User:Jacobbeierle/sandbox

Neonatal withdrawal or neonatal abstinence syndrome (NAS) is a withdrawal syndrome experienced by infants exposed in utero to licit or illicit drugs, most notably opioids. There are two types of neonatal withdrawal: prenatal, caused by discontinuation of transmission of drugs taken by the pregnant mother to the fetus at birth, and postnatal, caused by discontinuation of drugs administered to the infant after birth.

Etiology
There are a wide range of drugs that can evoke neonatal withdrawal, including, but not necessarily limited to: opioids (including those used in opioid replacement therapies), tobacco, ethanol, hallucinogens, amphetamines, selective serotonin reuptake inhibitors (SSRIs), barbiturates, and benzodiazepines. Neonatal abstinence syndrome does not happen in prenatal cocaine exposure. Premature birth and exposure to other drugs may instead be the cause of symptoms.

Mechanisms
Like nutrients and oxygen, an unborn fetus can be exposed to licit and illicit drugs in a mother's bloodstream via transfer through the placenta. With regular exposure to drugs used by the mother, the fetus develops physical dependence. At birth, the discontinuation of this transfer, and therefor the discontinuation of drug exposure, precipitates withdrawal in the newborn. The exact molecular mechanism that governs the acquisition of dependence, particularly in opioids, is poorly understood.

Signs and symptoms
Onset and severity of neonatal withdrawal can vary considerably from case to case and depends on factors such as the drug used during pregnancy, the amount and frequency of drug use, the time during pregnancy in which drugs are used, genetic factors, and maternal factors such as malnutrition, stress, and infections related to illicit drug use. Symptoms often begin within 1 to 3 days after birth, but may take weeks to appear. While the exact presentation of symptoms depend on the drug used during pregnancy, typical symptoms are tremors, irritability, disturbed sleep, poor feeding, vomiting, diarrhea, poor weight gain, fever, and in extreme cases, seizures. See below for more specific symptoms of specific withdrawal syndromes. Because of these symptoms infants suffering from neonatal withdrawal are monitored closely after birth, with the duration of monitoring dependent on the severity of withdrawal and the specific drug.

Opioid Withdrawal
The onset of neonatal opioid withdrawal is dependent on the opioid used by the pregnant mother, frequency of use, dosage being used, and genetic factors. It is likely because of this multifactoral nature of neonatal opioid withdrawal that a varying range of symptom onset times are observed. Heroin withdrawal has been reported to present within 24 hours of birth, 24-48 hours after birth , and 48-72 hours after birth , whereas methadone has been reported to take 24-72 hours , 48-72 hours , or 7-14 days to elicit withdrawal. Regardless, heroin elicits a withdrawal phenotype sooner and resolves faster than methadone and buprenorphine. Opioids, particularly those used therapeutically for pain management and those abused in opioid use disorder, primarily activate the mu opioid receptor. Because these receptors are primarily located within the central nervous system and gastrointestinal tract, symptoms seen in neonatal withdrawal primarily effect these systems. Symptoms of neonatal opioid withdrawal are often organized into 3 categories: central nervous system effects, gastrointestinal effects, and metabolic, vasomotor, and respiratory effects. Central nervous system effects include tremors, sleep disturbances, increased muscle tone, spastic muscle contractions, irritability, excessive crying, and seizures. Gastrointestinal manifestations present as poor feeding, loose stools, regurgitation, vomiting, and weight loss. Finally, metabolic, vasomotor, and respiratory effects can include fever, sweating, molted skin, and tachypnea.

Infants born prematurely seem to show lower risk of withdrawal and less severe withdrawal, but it is unclear if this stems from the less developed state of the neonatal central nervous system, decreased drug exposure, poorer drug transport across the placenta, decreased clearance of drug, or a deficit in reliable ways to measure withdrawal in preterm infants.

Heroin withdrawal
Onset of symptoms from heroin withdrawal have been reported to occur immediately after birth to 72 hours old. Severe diarrhea is more commonly seen in heroin opioid withdrawal, and these infants are more likely to be born prematurely and have meconium staining.

Methadone and Buprenorphine withdrawal
The substitution of illicit opioid use for an opioid replacement therapy such as methadone or buprenorphine is the current standard of care for pregnant mothers addicted to opioids. Opioid replacement therapies have been shown to reduce illicit opioid use, reduce infections like hepatitis and HIV, improve nutrition of the mother during pregnancy, and increase infant birth weight. Infants exposed to methadone in the womb have been shown to have less intrauterine growth restriction and preterm births when compared to infants only exposed to heroin. In addition, mothers using methadone over illicit opioids also benefit from counseling, monitoring for infection, overall improved pregnancy and infant outcomes, fewer perinatal complications, and reduced neonatal death. However, opioids used in replacement therapies are not without consequences, and produce withdrawal symptoms like their illicit counterparts. There is an increased risk and severity of neonatal opioid withdrawal in infants exposed to methadone when compared to infants only exposed to heroin during pregnancy. However, meta analysis of the existing literature has failed to correlate methadone dose with increase severity or incidence of neonatal opioid withdrawal. Methadone has been reported to take 24-72 hours, 48-72 hours , and 7-14 days to elicit withdrawal symptoms.

