1 Neonatal Drug Withdrawal John Wareham, MD Department of Neonatology, St. Vincent Women s Hospital
2 Neonatal Drug Withdrawal What are we going to cover? Overview of the problem in neonates Opioid exposure/dependence (Newborn Abstinence Syndrome) Review a few other drugs THC, cocaine and other stimulants, Selective Serotonin Uptake Inhibitors (SSRIs) Current methods for drug screening newborns Long term outcome Selected topics
4 2009 National Survey on Drug Use and Health Surveyed population 12 years or older. 8.7%, 23.7%, and 27.7%, respectively, reported recent use of illicit drugs, binge or heavy alcohol ingestion and use of tobacco products. 4.5% of pregnant women years of age reported recent use of illicit drugs (marijuana, cocaine, hallucinogens, heroin, methamphetamines, and nonmedical use of prescription drugs). Binge or heavy drinking in the first trimester was reported by 11.9% and recent tobacco use by 15.3%. In the year old range, the use of illicit drugs and smoking were higher in pregnant women than in those not pregnant.
5 Discharge Data from Agency for Health Care Research and the Florida Department of Health Using ICD 9 code for neonatal withdrawal syndrome the number of infants coded at discharge increased from 7653 in 1995 to 11, 937 in In Florida, the number of newborns discharged with ICD 9 code increased from 0.4 to 4.4/1000 live births from 1995 to Part of this increase, though exactly how much is not known, is thought to be from the more liberal use of prescription opiates in pregnant women to help with pain from a number of etiologies.
6 St. Vincent Women s NICU Number 10 (8 outborn) Gestation al Age 37.4 weeks Birth weight Length of Stay kg 34.1 days Admitting diagnosis of Drug Withdrawal
7 Neonatal Abstinence Syndrome and Associated Health Care Expenditures JAMA, May 9, 2012;307(18); This article was a retrospective cross sectional analysis of national samples using several large databases. Authors were from the University of Michigan. Infants with NAS were identified from a cross sectional analysis of pediatric discharges in 2000, 2003, 2006, and 2009 using the Healthcare Cost and Utilization Project s Kids Inpatient Database (KID). The database samples 80% of pediatric discharges and 10% of uncomplicated births. Using the KID, NAS patients were identified using the ICD 9 CM code of (drug withdrawal syndrome in a newborn). Using another database, the Nationwide Inpatient Sample (NIS), delivering mothers were identified by common delivery diagnosis related groups.
8 Neonatal Abstinence Syndrome and Associated Health Care Expenditures JAMA, May 9, 2012;307(18); Iatrogenic NAS was looked for by searching NICU discharge data for the diagnoses of very low birth weight, PVL, IVH, NEC, spontaneous bowel perforation, or BPD. Data would probably have been more accurate if search included pulmonary hypertension, ECMO, and congenital heart disease.
13 Conclusions Between 2000 and 2009 total hospital charges for NAS were estimated to have increased from 190 to 720 million dollars (includes inflation). The CDC found that the sales and deaths related to opiate pain relievers quadrupled between 1999 and The majority of costs related to NAS are shouldered by Medicaid. We are no better at getting infants with NAS home than we were in 2000.
16 Neonatal Drug Withdrawal This is a nationwide problem. In Indiana, this is a problem in every county. The classic drugs of abuse that cause neonatal withdrawal are opioids such as heroin and morphine. Prescription pain medications such as oxycodone (Percocet), hydromorphone (Dilaudid), and propoxyphene (Darvon) are currently a hot issue. Stimulant drugs, such as cocaine and amphetamine, cause symptoms/signs and probably harm in neonates. Marijuana, the most common illicit drug detected on drug screens, still is a source of debate concerning withdrawal. Selective serotonin reuptake inhibitors (SSRIs) have become a problem because of their frequent prescription to pregnant women with depression and the emergence of a neonatal withdrawal syndrome. Also, complicating the use of SSRI s is their frequent prescription to mothers for postpartum depression. It is not clear that these drugs are safe for breast feeding.
17 Neonatal Drug Withdrawal When talking about neonatal drug withdrawal, most people are referring to neonatal withdrawal from opiates, which is called the neonatal abstinence syndrome (NAS). The actual incidence of NAS is not known, but has probably increased. While there is a fair amount of information on the short term effects of drug exposure, the long term effects of fetal drug exposure (other than to drugs associated with teratogenicity and birth defects), in most instances, are unknown. Alcohol may be the exception. The optimal treatment for fetal drug exposure that results in withdrawal is not known. As an additional problem in NICU s, the use of narcotics and/or benzodiazepines to provide analgesia or sedation for hospitalized infants puts that population at risk for drug dependency and withdrawal. Is there a difference between a neonate withdrawing after a fetal exposure and a neonate withdrawing after a neonatal exposure?
