eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Neonatology

Perinatal Drug Abuse and Neonatal Drug Withdrawal

Author: Marvin Wang, MD, Clinical Instructor, Department of Pediatrics, Harvard Medical School; Co-director of Newborn Nurseries, Attending Physician, Department of Pediatrics, Massachusetts General Hospital,
Contributor Information and Disclosures

Updated: Sep 28, 2009

Introduction

Background

The use and abuse of addictive drugs has occurred throughout many centuries. Only recently have certain drugs under question become defined as "illicit." Many pregnant women use such medications without prior consideration to the adverse effects of these substances on their unborn children. The effects of chemicals, such as opiates, cocaine, nicotine, alcohol, and new recreational drugs, on fetal development have been seriously studied only in the last 30 years.

The difficulty in evaluating research in this area is enormous. Clear methods for differentiating drug use from drug abuse are not established. The question of whether the mere presence of the chemical in maternal serum results in fetal damage needs to be answered. Evaluating if the mother in question has told the whole truth about her drug use is difficult. Given the stigma of substance abuse during pregnancy, lack of disclosure by the mother to her health provider is common because such damaging information could ultimately lead to the separation of mother and child.

Many confounding factors may be recognized, such as the probability of polysubstance use and how this affects single-drug studies. Additionally, the fact that a mother has used an illicit drug (or even a legal substance such as alcohol or tobacco) intertwines with many other factors that can affect a child. Socioeconomic status, support systems, role of the father, lack of prenatal care, and the caregiving ability of the mother all play tremendous roles in child development.

Pathophysiology

Maternal alterations

Almost all drugs of abuse follow a similar mechanism of action in the adult brain; this mechanism alters the pathways for reward. Through complex neurochemical interactions, various chemicals act to increase dopaminergic pathways from the midbrain ventral tegmental area (VTA) to the nucleus accumbens (NAc) in the striatum. Additionally, the NAc provides a negative feedback loop to the VTA using the inhibitory monoamine gamma-aminobutyric acid (GABA). Blocking such a pathway also attenuates the reward mechanism in the adult brain.

Fetal alterations

Although the full spectrum of physical damage that drugs of abuse can cause cannot be documented, one thing is certain: the effect of maternal drug use on fetal brain development is the most critical and most studied effect. The 2 broad classes of fetal brain insult are as follows:

1. In the first 20 weeks of gestation, damage can occur during cytogenesis and cell migration.
2. In the second half of gestation, damage can occur during brain growth and differentiation.

Continuous abuse, especially during the first half of gestation, is likely to disrupt the complicated neural wiring and associative connections that allow the developing brain to learn and mature. Most drugs of abuse freely cross the placental barrier; however, damage to the fetus also can occur via indirect methods. In particular, the vasoconstrictive properties of cocaine have been discussed as a potential cause for the delivery of growth-retarded infants.

Frequency

United States

The definitions of maternal drug abuse and newborn withdrawal syndrome have been difficult to standardize (see Background). Therefore, documented disease prevalence varies tremendously. The prevalence of prenatally exposed newborns to one or more illicit drugs averages approximately 5.5%, with a range of 1.3-50%. Variations depend on the geographical detail (eg, local vs state) as well as the method of testing (eg, maternal history, urine testing, meconium testing, a combination of these tests).

In 1998, Lester reported that the Maternal Lifestyles Study (MLS), a multicenter clinical study, evaluated the effects of fetal exposure to opiates, cocaine, or both in the United States.² The overall exposure rate was 10%. Of these pregnancies, the rate of perinatal morbidity was higher than the nonexposed group but was less than 5% overall. Prematurity, lower growth parameters, compromised cognitive ability, and neurological symptoms were barely significant compared with nonexposed newborns.

The National Household Survey on Drug Abuse (NHSDA) reported that, from 1996-1998, 14.8% of pregnant women consumed alcohol.³ During that same period, 2.8% of the surveyed women were reported to have used an illicit substance. Of those using illicit substances, two thirds were using marijuana, and one tenth were using cocaine.

International

Perinatal drug abuse and neonatal drug withdrawal is probably a recognized problem in neonatal and postnatal care in every country in the world.