More recently, buprenprphine has started to be used as an opioid replacement therapy for pregnant women with opioid use disorders. Infants born to buprenorphine treated mothers show a decreased hospital stay, shorter duration of treatment , and lower cumulative morphine dose to treat withdrawal as compared to those born to mothers treated with methadone. Advantages of buprenorphine for the pregnant mother include fewer drug interactions and a lower risk of overdose, both of which can impact fetal health. These advantages are limited by a reduced efficacy of buprenorphine as an opioid replacement therapy in patients with very high opioid use.

Alcohol withdrawal
Though the use of alcohol by the mother before birth can cause serious long-term effects in her newborn, the infant may also be born with a dependence on alcohol. Onset of symptoms of alcohol withdrawal typically occur within 3-12 hours after birth and include seizures, poor sleeping, hyperphagia, diaphoresis, and hyperactivity.

increased muscle tone, exaggerated startle reflex, irritability and jitteriness.

Amphetamine withdrawal
Infants experiencing amphetamine withdrawal are more likely to be born prematurely and experience restricted intrauterine growth.

It may also be small for gestational age. It may show signs of respiratory distress, infection, exaggerated startle reflex, sleep pattern disturbances. These infant are also at risk for poor weight gain, frequent infections, developmental delays and emotional problems.

Barbiturate withdrawal
Onset of barbituate withdrawal typically occurs within 1-14 days and includes sever tremors, diarrhea, vomiting, hyperphagia, and disturbed sleep.

Caffeine
Vomiting, bradycardia, tachypnea, excessive crying and sleep difficulties can be seen in infants withdrawing from caffeine. At their earliest, these symptoms are seen immediately after birth.

Marijuana withdrawal
Withdrawal from marijuana can initiate a preterm birth and meconium staining.

Lysergic acid (LSD)
LSD use by the mother produces symptoms. Since polydrug abuse often accompanies the use of LSD the symptoms may be masked. Abnormal feeding, tremors and hypertonia can be seen in the infant. Withdrawal symptoms manifest as hypertonia, tremors, poor feeding, and abnormal feeding patterns.

Nicotine
Symptoms of nicotine withdrawal can become apparent as long as five days after delivery and last for months. The symptoms of nicotine withdrawal in the infant are excitability and hypertonicity.

Selective Serotonin Reuptake Inhibitors
Onset of withdrawal is in the span of days to weeks, and can include tremors, difficulty feeding, sleep disturbances, hypoglycemia, seizures, and tachypnea.

Diagnosis
Confirming drug use by a pregnant mother is primarily done in two ways: acquiring a maternal drug history, and toxicology testing. Acquiring a detailed history of maternal drug use is critical, however, these questionnaires under report drug use. In addition, using toxicology tests of both the mother and infant can be used to determine drug use during pregnancy. Maternal testing can prove a difficulty, as the laws governing the need for consent of the mother in the United States may vary from state to state. Practices governing the screening of infants are less uniform, and screening an infant can provide valuable information in treating withdrawal. Urine and cord blood are useful indicators of drug use in the last hours to days of fetal life, but low drug concentrations can often lead to false negatives. Hair testing can be used to detect the presence of drug in the last trimester of pregnancy, but is limited by the need to collect enough hair. Finally, meconium testing can be used to detect drugs present since the second trimester. Results are best if tested before feeding from breast milk which can transfer illicit opioids to the infant, and contamination from urine must be carefully avoided.

After birth, several scoring systems can be used to gauge the severity of neonatal withdrawal. Most commonly used is the Finnegan Scoring System, first developed in 1975, and a more recent version amended for simplicity denoted as the MOTHER NAS scale. Other scales used to assess the severity of neonatal withdrawal include the Lipsitz Neonatal Drug Withdrawal Scoring System, and the Neonatal Narcotic Withdrawal index. The subjectivity of these tests is often a worry when assessing the severity of neonatal withdrawal, and training of staff working with these at need infants is important to improving care.

There are also many conditions that can share symptoms of neonatal withdrawal, including hypoglycemia, hypocalemia, hyperthyroidism, intracranial hemorrhage, respiratory distress, sepsis, or central nervous system disorders. It is important to carefully consider these during the diagnosis of neonatal withdrawal.

Prevention
During pregnancy, abstinence on the part of the pregnant mother can decrease the severity, or even prevent the infants from developing neonatal withdrawal. However, there are associated risks to detoxification during pregnancy, especially in opioid use, including preterm birth and miscarriage. Consulting with a health care professional is the best way to ensure the health of a developing fetus and consulting a physician before starting or stopping drug use is the best course to manage these risks.

