Learning Objectives:After participating in this continuing education activity, the provider should be better able to:
1. Create treatment plans for patients who use illegal substances.
2. Compare how different substances affect both maternal and fetal health.
3. Explain long-term effects on the neonate.
Substance use in pregnancy can cause both maternal and fetal complications creating a significant public health concern. Maternal drug use in the United States has been increasing over the past decade, which has led to an increase in neonatal admissions and adverse health outcomes in the affected infants in the first year of life.1 It has been reported that 6.3% of pregnant women in the United States have used at least one illicit substance during their pregnancy, many of whom have used more than one drug.2 Illicit drugs include marijuana, cocaine, heroin, hallucinogens, inhalants, and prescription psychotherapeutics used nonmedically.
In 2017, the National Survey on Drug Use and Health, which interviewed over 67500 people in the United States, revealed marijuana was the most commonly used illicit drug, followed by nonmedical use of psychotherapeutics, cocaine, and hallucinogens.2
The effect of any illicit drug on pregnancy outcomes is difficult to assess due to limited data and other factors influencing outcomes, such as polysubstance use, poor nutrition, poverty, comorbid disorders, and inadequate prenatal care. In addition, patients are not likely to provide reliable information regarding the extent of drug use during pregnancy and drug dosages. This article reviews the most commonly used illicit substances in pregnancy and their effect on fetal outcomes with the anticipation that physicians will be better able to screen and care for these women.
Stimulants
Stimulants, known as "uppers," are frequently abused due to their performance-enhancing and euphoric effects. Stimulants include cocaine, amphetamines, and methamphetamines.
Cocaine use in pregnancy has multiple deleterious effects on both the mother and the fetus. Cocaine crosses the placenta and fetal blood-brain barrier. The mechanism of fetal and placental damage is due to vasoconstriction. One meta-analysis of 31 studies that looked at maternal antenatal cocaine exposure found that cocaine use during pregnancy significantly increased the risks of preterm birth, low birth weight, small-for-gestational age infant, shorter gestational age at delivery, and reduced birth weight.3 Other studies have shown that maternal antenatal cocaine use increased risks of miscarriage, placental abruption, and intrauterine growth restriction. It is also well known that cocaine use in pregnancy can be associated with severe maternal hypertension and a preeclampsia-type syndrome, which can include acute pulmonary edema, seizures, arrhythmias, and sudden death.
Newborn infants with prenatal cocaine exposure may exhibit neurobehavioral abnormalities that are seen most commonly between 48 and 72 hours of life. One study demonstrated that infants exposed to cocaine compared with control infants were more likely to have central and autonomic neurologic symptoms including tremors, high-pitched cry, irritability, excess suck, hyperalertness, and episodes of either apnea or tachypnea.4 Furthermore, prenatal cocaine exposure can cause structural deficits in the infant brain that have been associated with functional connectivity and neurobehavioral disruptions.5,6
After alcohol and marijuana, methamphetamine is the drug most frequently abused in many Western and Midwestern states. In pregnant women, admissions for the treatment of methamphetamine abuse increased from 8% in 1994 to 24% by 2006.7 Women whose deliveries were complicated by amphetamine use also had a significantly higher course of cannabis, cocaine, alcohol, and sedatives compared with controls.8 Although amphetamines and their byproducts cross the placenta,9 no fetal structural abnormalities have been associated with perinatal amphetamine exposure.10 However, methamphetamine exposure during pregnancy has been associated with maternal and neonatal morbidity and mortality. For example, methamphetamine exposure was associated with a 2- to 4-fold increase in risk of fetal growth restriction, gestational hypertension, preeclampsia, placental abruption, preterm birth, lower birth weight, lower Apgar scores, intrauterine fetal demise, neonatal death, and infant death.11-15
Opioids
The term "opioid" refers to natural and synthetic substances that activate m-opioid receptors in the central nervous system. Examples of opioids include morphine, codeine, heroin, methadone, fentanyl, hydromorphone, and buprenorphine.