18 Neonatal Drug Withdrawal Withdrawal or toxicity? Maternal use of certain drugs can cause transient neonatal signs consistent with withdrawal or acute toxicity or sustained signs consistent with a lasting drug effect. Opioid exposure of the fetus often causes withdrawal, cocaine exposure probably causes toxicity/drug effects, but not a true withdrawal. Signs and symptoms of withdrawal worsen as the drug level decreases, the signs and symptoms of acute toxicity improve as the drug level decreases.
19 Mechanisms of Drug Injury in the Fetus Early in gestation, during the embryonic stage, drugs can have teratogenic effects. During the fetal period, after the major structural development has been completed, drug effects are more subtle. These effects include abnormal growth and/or maturation, alterations in neurotransmitters and their receptors, and brain organization. Drugs of abuse mimic naturally occurring neurotransmitters marijuana acts as anandamides, opiates as endorphins, cocaine and stimulants act within the mesolimbic dopaminergic pathways to increase dopamine and serotonin within the synapses.
20 Mechanisms of Drug Injury Important indirect effects of drugs of abuse on the fetus are altered maternal health behaviors attributable to the mother s addiction. These altered behaviors include poor nutrition, decreased access to and compliance with health care, increased exposure to violence, and increased risk of mental illness and infection. Of all the mechanisms of injury, perhaps the most concerning is the chronic exposure of the developing nervous system to drugs that mimic the activity of neurotransmitters and their receptors. During fetal development neurotransmitters are very important in guiding the development of the brain.
21 Neonatal Drug Withdrawal Opiates By far, the most common neonatal drug withdrawal comes from intrauterine opioid exposure. The typical clinical findings associated with opioid withdrawal are called the Neonatal Abstinence Syndrome (NAS). Withdrawal signs develop in 55 94% of neonates exposed to opioids in utero. Neonatal withdrawal signs have also been described in infants exposed to benzodiazepines, barbiturates, SSRI s and alcohol.
23 Opioids Opioids are a class of natural, endogenous, and synthetic compounds that activate primarily mu opioid receptors in the CNS to produce supraspinal analgesia. Morphine is a natural opioid and is extracted from the opium poppy. Codeine, heroin, hydromorphone, fentanyl, and methadone are all synthetic opioids. Opioids acutely inhibit the release of noradrenaline at the synaptic terminals. With chronic opioid exposure, tolerance develops and the rate of noradrenaline release increases toward normal. Abrupt cessation of exogenous opioids results in a supranormal release of noradrenaline and produces the autonomic and behavioral signs characteristic of opioid withdrawal.
24 Opioid Abuse in Pregnancy Opioids are small lipophilic compounds that freely cross the placenta and blood brain barrier. Maternal detoxification may be associated with increased risk of fetal distress and fetal loss. Maintenance programs with methadone for pregnant women sustain opioid concentrations in the mother and fetus in ranges that minimize opioid craving, suppress abstinence symptomatology, block heroin induced euphoria, and prevent fetal stress. Unfortunately, because of its addictive properties, the use of methadone makes detoxification after delivery unlikely and produces a longer course of NAS than with heroin exposure.
25 Opioid Withdrawal Since the opioid receptors are concentrated in the CNS and GI tract, you get the signs and symptoms seen in the previous chart. Excess environmental stimuli and hunger exacerbate the perceived severity of NAS. Hence, frequent feeds and a quiet room are part of the treatment of withdrawal. Signs of neonatal withdrawal often begin in the first 24 hours after birth with heroin. In methadone, the withdrawal tends to begin between 24 and 72 hours. However, for both opioids, withdrawal has been reported to take up to 5 7 days to develop.
26 Opioid Withdrawal For buprenorphine, withdrawal onset peaks at 40 hours, is at its worst at 70 hours. The different time courses reflect variations in the half lives of drug elimination. The incidence and severity of NAS are greater in infants exposed to methadone compared with infants exposed to heroin or buprenorphine. However, up to 50% of infants exposed to buprenorphine may withdraw. Daily maternal methadone dose has not been consistently correlated with the incidence or severity of NAS. Maternal methadone metabolism is probably a more important determinant than the actual daily dose.
27 Preterm Opioid Withdrawal Preterm infants do not withdraw as frequently or as severely. It is not known whether that is due to the less mature nervous system or being exposed to a lower total dose of narcotic or both. Preterm infants also have less body fat and opiates are lipophilic.
