are two types of NAS: prenatal and postnatal. Prenatal NAS is caused by discontinuation of drugs taken by the pregnant parent, while postnatal NAS is caused by discontinuation of drugs directly to the infant. on eMedicine
Signs and symptoms Those diagnosed with NAS may exhibit signs and symptoms that vary depending on the type of drugs used by the parent, how long the drugs were used, the amount of drug used that made it to the child, and symptoms associated with premature birth. Symptoms can appear as soon as 24 to 48 hours and as late as 5 to 10 days after birth. If the neonate (a newborn less than 4 weeks of age) is expected to have NAS, they may need to stay in the hospital to be monitored for a week. A baby born at full-term may commonly exhibit symptoms such as mottling (net-like bluish-red skin due to swollen blood vessels), irritability, trembling, excessive or high-pitched crying, sleeping problems, increased muscle tone, overactive reflexes, seizures, yawning, stuffy nose, sneezing, poor feeding, rapid breathing, slow weight gain, vomiting, diarrhea, sweating, fever or unstable temperature. These symptoms mainly arise from the dysregulation of four physiological and or behavioral systems: state control and attention which influence irritability and avoidance of eye contact; motor and tone control which influence tremors and seizures, sensory processing which influences hypersensitivity or hyposensitivity, and autonomic control which influence patterns of respiration and fever. Each of these can influence the dysregulation of another system. For example, hypersensitivity in the sensory processing system can cause poor feeding due to the inability to relax, which therefore ultimately results in weight loss or poor weight gain.
Signs and symptoms are also grouped into three systems by the Finnegan Neonatal Abstinence Scoring System (FNASS): Central nervous system. Includes deficiencies in sleep after eating and myoclonic (uncontrolled movement) jerk. Metabolic, vasomotor, and respiratory. Includes symptoms like a stuffy nose and tachypnea. Gastrointestinal. Includes excessive sucking and poor feeding.
Babies born prematurely (before 37 weeks) often exhibit less symptoms or in less severity than those born at full term (38 to 42 weeks). This is due to being exposed to the drug for a lesser period of time during pregnancy. Premature babies with NAS tend to recover at a much faster rate than a full term baby would.
Both neonatal and maternal factors such as gestational age (length of pregnancy starting from the first day of the last menstrual period), maternal substance use, genetics, and gender play a role in the symptoms expressed by the neonate. Every infant is unique in which symptoms are expressed. Males are prone to having more severe symptoms compared to females and those with hypermethylation at the OPRM1 and COMT gene sites experience more severe symptoms as well. Symptoms can also appear and disappear and fluctuate in severity over time within the same infant and withdrawal period. Untreated NAS symptoms can cause developmental issues such as altered cognitive, social, emotional, and behavioral capacities that appear later in life. Long term effects vary by the substance that the neonate gets exposed to but they most commonly have been shown to affect growth, behavior, cognitive function, vision problems, motor problems, language, academic achievement, otitis media (infection or inflammation of the middle ear), and predisposition to self utilization of drugs. Alcohol exposure could lead to poor growth. Tobacco exposure can increase the risk of obesity. Alcohol, nicotine, and opiate exposure have shown to lead to attention deficits. Nicotine and alcohol exposure affect learning and memory. Cocaine exposure affects visual and motor skills, attention, and memory. Cannabis has been shown to have adverse effects on deep problem solving skills and visual memory. Nicotine exposure has led to poor reading abilities. Alcohol and cocaine led to a decreased use of language. Opioid exposure has led to visual impairments such as reduced ability to see fine detail and uncontrolled eye movements. Heroin exposure led to lower weight, height, and head circumference as well as decreased cognitive function that resulted in lower perceptual, quantitative, and memory areas of cognition. Some common drugs that could result in NAS withdrawal or withdrawal-like symptoms in neonates are: Opioids; agonists such as morphine, codeine, methadone, meperidine, oxycodone, propoxyphene, hydromorphone, hydrocodone, fentanyl, tramadol, and heroin, antagonists such as naloxone, and naltrexone, and mixed agonist-antagonists like pentazocine and buprenorphine; CNS stimulants; amphetamines such as dextroamphetamine, methamphetamine, amphetamine sulfate, amphetamine congeners, benzphetamine, diethylpropion, fenfluramine, phendimetrazine, phentermine, cocaine, methylphenidate, pemoline, phencyclidines, and nicotine; CNS depressants; alcohol, barbiturates, benzodiazepines, other sedative hypnotics, methaqualone, glutethimide, chloral, hydrate, cannabinoids, cannabis, and hashish; Hallucinogens; indolealkylamines, phenylethylamines, phenylisopropylamine, inhalants, solvents and aerosols, nitrites, and nitrous oxide.
Cannabis
There are pre- and post-natal exposure risks of neurobehavioral disorders. Exposure during pregnancy can cause low birth weight, reduced head circumference, cognitive deficits, emotional dysregulation, high impulsiveness, and higher risk to develop a substance disorder. The effects can continue into early adulthood.