Mortality/Morbidity

• Neonatal withdrawal syndrome occurs in 60% of all fetuses exposed to drugs. Withdrawal syndromes for heroin, codeine, methadone, and meperidine have been extensively described. As more psychotropic medications are prescribed, more withdrawal syndromes are described. Heroin, cocaine, and amphetamine withdrawal usually occurs within the first 48 hours of life; however, a syndrome associated with intrauterine cocaine use has not been well defined. Methadone withdrawal can occur up to 2 weeks after birth but most likely occurs within the first 96 hours after birth. The syndrome is typically an autonomic multisystemic reaction, the symptoms of which are mostly neurological and may be prolonged.
• Alcohol is the only drug of abuse that is well associated with other teratogenic effects. The classic triad of fetal alcohol syndrome (FAS) consists of growth retardation, physical anomalies (with characteristic facies), and CNS dysfunction. The risk of delivering child with FAS increases with gravidity in mothers with alcoholism. Milder forms of FAS have also been described, representing a dose-dependent version of the entire syndrome. More severe aspects are associated with first trimester use of alcohol, especially in those women with a poor diet. At this time, a safe level of alcohol use during pregnancy is not known; therefore, the amount of alcohol that can be consumed without resulting in any part of the FAS spectrum is unknown.
• Poor feeding is a common issue with withdrawing infants. Increasing evidence suggests that neurological alterations occur during withdrawal that prevent normal autonomic functions. Newborns, in particular, depend on their reflexive suck and swallow abilities, which may be significantly affected by intrauterine drug exposure. As such, poor feeding alone can start a cascade of other diagnoses.

Race

• The difficulty in assessing drug use confounds research into racial differences.
• Overall, cocaine use is higher among African American women (5% of all African American women) than Caucasian women (2% of all Caucasian women). Prevalence rates are lower among Asian and Pacific Islander women.
• The use of amphetamines, opioids, and cannabinoids appears to be equal between African American and Caucasian women.

Sex

By definition, perinatal drug abuse is a disease exclusively of pregnant women; however, several interesting epidemiological patterns emerge among mothers who abuse substances. These patterns include the following:

• Genetics: Approximately 60% of mothers who abuse drugs describe a family history of substance abuse, particularly alcoholism. The closer the relative who abuses drugs, the higher the potential for the patient to be an abuser as well. Twin and adoption studies show a weaker genetic role in women than in men. Environmental factors may play a more dominant role for mothers who abuse substances. Patients who describe families of alcohol abuse also describe greater parental-marital conflicts and parent-child conflicts during their childhoods.
• Sexual abuse and domestic violence: In a sample of 1099 women, Wilsnack et al reported that those with a history of being sexually abused in childhood were 2.5 times more likely to abuse substances and 3 times more likely to abuse alcohol than those who were not sexually abused.⁴ In another study, Hien et al reported that 60% of women who abuse substances claimed to have an adult partner who committed domestic violence.⁵ Likewise, many women report that their own drug use is initiated by their male partners.
• Psychiatric comorbidity: A report from the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area Survey showed that people who abuse substances were 4.5 times more likely to have a comorbid mental disorder than those individuals who do not abuse substances.⁶ Of those with a lifetime alcohol or drug disorder, more than 50% were likely to have a comorbid psychiatric disorder. Females with comorbidities to their substance abuse were more likely than men to have affective and anxiety disorders. Also, comorbidity varies with the drug of abuse. People with opioid addictions tend to have a higher associated comorbidity of affective, anxiety, and personality disorders. Cocaine addiction tends to be associated with attention deficit hyperactivity disorder (ADHD).

Age

• Little data on the age stratification of substance abusing mothers is available. Research has focused on the adolescent mother. In particular, a link between adolescent pregnancy and substance use may be present.
• If teenage pregnancy is believed to be a high-risk condition, then those individuals may be prone to other high-risk behaviors. Evidence does support a clustering of teen pregnancy with substance abuse, most notably abuse of cigarettes, alcohol, and marijuana.
• However, the statement that most pregnant and parenting teenagers abuse substances is a gross oversimplification. The literature supports that most pregnant teenagers do not use substances. Among those teens that do use substances, the amount used is far lower than the amount used by adult users who are pregnant.