Opioid use in pregnancy has increased exponentially in the past decade, which parallels the epidemic in the general population. The prevalence of opioid use by pregnant women in the United States at the time of delivery quadrupled between 1999 and 2014 based on data from 28 states (from 1.5 to 6.5 per 1000 deliveries).16 Pregnant women with opioid use disorder generally have other mental health conditions such as depression, history of trauma, posttraumatic stress disorder, and anxiety. The rising prevalence of opioid use in pregnancy has led to a sharp increase in neonatal abstinence syndrome (NAS), from 1.5 cases per 1000 hospital births in 1999 to 6.0 per 1000 hospital births in 2013, with an associated $1.5 billion in related annual hospital charges.17 Over 30% of pregnant women in substance use treatment programs were found to have moderate to severe depression, and over 40% had symptoms of postpartum depression.18 Furthermore, these women are at an increased risk to use other substances, such as tobacco, marijuana, and cocaine.
There are numerous obstetrical and neonatal complications that have been associated with opioid dependence in pregnancy. Opioid-dependent pregnant women have an increased risk of spontaneous abortion, placental insufficiency, preterm birth, intrauterine growth restriction/oligohydramnios, chorioamnionitis, preeclampsia, placental abruption, intrauterine fetal demise, septic thrombophlebitis, and postpartum hemorrhage.15-17
There is a well-known risk of NAS associated with in utero exposure to opioids. NAS is defined by signs of opioid withdrawal. The pathophysiology of NAS is not well understood, but it is thought to involve altered levels of neurotransmitters such as norepinephrine, dopamine, and serotonin.19 Symptoms include sleep and wake cycle disturbances, alterations in tone or movement, autonomic dysfunction, easy overstimulation, sensitivity, or hyperarousal, difficulty with feeding and gastrointestinal issues. Among infants with prenatal exposure to opioids, the reported rate of NAS requiring pharmacotherapy ranges from 42% to 94%.20-22
Pharmacotherapy with either methadone or buprenorphine (opioid agonists) has been used for treatment of opioid use disorder. These medications help prevent opioid withdrawal symptoms and help reduce relapse risk. Methadone is provided to patients on a daily basis by a registered opioid treatment program. During the antepartum period, methadone should continue to be managed by addiction treatment specialists within registered opioid treatment programs. It is important to keep open communication between the obstetrician and the opioid treatment program. The methadone dosage may need to be adjusted throughout the pregnancy to avoid withdrawal symptoms. Evidence also supports the use of buprenorphine for opioid use disorder treatment during pregnancy. Some advantages of buprenorphine over methadone include fewer drug interactions, being able to take the medication at home (without the need for daily visits to an opioid treatment program), and less need for dosage adjustments throughout pregnancy.23
Benzodiazepines
Benzodiazepines are prescribed for a variety of conditions including anxiety, insomnia, and muscle relaxation. They act as [gamma]-aminobutyric acid type A (GABA-A) receptor agonists, exerting a calming effect on the brain. Short-term effects include relaxation, lethargy, sedation, and fatigue, whereas higher doses can lead to temporary euphoria, confusion, dizziness, slurred speech, vertigo, mood swings, and visual distortion.24 Benzodiazepines can be used during pregnancy to manage severe anxiety or agitation, but in some instances these medications are used illegally. A systematic review of more than 1 million subjects suggested that benzodiazepines were not associated with an increased risk of congenital malformations.25 However, benzodiazepines appear to be associated with spontaneous abortion. A meta-analysis, which included approximately 600 pregnant women treated with benzodiazepines during the first trimester and a similar number of unexposed control women, found that benzodiazepines were associated with an increased risk of spontaneous abortion.25 Furthermore, one study demonstrated that maternal use of benzodiazepines may increase the risk for preterm birth and low birth weight.25,26
Benzodiazepines cross the placenta. Chronic administration of benzodiazepines during pregnancy, especially close to delivery, can cause neonatal toxicity and withdrawal, including low Apgar scores, apnea, hypothermia, hyperreflexia, hypertonia or hypotonia, irritability, lethargy, restlessness, tremor, diarrhea, poor feeding, and vomiting. When used in conjunction with opioids, the risk for NAS increases.24 These symptoms may persist as long as 3 months postpartum.23,26-28 There is insufficient data to suggest psychomotor developmental delay after the newborn period.24
Long-term effects of benzodiazepine use are associated with maternal tolerance, physiologic and psychologic dependence, and withdrawal. Diazepam and alprazolam are associated with the highest risk of abuse due to their rapid onset and hedonic effects. Symptoms of withdrawal can occur in patients who have taken benzodiazepines continuously for over 3 to 4 weeks and discontinue abruptly. Acute withdrawal begins within 24 hours and peaks in 1 to 9 days. Symptoms include cardiovascular and central nervous system excitability, psychologic effects, gastrointestinal symptoms, seizures, and delirium. For this reason, maternal benzodiazepine use should not be abruptly discontinued during pregnancy. Instead, an interdisciplinary tapering regimen is recommended.24
Tobacco
A study of US birth certificate data from 2014 reported that 8% of women reported smoking tobacco at any time during pregnancy.29 Several mechanisms have been hypothesized to explain the adverse pregnancy outcomes associated with maternal smoking. These include impaired fetal oxygenation, altered fetal development and physiologic response, and toxin exposure.30,31 In addition to impairing fetal oxygen delivery, nicotine use during pregnancy impacts fetal development.