Treatment
The end goal of all treatments for neonatal withdrawal is to ablate the physical dependence on a drug. Secondary to this, treatment aims to alleviate discomfort experienced by the infant created by withdrawal. Infants born at risk for neonatal withdrawal need to be monitored after birth for a period of time that depends on the drug in question. For example, infants exposed to low doses of short acting opioids can be discharged after 3 days of not exhibiting symptoms, whereas infants born with exposure to drugs with longer half lives should be monitored for one week prior to being discharged. Severity of neonatal withdrawal is typically determined via one of the diagnostic questionnaires mentioned above, and these questionnaires are used to determine when to employ pharmacological treatment over non-pharmacological treatment.

Other treatments may be used to address secondary complications stemming from withdrawal, such as IV fluids and electrolytes to combat dehydration from vomiting and diarrhea, lactose free calorie dense diet to compensate for poor weight gain , and ointments to treat diaper rash stemming from diarrhea.

Non-Pharmacological Treatment
Non-pharmacological treatment is the first line of therapies used to treat infants experiencing withdrawal as they are cheaper and easier to implement, have less risk of complications, and carry less ethical issues compared to pharmacological interventions. In general, the standard of care is to minimize stimulation from light and noise, received by the infant (in the form of light or noise),

Breast feeding of infants has been associated with shorter hospital stays, less intense neonatal withdrawal, and a lower incidence of pharmacological intervention. There are instances where breast feeding is not appropriate, however, including when a mother has HIV, polydrug abuse, or is using illicit drugs. In these conditions it is the transfer of these substances or conditions that makes breast feeding inappropriate. Methadone and buprenorphine, however, are lactation category C drugs, and only transfer into breast milk at rates of >1% the maternal dose and are therefore considered safe to breastfeed while taking.

Rooming in consists rooming both the mother and infant in the same hospital room, and has been shown to decrease the severity of neonatal withdrawal, lead to shorter hospital stay duration, and reduce the duration of treatment.

Swaddling has also been shown to have benefits, including decreased crying and increased sustained sleep in withdrawing infants.

Pharmacological Treatment
If an infant's withdrawal is severe enough non-pharmacological treatment is paired with pharmacological interventions. This decision is based on the non-biased questionnaires mentioned earlier, however, there is no standardized threshold for initiating pharmacological interventions. To parallel this, there is no accepted standard of care for pharmacological intervention of neonatal withdrawal, leaving individual institutions to decide the course of action they deem appropriate. First line pharmacological interventions aim to improve the symptoms of withdrawal by providing the infant with a form of the drug they are withdrawing from and slowly decrease the dosage until abstinence is achieved. These treatments are, however, self limiting, as the ultimate goal of treatment in neonatal withdrawal syndrome is to eliminate physical dependence, and providing an infant with more of that drug prolongs the process of eliminating withdrawal and increases hospital stay and treatment. In treating opioid withdrawal, the most common first line of treatment in the United States is oral morphine. Morphine's short half life it must be administered every 3-4 hours, but this frequent dosing provides for a more flexible dosing regiment. In neonates withdrawing from opioids, morphine has been shown to improve feeding, reduce diarrhea, and blunt infant agitation. However, treatment with morphine increases the length of stay in the hospital. Methadone is an another available treatment who's longer half life only necessitates dosing twice a day, however this provides less flexibility in dosing and makes it harder to completely wean infants off of opioids.

When pharmacological first line interventions fail to abate symptoms sufficiently, or proves to be too dangerous, second line medication can be used to reduce the severity of symptoms. These second line drugs do not alleviate withdrawal by replacing the drug abused during pregnancy, but instead work through different mechanisms to alleviate symptoms. Phenobarbital is a long acting barbiturate that is used as the treatment of choice in sedative-hypnotic withdrawal, but is also used as a second treatment for infants with opioid withdrawal. Phenobarbital works by supressing central nervous system activity, and is ineffective at treating the gastrointestinal symptoms of opioid withdrawal. Clonidine is another second line treatment used in opioid withdrawal that acts as an adrenergic α2 receptor antagonist. Antagonism of the α2 receptor helps reduce autonomic nervous system activity and aleviates symptoms such as tachycardia, restlessness, and diarrhea.

Epidemiology
A 2012 study from the University of Michigan and the University of Pittsburgh published in the Journal of the American Medical Association analyzed information on 7.4 million discharges from 4,121 hospitals in 44 states, to measure trends and costs associated with NAS over the past decade. The study indicated that between 2000 and 2009, the number of mothers using opiates increased from 1.19 to 5.63 per 1,000 hospital births per year. Newborns with NAS were 19% more likely than all other hospital births to have low birthweight and 30% more like to have respiratory complications. Between 2000 and 2009, total hospital charges for NAS cases, adjusted for inflation, are estimated to have increased from $190 million to $720 million.

Neonatal abstinence syndrome in Canada are significant.

Complications
Drug and alcohol use during pregnancy can lead to many health problems in the baby besides NAS. These may include: Neonatal abstinence syndrome treatment can last from 1 week to 6 months. Even after medical treatment for NAS is over and babies leave the hospital, they may need continued treatment for weeks or months.
 * Birth defects
 * Low birth weight
 * Premature birth
 * Small head circumference
 * Sudden infant death syndrome (SIDS)
 * Problems with development and behavior