Clinical

History

• Pregnancy actually offers an excellent opportunity for a mother to seek help and to change her life to protect another. However, given the large numbers of mothers who abuse drugs and whose use goes undetected by their obstetricians and pediatricians, the history-taking practice in prenatal settings must change if this part of the medical evaluation is to be useful.
• Previous attempts at universal toxicology screens for women who are pregnant typically have uncovered one half of all women who abuse drugs. Urine toxicology in combination with a well-performed history is likely to have synergistic results in discovering mothers who abuse substances.
• All too often, the wish to perform an efficient prenatal screening consists solely of asking whether the woman who is pregnant uses drugs. Such questioning carries such stigma and lack of empathy that it is likely to prevent a mother-to-be from admitting her habit of substance abuse. Questioning should be nonjudgmental (ie, ask in a neutral tone of voice), specific (ie, ask about each potential drug of abuse starting with the least innocuous to the most), and asked in succession with the other standard screening inquiries (eg, general medical condition, diet).
• Although several perinatal complications have been thought to be highly associated with in utero drug use, none are pathognomonic. Multiple studies have reported an association of maternal cocaine and tobacco use and placental abruption.
• Methadone is perhaps the most commonly seen medication in the withdrawing infant. Clinicians can be somewhat prepared to care for these infants because such information is made available during the prenatal visit. In assessing the history of the maternal methadone dose, one must consider a great deal of conflicting data concerning the predictability of withdrawal severity with maternal methadone concentrations. The most data, however, appear to show no correlation between maternal dose and neonatal withdrawal severity.⁷
• Buprenorphine has become a rapidly popular withdrawal treatment medication for pregnant women.^8,9,10,11 As a partial opiate agonist, it has a ceiling effect in pleasurable effects and has shown increased compliance while also demonstrating lower transference through the placenta compared with methadone due to its greater molecular weight.

Physical

Severity of newborn withdrawal from substances depends on the drugs and the frequency of use by the mother during pregnancy.

• Nonopiate drug withdrawal: Withdrawal syndromes that are related to individual nonopiate drugs have been difficult to study. The high prevalence of polydrug use prevents clinicians from witnessing the effects of isolated medications. At this time, little data supports a description of a cocaine-abstinence syndrome.
• Alcohol withdrawal: Signs of alcohol withdrawal may include hyperactivity, crying, irritability, poor sucking, tremors, seizures, poor sleeping patterns, hyperphagia, and diaphoresis. Signs usually appear at birth and may continue until age 18 months. Withdrawal typically appears within 3-12 hours after delivery.
• Barbiturate withdrawal: Signs may include irritability, severe tremors, hyperacusis, excessive crying, vasomotor instability, diarrhea, restlessness, increased tone, hyperphagia, vomiting, and disturbed sleep.
• Marijuana withdrawal: For marijuana, a mild opiatelike withdrawal syndrome has been observed. Signs may include fine tremors, hyperacusis, and a prominent Moro reflex; however, these symptoms rarely require treatment.
• Nicotine withdrawal: Mild signs are observed, including fine tremors and variations in tone; recent data have shown that maternal smoking was associated with subtle neonatal behaviors, such as poor self-regulation and an increased need for handling.¹² These behaviors are suggestive that neonatal withdrawal is possible for nicotine exposure in utero.
• Acute narcotic withdrawal: This withdrawal usually begins 24-48 hours after birth, depending on the time of last dose. However, signs may not appear in the infant until 3-4 days after birth.
• Methadone withdrawal: Symptoms typically appear within 48-72 hours but may not start until the infant is aged 3 weeks. This is particularly true for infants whose mothers took excessively higher doses. Conflicting data has emerged concerning withdrawal severity and higher in-utero methadone doses. Data has shown that coexposure with nicotine increases the severity and duration of the neonatal withdrawal.
• Buprenorphine withdrawal: Symptoms typically occur within the first 72 hours. Typically, fewer postnatal complications are reported compared with methadone, but 10% of infants exposed to buprenorphine are delivered prematurely compared with 7% of infants who are not exposed.¹⁰
  • A neurological follow-up study revealed no significant differences in infants who received buprenorphine compared with infants who did not at age 4 months. However, some studies have seen increased levels of jitteriness, jerky movements, and lower limb hypertonia as late as age 9 months. However, effects of polydrug use cannot be ruled out.
  • As many as 85% of infants exposed to buprenorphine have shown signs of neonatal withdrawal; however, the syndromes and duration of treatment appear to be milder in comparison with infants exposed to methadone.
• Opiate withdrawal: Signs of neonatal abstinence syndrome (NAS) include hyperirritability, gastrointestinal dysfunction, respiratory distress, and vague autonomic symptoms (eg, yawning, sneezing, mottling, fever). Tremors and jittery movements, high-pitched cries, increased muscle tone, and irritability are common. Normal reflexes may be exaggerated. Loose stools are common, leading to possible electrolyte imbalances and diaper dermatitis.
  • Long-term symptoms have been difficult to study, but evidence supports that these children show hyperphagia, increased oral drive, sweating, hyperacusis, irregular sleep patterns, poor tolerance to environmental changes, and continued loose stools.
  • NAS appears to be less severe if the mother has used opiates longer than one week prior to delivery.
• Cocaine: Acute signs such as tremors, high-pitched cry, irritability, excess suck, hyperalertness, apnea, and tachycardia can be seen with the first 72 hours of life. However, because these signs can be seen before the typical half-life of a dose immediately prior to delivery, one can argue that these signs are more typical of intoxication, rather than withdrawal.
• Amphetamines: Whether amphetamine use during pregnancy affects neonatal outcome remains unclear. Increasing evidence suggests that it is associated with an increased risk of prematurity and intrauterine growth restriction and the risk of congenital anomalies does not appear to be increased.^13,14 As well, although several reports of neonatal amphetamine withdrawal are documented, each case involved polydrug use during the pregnancies.
• Phencyclidine: Because the number of known phencyclidine use during pregnancies is limited, little is known of the neonatal consequences. Some studies have reported neurobehavioral abnormalities in the immediate neonatal period, such as hypertonicity, irritability, sleep problems, and temperature instability. However, as in many other observational reports, these typically include patients with polydrug use during the pregnancy.
• Antidepressants: Perhaps no class of medications is more studied than the current generation of selective serotonin reuptake inhibitors (SSRI). Because of their widespread use, concern over possible fetal or infant effects have been well studied.¹⁵ In general, no withdrawal syndrome has been associated with SSRIs. However, infants have been noted to show jitteriness, respiratory distress, and other neonatal complications. They are more commonly observed in newborns whose mothers were taking a short-acting SSRI such paroxetine (Paxil). Debate rises over whether these symptoms are actually withdrawal or, more likely, a drug intoxication effect. Of all SSRIs studied, intrapartum use of sertraline (Zoloft) has shown the safest neonatal clinical profile.