Regarding pregnancy outcomes, cigarette smoking has been associated with numerous adverse pregnancy outcomes, including spontaneous pregnancy loss, placental abruption, preterm premature rupture of membranes, placenta previa, preterm labor and delivery, low birth weight, and ectopic pregnancy.32 In a meta-analysis of 142 studies, maternal smoking increased the risk of stillbirth by nearly 50% and the risk of neonatal death by over 20%.33 Meta-analyses have shown that maternal cigarette smoking is associated with a significant reduction in the risk of preeclampsia.34 This benefit of smoking does not outweigh the numerous risks associated with smoking during pregnancy.
Postnatal morbidities that have been associated with maternal smoking include sudden infant death syndrome, respiratory infections (eg, bronchitis and pneumonia), asthma, atopy, otitis media, infantile colic, bronchiolitis, short stature, lower reading and spelling scores, shorter attention spans, hyperactivity, childhood obesity, and decreased school performance.
Vaping
Of note is the recent epidemic of vaping-induced lung injury. Clusters of cases in most states across the United States report acute, severe respiratory distress after using e-cigarette (vaping) products.35,36 Electronic vapor products (EVPs), also known as electronic cigarettes or e-cigarettes, vapes, e-hookahs, and vape pens, use an electronic delivery system that aerosolizes nicotine and tetrahydrocannabinol (THC), producing a vapor similar to cigarettes.37 The use of EVP has increased incrementally in recent years. In a survey of women in United States from 2014 and 2017, approximately 3% of women 18 to 44 years old used an EVP; use was similar among pregnant and nonpregnant women (3.6% and 3.3%, respectively).38 According to the 2015 Pregnancy Risk Assessment Monitoring System, studies of women in Oklahoma and Texas demonstrated that 7% used an EVP around the time of pregnancy.39 The mechanisms of acute toxic lung injury include acute eosinophilic pneumonia, organizing pneumonia, lipoid pneumonia, diffuse alveolar damage, diffuse alveolar hemorrhage, hypersensitivity pneumonitis, rare giant cell interstitial pneumonitis, and acute respiratory distress syndrome. EVP fluids, even when legally purchased, have been shown to contain several potentially toxic compounds: nicotine, carbonyls, volatile organic compounds (eg, benzene and toluene), particles, trace metal elements, bacterial endotoxins, and fungal glucans.35,36 Despite ongoing investigations into its harms, obstetricians should discourage patients from EVP use. Moreover, it should be emphasized that EVP should not be used as a method of smoking or THC cessation.
Marijuana
Marijuana is the most commonly used illicit drug in pregnancy. In a survey of self-reported cannabis use by pregnant women in the United States, there was an increase from nearly 6% to 12% between 2002 to 2003 and 2016 to 2017.40 Another study from the United States National Survey on Drug Use and Health database demonstrated that the percentage of women who believed that regular marijuana use was of no risk during pregnancy increased from 4.6% in 2005 to 19% in 2015.41 Of note, many states either have or are trying to legalize marijuana, which we believe will lead to an increased use of this drug by pregnant women.