28 Deciding When to Treat the Newborn with NAS Once a newborn becomes symptomatic, you must decide how to manage the withdrawal. First line of treatment is nonpharmacologic using frequent feedings, a quiet environment, comforting techniques, etc. If the nonpharmacologic approach is not successful, then medication may be required. In deciding when to move to medication, a withdrawal scoring system is helpful. There are two frequently used, the Lipsitz tool and Finnegan s Neonatal Abstinence Scoring Tool. The Finnegan Tool (not modified!!) is probably the most utilized.
29 Neonatal Abstinence Scoring Tool
30 Pharmacologic Therapy of NAS The optimal screening scores for the initiation of pharmacologic therapy by any published abstinence scoring system are unknown. If nonpharmacologic treatment fails, then the drugs of choice are oral morphine or methadone (94% first choice in UK, 83% first choice in US). Paregoric is no longer used because it contains multiple other opioids as well as camphor, anise oil, alcohol, and benzoic acid. Tincture of opium contains a 25 fold higher concentration of morphine than currently available oral morphine preparations making accidental overdose a concern. When a second drug is needed, phenobarbital is commonly picked. However, clonidine may be taking it s place.
31 Clonidine Clonidine is an alpha 2 adrenergic receptor agonist that is being used with an opioid or other drug to reduce withdrawal symptoms. It s more common uses are in hypertension, ADHD, anxiety disorders and certain pain conditions. Clonidine reduces CNS sympathetic outflow and moderates symptoms of autonomic over activity such as tachycardia, hypertension, sweating, restlessness and diarrhea. Cessation of clonidine treatment can result in a rebound of autonomic activity, so it must be weaned. NICU s are starting to use it in infants with more severe symptoms or those difficult to wean off methadone or morphine.
32 Other Drugs Marijuana Cocaine and other stimulants SSRIs Aquired drug dependency (in the NICU and PICU) Alcohol and cigarette smoke
33 Marijuana Marijuana is the most common drug of abuse found in newborn drug tests in our practice. The main chemical compound in marijuana, 9 tetrahydrocannabinol (THC), crosses the placenta. The major metabolite, 11 nor 9 carboxy THC does not. In animal species, it appears that the placenta limits the passage of THC with fetal concentrations being below the maternal concentrations. There is still debate about the existence of a withdrawal syndrome. Long term, studies have suggested that there may be effects on attention and impulsivity in children exposed to marijuana during pregnancy. There is also the suggestion that prenatal marijuana exposure decreases academic achievement, especially in the areas of reading and spelling.
34 Cocaine and Other Stimulants Both cocaine and methamphetamine increase the risk of preterm birth, placental abruption, fetal distress, and IUGR in pregnant women. A true abstinence syndrome after exposure to CNS stimulants such as cocaine and amphetamine has not been defined. The neurobehavioral abnormalities that occur frequently 2 3 days after birth in neonates with intrauterine exposure include irritability, hyperactivity, tremors, high pitched cry, and excessive sucking. Since cocaine and its metabolites may be detected in exposed infants for up to 7 days after birth, the signs may relate more to drug effect than withdrawal.
35 Selective Serotonin Reuptake Inhibitors (SSRIs) This class of antidepressant medications became available for widespread use in They are now the most frequently used drugs to treat depression. Included are such well known names as Prozac (fluoxetine), Zoloft (sertraline), Lexaprol (escitalopram), and Paxil (paroxetine). SSRIs block the reuptake of serotonin into the presynaptic neuron thereby increasing the concentration of serotonin in the presynaptic cleft available to bind to serotonin receptors on the postsynaptic neuron.
36 SSRIs Third trimester use of SSRIs can produce neonatal signs that include continuous crying, irritability, jitteriness, shivering, fever, tremors, hypertonia, tachypnea, feeding difficulty, sleep disturbance, hypoglycemia, and seizures. The onset of signs varies from several hours to several days after birth. Signs typically resolve within 1 2 weeks. Again, it is unknown whether this is a withdrawal syndrome or serotonin syndrome (serotonin overload). Clinical course is frequently one of a slow resolution of signs, which may be more consistent with a hyperserotonergic condition rather than withdrawal. Only paroxetine (Paxil) produces a ratio of infant to maternal plasma concentration that is consistently low (<0.1) with breast feeding.