Cocaine
Newborn infants with cocaine exposure manifest abnormal neurobehavioral changes. These are typically found between 48 hours and 72 hours of life. Cocaine is a vasoconstrictor, which is the main mechanism that causes harm to the fetus and placenta. As the drug is capable of crossing the blood–brain barrier and placenta, they will experience shortcomings. In a 2005 randomized case-controlled prospective study, cocaine-exposed infants displayed jitteriness, tremors, irritability, excessive sucking, extreme alertness, abnormal breathing and autonomic instability. Based on how much of the drug the infant was exposed to, there is a positive dose-response relationship between exposure of cocaine and hyperactivity.
Alcohol
Alcohol, a central nervous system depressant, is one of the most commonly used drugs. With long-term exposure of alcohol to newborn infant, there are withdrawal symptoms. These are characterized by tremors, hypertonia, restlessness, excessive mouthing movements, inconsolable crying and reflex abnormalities. There are direct effects known as fetal alcohol spectrum disorder.
Nicotine
Nicotine-exposed infants may showcase more NAS signs. However, it is not certain if the effects is due to it being a transient drug effect or a true withdrawal. There can be an increase in tone and alertness with poor self-regulation.
Causes
The drugs involved can include opioids, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs) ethanol, benzodiazepines, anticonvulsants, and muscle relaxants. Opioids have become the most associated with NAS due to the growing opioid crisis leading to increased opioid use during pregnancy. Although NAS generally includes opioid and nonopioid exposures, studies have shown that such cases have primarily resulted from in utero opioid exposure, thus resulting in the use of neonatal opioid withdrawal syndrome (NOWS) as a subset of NAS. Neonatal abstinence syndrome does not happen in prenatal cocaine exposure (with babies exposed to cocaine in utero) in the sense that such symptoms are difficult to separate in the context of other factors such as prematurity or prenatal exposure to other drugs.
Although the main pathophysiology of NAS is still not fully understood, there are several potential mechanisms and pathways that are being investigated that may be related to the development of NAS caused by abnormal levels of neurotransmitters and inadequate expression of opioid receptors. Due to the differing substances that can lead to NAS, each substance can result in a different cause leading to the symptoms of NAS. Examples of such differences include: opioid withdrawal resulting in decreases in serotonin and dopamine with an increase in corticotrophin, norepinephrine, and acetylcholine; TCA withdrawal resulting in a cholinergic rebound phenomenon; and methamphetamine withdrawal resulting in a decrease in dopamine, serotonin, and other monoamines.
Risk factors Several studies have shown that multiple risk factors, ranging from social aspects to genetics, can contribute to the severity of NAS and the recovery process. Mutations in the genes for opioid receptor expression (mu-opioid receptors OPRM1, delta-OPRD1, and kappa-OPRK1 genes) and the dopamine metabolism pathway (COMT gene) have been associated with quicker recovery resulting in shorter duration of treatment. Environmental influences that can affect expression of the aforementioned genes, like DNA methylation that results in decreased OPRM1 gene expression, have also been associated with increased severity of NAS. Some non-genetic risk factors include smoking and methadone use during pregnancy that can result in increased severity of NAS.
Diagnosis According to the 2020 guidelines from the American Academy of Pediatrics (referred to as the AAP 2020 Guidelines), diagnosis of NAS is determined through clinical assessment, neonatal testing, as well as diagnosis by exclusion to make sure that there are no other potential causes for the neonatal symptoms. In addition to assessing the newborn, clinicians must also conduct a full evaluation of the social and medical history of the mother.
Clinical assessment as described by the AAP 2020 Guidelines mainly consists of performing a standardized assessment to measure both the presence and severity of withdrawal symptoms being presented by the neonate at risk of NAS. The main scoring system associated with this standardized assessment is the modified Finnegan score, also known as the Modified Finnegan Neonatal Abstinence Score. The scoring system assesses the neonate and observes the severity of the following characteristics: crying; sleeping; moro reflex; tremor; increased muscle tone; excoriations of chin, knees, elbows, toes, and nose; myoclonic jerks; generalized convulsions; sweating; hypothermia; and many others. This same assessment can be used in assessing the response that the neonate is having to the chosen treatment.
According to the AAP 2020 Guidelines, neonatal testing refers to laboratory testing of the infant's urine, meconium, and umbilical cord tissue. Although these tests are recommended per guidelines, there are several considerations to understand when performing these tests. With urine toxicology tests, samples must be collected immediately after birth since these tests only capture a short window of substance exposure due to the rapid metabolism and elimination of most drugs of concern. Although meconium and umbilical cord tissue testing provides a larger window of observation for substance exposure, it is not recommended if the mother is already receiving treatment for opioid use disorder (OUD) with frequent toxicology testing since this will not provide any additional information.
Management