Perinatal Drug Abuse and Neonatal Drug Withdrawal

The use and abuse of addictive drugs has occurred throughout many centuries. Only relatively 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 40-50 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 of these factors play tremendous roles in child development.

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. ^[1]

Note that many states in the United States are decriminalizing marijuana use, for medical and nonmedical uses. An overall 9.8% of women self-report prepregnancy marijuana use, 4.2% during pregnancy, and 5.5% post pregnancy, primarily as a means of stress/anxiety relief or relief from vomiting or pain. ^[2]

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 two 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.

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 fetal alcohol syndrome (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 (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.

United States data

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.

Studies showed 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]

In a 2018 retrospective study (1999-2014), the national prevalence of opioid abuse in the United States increased by 333%, from 1.5 cases per 1,000 delivery hospitalizations to 6.5 per 1,000 delivery hospitalizations, an average annual increase of 0.4 per 1,000 delivery hospitalizations per year. ^[6] ​

In 2020, between 8-11% of pregnant women aged 15 to 44 used illicit drugs, tobacco products, or alcohol in the past month. Marijuana is the most commonly used illicit drug among pregnant women. ^[7]  Nearly 1 in 12 newborns in the United States in 2020 experienced prenatal exposure to alcohol, opioids, marijuana, or cocaine. ^[8]

International data

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

O’Donnell and colleagues measured the birth prevalence of neonatal withdrawal syndrome over time, associated maternal characteristics, and child protection involvement. ^[9] This retrospective cohort study used linked health and child protection databases for all live births in Western Australia from 1980 to 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. 

Race-related demographics

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.

Sex-related demographics

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. ^[10] In another study, Hien et al reported that 60% of women who abuse substances claimed to have an adult partner who committed domestic violence. ^[11] 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. ^[12] 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-related demographics

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.

Prognosis

Growth deficiency

Children with prenatal nicotine exposure exhibit appropriate catch-up growth but are known to have smaller lungs and, possibly, decreased ventilatory drive in response to carbon dioxide.

Children with prenatal amphetamine and cocaine exposure exhibit catch-up growth within 2 years of life.

Children with prenatal opiate exposure typically do not exhibit changes in growth parameters.

Infants exposed to buprenorphine have not exhibited significant differences in growth parameters compared to infants who have not been exposed.

Cognitive and developmental defects

Infants exposed to nicotine tend to score higher on auditory habituation but lower on the orientation cluster of the Brazelton Newborn Behavioral Assessment Scale (NBAS).

Infants exposed to alcohol may develop intellectual disability, which is one of the hallmarks of fetal alcohol syndrome (FAS). An apparent dose-dependent relationship is present, and FAS now accounts for approximately 33% of all intellectual disability. Milder cognitive effects include prolonged language delays and sleep dysfunction. Newborns exposed to alcohol also tend to be hypotonic.

Infants exposed to cocaine may exhibit fetal brain malformation resulting from changes in the homeostatic neurochemistry. Serious debate surrounds the actual deleterious effects of in utero cocaine exposure. Consequences previously described include altered behavior on NBAS scores (eg, poor state regulation, decreases in alertness and orientation, abnormal reflexes, tone and motor maturity), increased tone (described as hypertonic tetraparesis), electroencephalogram (EEG) changes, abnormal auditory brainstem responses, ^[13] and prolonged behavioral and language delays. However, data are inconsistent to prove that cocaine is solely responsible for these problems. Prenatal cocaine exposure can negatively affect the overall quality of maternal-child interaction during early childhood. ^[14] Research on this topic has been difficult, as confounding variables (eg, postnatal psychosocial issues, polydrug use in pregnancy) are difficult to control.

Prior conventional wisdom dictated that neurological morbidity was associated with cumulative postnatal risks preventing proper development. Prospective studies have shown no direct effect of cocaine exposure on development at age 3 years after correcting for race, parity, and socioeconomic status. However, data have also shown that infants exposed to cocaine may require more educational services than infants who are not exposed. ^{[15, 16]} The effect was magnified if the infants also had low birth weight or if they had low intelligence quotient (IQ).