37 Aquired Opioid and/or Benzodiazepine Dependency This refers to drug dependency generated in sick neonates from the use of opioids and benzodiazepines. ECMO patients are heavily represented in this patient population. Most of the data comes from Peds ICUs, not NICUs. Drug infusions, such as with fentanyl and midazolam, are especially good at generating dependency. Withdrawal signs and symptoms from the two drugs overlap, making it hard to separate the two in weaning. This issue leads to significant prolongation of hospital courses.
38 Aquired Opioid and/or Benzodiazepine Dependency For those infants who receive prolonged cumulative exposure to these two classes of drugs, the AAP offers some guidelines. Each clinical unit needs to establish its own dose levels above which withdrawal is likely. As a rule for fentanyl infusions, a cumulative fentanyl exposure of >2 mg/kg or >7 days duration predicts a likelihood of dependency of over 50%, but less than 100%. These infants should go into a weaning schedule over weeks. Infants who do not reach the cumulative exposure to either opioids or benzodiazepines can be weaned rapidly. In such cases, many of the infants will not withdraw (BUT, some will). If withdrawal occurs after a rapid wean, it is usually within 24 hours of the last dose.
39 Aquired Opioid and/or Benzodiazepine Dependency As previously mentioned, withdrawal from benzodiazepines overlaps the signs and symptoms of NAS. Once weaning has been established, iv benzodiazepines can be converted to oral lorazepam. The weaning duration will be proportional to the length of treatment with the iv benzodiazepine.
40 Alcohol and Cigarette Smoke These are legal drugs that are frequently used in pregnancy. Maternal smoking exposes the fetus to more than 4000 compounds. Of these, about 30 have been associated with adverse health outcomes. The best known is nicotine. Nicotine concentrations are higher in the placenta, amniotic fluid and fetus than in the maternal serum. Exact mechanisms by which nicotine causes harm to the fetus are unknown, but likely includes hypoxia, undernourishment of the fetus and direct vasoconstrictor effects on the placental and umbilical vessels. Nicotine has also been shown to have direct negative effects on brain development.
41 Alcohol and Cigarette Smoke Ethanol readily crosses the placenta with significant concentrations identified in amniotic fluid and maternal and fetal blood. Possible mechanisms of injury include direct teratogenic effects during the embryonic and fetal stages of development, toxic effects on the placenta, altered prostaglandin and protein synthesis, hormonal alterations, nutritional effects, altered neurotransmitter levels in the brain, altered brain morphology and neuronal development, and hypoxia.
42 Lab Screening Urine testing of the mother and infant has the advantage of short turn around time, but a brief window of time screened. Meconium screening of the newborn has the advantage of a much longer screening window, but the testing is messy and requires 1 2 weeks for results. The infant has often been discharged prior to the results. Testing of umbilical cord samples is relatively new and comparable to meconium testing in accuracy. Results can be available in 2 3 days.
44 Long Term Outcome The long term neurodevelopmental outcome of infants who withdraw is really not known. It is very difficult to tease out the drug effects from the family/social issues. The available data tends to be reassuring, at least as far as marked impairment in intelligence. Whether it is looking at infants who seize secondary to opioid withdrawal or drug toxicity from cocaine, most of the infants appear to do OK cognitively. With opiates and other drugs, long term problems in the neurobehavioral and learning areas may be the most common. The fact that infants exposed to opiates, cocaine, etc. are not routinely devastated as older children doesn t mean they achieve to the degree they would have without a drug exposure. In this area the data is pretty sparse.
47 Methadone Dosing and the NAS Studies comparing maternal methadone dose and the risk of withdrawal have been contradictory. For every study showing a link, another study shows there is not. There are a number of reasons for this lack of correlation: Variation in study design studies where the mothers received higher doses tended to find no relationship, studies finding a relationship tended to use lower doses. Variability in maternal methadone metabolism even using a similar daily dose, fetuses will see different total doses of methadone based on their mothers ability to metabolize the drug.
48 Methadone Dosing and the NAS There are better ways to predict the chance of withdrawal in neonates born to mothers on methadone, but they are not as easily obtained as the total daily dose of methadone. Cord and serum methadone value at 48 hours of age as well as the rate of decline are better predictors. The lower the cord value of methadone and the more rapid the decline in serum value, the more severe withdrawal is likely to be.