Causes

Through multiple mechanisms, all drugs of abuse can cause molecular and cellular changes that ultimately lead to changes in neural migration, cell structure, neurotransmitter dynamics, and overall brain formation. These alterations are likely associated with a whole range of behavioral and cognitive changes. Maternal polydrug use is likely to be far more damaging than use of any single drug.

• Ethanol
  • Alcohol produces teratogenic effects associated with FAS and its variations. The suggested pathway for teratogenicity involves a direct effect on the anterior neural tube and surrounding structures. This leads to decreased brain development as well as typical FAS facies. The continuum of clinical outcomes within this disorder is broad. From the most severe form (FAS) to milder forms, such as alcohol-related neurodevelopmental disorder (ARND), issues of somatic growth, brain growth and development, and facial dysmorphisms can occur.
  • In animal models, evidence shows disruption in the hippocampus, cortical cytostructure, and neuronal migration. Changes in subsequent behavior in animal models reveal deficits in object permanence, increased distractibility, and delays in gross motor development.
• Nicotine
  • Studies on in utero effects of nicotine have typically focused on low birth weight and smaller head circumference. Evidence suggests that nicotine causes more than 50% of all low birth weight babies.
  • Further studies on nicotine's effects on behavior and neurochemistry are eagerly anticipated.
• Cocaine
  • Cocaine can freely cross the placental barrier. A widely held belief was that cocaine caused fetal hypoxia due to placental vasoconstriction.
  • Animal studies have shown disruptions in the neural and glial organization and migration.
  • Dopamine, serotonin, or both may mediate withdrawal from cocaine.
  • From a behavioral standpoint, cocaine has been shown to attenuate an animal's classic conditioning ability to noxious stimuli. Adult animal models of cocaine exposure tend to show a higher predisposition to self-administration for reward.
• Opiates
  • In utero opioid exposure has consistently shown a decrease in nucleic acid synthesis and protein production in the brain, suggesting that overall brain growth is compromised. Effects on neurotransmitter concentrations and production have not been confirmed.
  • Behaviorally, prenatally exposed animals tend to show decreased exploration and increased response latency to noxious stimuli.

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