There are conflicting data regarding the risk of preterm delivery and low birth weight in women who use marijuana during pregnancy. The American College of Obstetricians and Gynecologists (ACOG) advises avoiding marijuana use during pregnancy because of concerns for the neurodevelopmental impact on the developing fetus and child.
In animal studies, THC crossed the placenta, producing fetal plasma levels that were approximately 10% of maternal levels after acute exposure. Significantly higher fetal concentrations were observed after repetitive exposures.42
Animal studies revealed that cannabinoid exposure in utero may disrupt normal brain development and function. In utero exposure to cannabinoids includes impaired cognition and increased sensitivity to drugs of abuse.43 Studies demonstrated that children who were exposed to marijuana in utero had lower scores on tests of visual problem-solving, visual-motor coordination, and visual analysis as compared with children who were not exposed to marijuana.44 In addition, marijuana exposure is associated with decreased attention span and behavioral problems and is a predictor of marijuana use by age 14 years.45 There is no evidence to suggest that marijuana causes structural anatomic defects in humans.
A meta-analysis of 31 studies comparing birth outcomes after marijuana use in pregnancy with no use during pregnancy found that there was no increased risk for low birth weight or preterm delivery.46 On the other hand, in a large population-based retrospective cohort study that compared over 9000 prenatal marijuana users with nonusers, marijuana users had twice the rate of preterm births as nonusers (12.0% vs 6.1%).47 More studies will be needed to assess marijuana impact on fetal development.
Alcohol
Alcohol consumption during pregnancy is common. A survey by the Centers for Disease Control and Prevention, from 2015 to 2017, showed that approximately 4% of pregnant women reported binge drinking (consuming >= 4 drinks on at least 1 occasion) within the prior 30 days and approximately 12% reported any alcohol consumption within the prior 30 days.48 All women seeking obstetric care should be screened for alcohol use within the first trimester of pregnancy. ACOG recommends screening for alcohol use with a variety of simple validated tools such as T-ACE (Figure 1).49
A safe level of alcohol consumption during pregnancy has not been determined. Alcohol is a teratogen that impacts fetal growth and development at all stages of pregnancy. Therefore, guidelines from medical societies across a multitude of countries recommend complete abstinence during pregnancy. Infants whose mothers consume alcohol during pregnancy can manifest fetal alcohol effects, alcohol-related birth defects, fetal alcohol syndrome, or they may have no deficits. The relationship between the amount of alcohol consumed during the prenatal period and the extent of damage alcohol will have on the infant is not known. The patterns of alcohol consumption and socioeconomic and ethnic factors also affect outcome of the fetus. Furthermore, binge drinking may have a greater negative effect than comparable consumption of low amounts of alcohol over several days (eg, 4 drinks in 1 sitting vs 1 drink a day for 4 days).
Fetal alcohol spectrum disorder (FASD) is a term to describe the range of physical, behavioral, and neurodevelopmental effects that can occur in an individual who was exposed to alcohol prenatally. FASD manifests as several characteristic facial features, including short palpebral fissures, thin vermillion border, and smooth philtrum. Physical features of prenatal alcohol exposure are present in up to 25% of affected children.50 Poor growth, which can begin in utero, may continue through infancy and childhood. Short stature can persist into adolescence and adulthood. For example, in a series of 1400 patients (newborn to adult) with confirmed alcohol exposure, 34% had height and/or weight below the 10th percentile.51 Alcohol exposure in the first trimester is associated with facial anomalies and major structural anomalies, including brain anomalies.52 The effects on the central nervous system are irreversible. In the second trimester, alcohol exposure increases the risk of spontaneous abortion, and exposure in the third trimester predominantly affects fetal weight and brain growth.52 However, neurobehavioral effects can occur with a range of exposure throughout pregnancy, even without facial or structural brain anomalies. Approximately 70% of children with heavy prenatal alcohol exposure (>4 drinks at least once per week or >14 drinks per week throughout the pregnancy) have neurobehavioral effects.53
Conclusion
Substance abuse in pregnancy is a significant health concern, as it can cause adverse maternal and neonatal outcomes. In addition to the effects of drug exposure in utero, there can be long-term health complications for the infant. Routine screening early in pregnancy is essential to early intervention.
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