49 Buprenorphine Because of the negative aspects of methadone use synthetic opioids have been developed as alternatives. Buprenorphine, a partial mu receptor agonist, was approved in 2002 by the FDA for the treatment of opioid dependence. Buprenorphine alone (Subutex) or in combination with naloxone (Suboxone) has been used as a first line treatment of heroin addiction and as a replacement drug for methadone. Neither methadone nor buprenorphine is approved by the FDA for use in pregnancy. There is some data that buprenorphine may produce less withdrawal in neonates and that the withdrawal, when it occurs, is shorter. However, the data is not extensive. Unfortunately, pregnant women on methadone tend to comply with their narcotic management more consistently than with buprenorphine. Conversion from methadone to buprenorphine during pregnancy requires hospitalization for it to be done safely (for the mother and fetus).
50 Management of NAS at the Community Hospital Referral of withdrawing newborns to a tertiary care hospital/nicu has advantages and disadvantages. The major advantages are care in a setting where infants with drug withdrawal are fairly frequent and resources for care are extensive. There are significant negatives however: The geographic distance between the parents home and the tertiary care hospital can be a significant roadblock to parental visitation. Families with a drug issue often have significant financial and transportation constraints. The infant is removed from the county where he/she will reside. That means the CPS office that may already be familiar with the family is working from afar.
51 Length of Hospitalization for Observation after Birth The length of observation in the hospital is dependent on the mother s history and the type and amount of drug being taken. Heroin withdrawal usually begins in the first 24 hours after birth, methadone withdrawal usually starts between 24 and 72 hours of age. However, both drugs have resulted in delayed withdrawal at 5 7 days of age. The peak onset of withdrawal in fetuses exposed to buprenorphine is ~40 hours. The AAP recommends that infants born to mothers who used a shorter acting opiate, such as hydrocodone, be observed for 3 days. Infants born to mothers using a long acting opiate such as methadone should be observed for 5 7 days.
52 Breast Feeding Breastfeeding has been associated with less severe NAS presents later and less often requires drug intervention. Breast feeding, safety wise, requires that the mother be in a supervised drug treatment program and that the mother be HIV negative. Generally, that means a methadone program. Methadone is excreted into breast milk, but at a low level. Dose range has been estimated at from 0.01 to 0.15 mg/day in the first 30 days of life. Maternal use of street drugs is a contraindication to breast feeding, with the possible exception of marijuana.
53 Breastfeeding Oral narcotic pain relievers, for the most part, should not be used in lactating mothers. Butorphanol, morphine, and hydromorphone are relatively safe, but still should be used in the lowest possible doses. In the case of SSRI s, all but Paxil (paroxetine) have case reports showing significant intake by breast feeding. The long term effects of this class of drugs is unknown, but serotonin is an important neurotransmitter and it s levels are manipulated in the CNS of developing infants by exposure to SSRI s.
54 Summary Every nursery should develop a protocol that defines indications and procedures for screening for maternal substance abuse. Additionally, a standardized plan should be in place for evaluating and treating infants at risk for or showing signs of withdrawal or drug effect. Infants with known intrauterine exposure to opioids and benzodiazepines should be observed in the hospital for 4 7 days. Outpatient follow up should be early. Breastfeeding, if safely possible, may help reduce the risk of withdrawal. However, the mothers must be closely supervised and HIV negative.
55 Summary There are not nearly enough drug dependency and pain management programs/professionals available to treat the need. Methadone treatment programs have not emphasized weaning off of opioids and have been uneasy with pregnancy. There is a paucity of data on best treatment and long term outcome.
56 Based on national data comparing 50 states and the District of Columbia, Indiana ranks 28th in preterm births* (12.4%) * less than 37 completed weeks gestation 29th in low birth weight* (8.3%) * less than 2,500 grams 18th in deliveries via cesarean section (30%) 39th on 1st trimester entry into prenatal care (63.3%) 39th in infant mortality (7.8) 36th in percent of babies who are ever breastfed (70.5%) Indiana received a grade of C on the March of Dimes 2011 Premature Birth Report Cards
57 References Sachs HC and the Committee on Drugs. The Transfer of Drugs and Therapeutics Into Human Breast Milk: An Update on Selected Topics. Pediatrics. 2013; 132(3): e Behnke M, Smith VC, the Committee on Substance Abuse and the Committee on the Fetus and Newborn. Prenatal Substance Abuse: Short and Long term Effects on the Exposed Fetus. Pediatrics. 2013; 131(3): e1009 e1024 Hudak ML, Tan RC, the Committee on Drugs and the Committee on the Fetus and the Newborn. Neonatal Drug Withdrawal. Pediatrics. 2012;129(2): e540 e560 Patrick SW, Schumacher RE, Benneyworth BD, Krans EE, McAllister JM and Davis MM. Neonatal Abstinence Syndrome and Associated Health Care Expenditures, United States JAMA. 2012; 307(18):