Perinatal Drug Abuse and Neonatal Drug Withdrawal

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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.

O’Donnell and colleagues measured the birth prevalence of neonatal withdrawal syndrome over time, associated maternal characteristics, and child protection involvement. [1] This retrospective cohort study used linked health and child protection databases for all live births in Western Australia from 1980-2005. Maternal characteristics and mental health-related and assault-related medical history were assessed using logistic regression models. The study showed the birth prevalence of neonatal withdrawal syndrome increased from 0.97 cases per 10,000 live births to a high of 42.2 per 10,000 live births, plateauing after 2002. Mothers with a previous mental health admission, with a low skill level, with Aboriginal status, or who smoked during pregnancy were significantly more likely to have an infant with neonatal withdrawal syndrome. These infants were at greater risk of having substantiated child maltreatment allegation and for entering foster care.

These results show an important pathway into child maltreatment and the need for well-supported programs for women who use illicit drugs during pregnancy and long-term support after birth of the child.

In 2011, the American Academy of Pediatrics published a clinical report detailing the recommended guidelines for the management of neonatal drug withdrawal. [2]

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.

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:

In the first 20 weeks of gestation, damage can occur during cytogenesis and cell migration.

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.

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. [3] 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. [4] 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.

Recent studies have shown an increase in the incidence of neonatal abstinence syndrome between 2000 and 2009, from 1.20 cases to 3.39 cases per 1000 hospital births per year. As well, the cost of treating an infant with neonatal abstinence syndrome increased from an estimated average of $39,400 in 2000 to $53,400 in 2009. [5]

International

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

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.

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

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. [6] In another study, Hien et al reported that 60% of women who abuse substances claimed to have an adult partner who committed domestic violence. [7] 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. [8] 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).

Little data on the age stratification of substance abusing mothers are 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 teenagers who do use substances, the amount used is far lower than the amount used by adult users who are pregnant.

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Marvin Wang, MD Clinical Instructor, Department of Pediatrics, Harvard Medical School; Co-director of Newborn Nurseries, Attending Physician, Department of Pediatrics, Massachusetts General Hospital,

Disclosure: Received research grant from: New England Pediatric Device Consortium.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Brian S Carter, MD, FAAP Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Attending Physician, Division of Neonatology, Children’s Mercy Hospital and Clinics; Faculty, Children’s Mercy Bioethics Center

Brian S Carter, MD, FAAP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Hospice and Palliative Medicine, American Academy of Pediatrics, American Pediatric Society, American Society for Bioethics and Humanities, American Society of Law, Medicine & Ethics, Society for Pediatric Research, National Hospice and Palliative Care Organization

Disclosure: Nothing to disclose.

Ted Rosenkrantz, MD Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine

Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Eastern Society for Pediatric Research, American Medical Association, Connecticut State Medical Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

David N Sheftel, MD, MD Assistant Professor of Pediatrics, Chicago Medical School at Rosalind Franklin University of Medicine and Science

David N Sheftel, MD, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics

Disclosure: Nothing to disclose.

Perinatal Drug Abuse and Neonatal Drug Withdrawal

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