A follow-up to the Maternal Lifestyle Study has shown that high exposure to cocaine, particularly with other drugs, is associated with behavioral issues in adolescence. However, protective factors such as beneficial bonding, community and family support, as well as stable home structure can attenuate the intensity of these behavioral issues. ^[17]

Infants exposed to opioids may have increased overall activity on NBAS testing. They tend to have difficulty being consoled. These infants also have been shown to have an early learning difficulty. ^[16]

Infants exposed in utero to methadone have been shown to have altered visual-evoked potentials, inferring a need for earlier visual assessments. ^[18]

Treatment length

Although length of treatment cannot always be correlated as a dose-dependent relationship with maternal use, data have suggested that, in mothers using high doses of methadone, for every daily dosage increase of 5.5 mg, an extra day in length of treatment time was added. Gestational age was not seen as significant. ^[19] However, data have also shown that infants born to mothers using methadone had increased length of treatment when concomitant benzodiazepine use or increased gestational age were associated. These findings were noted even when controlling for maternal methadone dose, concomitant use of tobacco or antidepressants, and trimester timing of initial dose. ^[20]

Several studies have compared the withdrawal effects of buprenorphine exposure with that of methadone exposure. In most cases, buprenorphine exposure was associated with decreased overall neonatal withdrawal treatment time and lower neonatal length of stay. Data on whether infants exposed to buprenorphine were more likely to require withdrawal treatment compared with infants exposed to methadone are conflicting. ^{[21, 22, 23]}

Morbidity/mortality

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 a 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. ^[24] As such, poor feeding alone can start a cascade of other diagnoses.

Complications

Perinatal complications include the following:

• Incidence of medical and obstetric complications increases with in utero drug exposure. In particular, the incidence of premature delivery, abruptio placentae, breech presentation, and intrauterine growth retardation are significantly increased in mothers who are dependent on drugs. The doses of analgesia are typically higher to match the tolerance to drugs already being used.

• In particular, cocaine use, with its vasoconstrictive properties, has been associated with an increase in vaginal bleeding, abruptio placentae, placenta previa, premature rupture of membranes, abortion, pneumothorax, pneumonia, malnutrition, and seizures.

• Amphetamine use presents similarly to cocaine use and is related to an increased rate of abruptio placentae, maternal hypertension, and renal disease. Hypertension can often be confused with preeclampsia, leading to an increased cesarean delivery rate.

• Opioid use has been shown to increase the rate of premature labor, premature rupture of membranes, breech presentation, antepartum hemorrhage, toxemia, anemia, uterine irritability, and infection (eg, HIV, hepatitis, syphilis).

• Alcohol use has been associated with an increased rate of abruptio placentae. Complications for mothers who drink alcohol heavily can include increased spontaneous abortions and premature placental separation.

• Cannabinoid use has been associated with an increased serum carboxyhemoglobin level. A slightly elevated incidence of precipitate labor, meconium staining, and dysfunctional labor occurs in mothers who use cannabinoids.

• Maternal methadone use has been correlated with infant complications, such as prematurity, symmetrical growth retardation, and increased risk of neonatal abstinence syndrome (NAS), admission to the neonatal intensive care unit (NICU), small for gestational age (SGA), and major congenital anomalies. ^{[25, 26]}

Prematurity is accompanied by a host of medical complications including asphyxia, neonatorum, intracranial hemorrhage, respiratory distress syndrome, hypoglycemia, hypocalcemia, septicemia, and hyperbilirubinemia.

Although gross generalizations, the following growth characteristics may occur as a result of exposure to drugs:

• Tobacco is described as perhaps the most common cause of low birth weight deliveries. Symmetric decreases are observed in all growth parameters, but these children exhibit appropriate catch-up growth.

• Alcohol may cause symmetric decreases in all growth parameters. Data supports a synergistic effect in growth retardation with concomitant cocaine abuse.

• Amphetamines and cocaine may cause symmetric decrease in all growth parameters. However, the growth-restricting effect of cocaine is more likely a result of maternal malnutrition. Likewise, growth retardation resulting from cocaine use tends to resolve with catch-up growth within 2 years after birth.

• Opiate use may result in normal growth parameters. In particular, newborns exposed to methadone tend to have higher-than-expected growth parameters.

Government programs are available to help the prevention of perinatal drug use. Many have published documents that address support for pregnant women who abuse substances, addiction prevention, and treatment programs and guidelines for clinicians managing patients who abuse substances. These publications are available to primary care physicians and obstetricians and can be obtained free of charge from the Substance Abuse and Mental Health Administration (SAMHSA).

The following Internet sites provide guidelines for providers:

• American Academy of Pediatrics

• National Institute on Drug Abuse (NIDA)

• Administration for Children and Families (ACYF) for programs on foster care, adoption, family support, Head Start, child abuse and neglect, and child welfare