Illicit and licit substance use during pregnancy and its effects on the woman, on the pregnancy, and on the fetal and postnatal development are complex.
With the increased use of cocaine during the latter half of the 1980s and 1990s, there was great interest in determining the effects of cocaine use during pregnancy. As research in this area progressed, many of the critical methodologic issues related to substance use research were highlighted.100,140,179,225,337
Substance-using women often have multiple risk factors for adverse pregnancy outcomes, such as low socioeconomic status, polysubstance use, ethanol and cigarette use, sexually transmitted infections, AIDS, malnutrition, and lack of prenatal care. Lack of prenatal care is highly correlated with premature birth, and smoking is associated with spontaneous abortion, growth retardation, and SIDS.152,330 Other factors not specifically related to substance use such as age, race, gravidity, and prior pregnancies also affect pregnancy outcome. Each of these factors represents a significant potential confounding variable when the effects of a particular xenobiotic such as cocaine or marijuana are evaluated during pregnancy and must be controlled for in research design. Many of these factors are also significant confounders in evaluation of postnatal growth and development.
There may be bias in the selection of study subjects. For example, if all the patients are selected from an inner-city hospital obstetrics service, there is potential for overestimating the effects of the xenobiotic being studied. If cohorts are followed over a long time, study subjects are frequently lost to follow-up. Are the ones who continue more motivated, or do they have more problems that need attention?
Categorizing patients into substance-use groups is difficult. Self-reporting of substance use is frequently unreliable or inaccurate, and making determinations about the nature, frequency, quantity (dose), or timing (with respect to gestation) of xenobiotic exposure is difficult. Because substance users frequently use multiple xenobiotics, it may be difficult to categorize subjects into particular xenobiotic-use groups, and patients using different xenobiotics may be grouped together. In fact, there may be no actual xenobiotic-free control groups.
When urine drug screens are used to identify substance users, there is a high probability of false negatives because drug screens reflect only recent use. This factor is particularly important because substance use tends to decrease later in pregnancy, and a negative urine drug screen in the third trimester or at delivery may fail to identify a woman who was using xenobiotics early in pregnancy. Testing for xenobiotics in hair or meconium may improve the accuracy of the analysis with regard to the entire pregnancy.39,160
Another bias involves selection of infants who are exposed to xenobiotics. Evaluating newborns who are “at risk,” show signs of withdrawal, or have positive urine drug screens will miss some exposed infants. When research concerns the neurobehavioral development of children exposed in utero to substances, it is important that the examiners performing the evaluation be blinded to the infants’ xenobiotic exposure category.
Finally, there may be a bias against publishing research that shows a negative or no significant effect.161
Chronic ethanol use during pregnancy produces a constellation of fetal effects. The most severe effects occur in the FAS, which is characterized by (1) intrauterine or postnatal growth retardation; (2) intellectual disability or behavioral abnormalities; and (3) facial dysmorphogenesis, particularly microcephaly, short palpebral fissures, epicanthal folds, maxillary hypoplasia, cleft palate, a hypoplastic philtrum, and micrognathia.32,200 A child can be diagnosed with FAS even when a history of regular gestational alcohol use cannot be confirmed.
In an attempt to formalize diagnostic criteria for FAS and other gestational alcohol-related effects, the Institute of Medicine proposed some additional descriptors that are in common use.300Partial FAS is applied to a child with some of the characteristic facial features and with growth retardation, neurodevelopmental abnormalities, or other behavioral problems. Alcohol-related birth defects are congenital anomalies other than the characteristic facial features described earlier, for example, cleft palate, which sometimes occurs with regular gestational alcohol use. Alcohol-related neurodevelopmental disorder describes neurodevelopmental abnormalities or other behavioral problems, which sometimes occur with regular gestational alcohol use. Fetal alcohol spectrum disorders (FASDs) is an umbrella term describing the range of effects that can occur in an individual whose mother drank alcohol during pregnancy.32,294
Differential expression of the syndrome may reflect the effects of varying quantities of ethanol ingested at critical periods specific for particular effects. The craniofacial anomalies probably represent teratogenic effects during organogenesis, but some CNS abnormalities and growth retardation may result from adverse effects later in gestation.
There is considerable controversy about what amount of alcohol consumption can cause FASD.221,229 Approximately 10% of women consume some alcohol during pregnancy, 2% are frequent users, and 2% binge. Of women who might become pregnant, about 50% drink some alcohol, 13% drink frequently, and 12% binge.52 Some researchers believe that the FASD is a result of alcoholism—chronic regular use or frequent binging—rather than to low concentrations of gestational ethanol exposure, no matter how little or how infrequent.4,115 A high level of consumption would be in the range of 50 to 100 mL of 100% ethanol (four to six “standard” drinks of hard liquor) regularly throughout pregnancy300 or binge drinking (at least five standard drinks per occasion), with a significantly elevated peak blood ethanol concentration.3,197 Literature suggests that behavioral abnormalities are associated with the reported consumption of as little as one drink per week.295 In this regard, neither a no-effect amount nor a safe amount of ethanol use in pregnancy has been determined,149 and therefore the US Surgeon General recommends no alcohol consumption during pregnancy.232
The incidence of FAS is 0.5 to 3 per 1000 live births; 4% of women who drink heavily may give birth to children with FAS.2,207 This means that several hundred children with FAS and several thousand with fetal alcohol effects will be born each year; thus, ethanol use is considered the leading preventable cause of intellectual disability in this country.300 Although the primary determinant of FAS and its effects is the amount of maternal ethanol consumption, there is some evidence that paternal ethanol exposure may play a contributing role.1
Ethanol use during pregnancy may lead to an increased incidence of spontaneous abortion, premature deliveries, stillbirths,198 neonatal ethanol withdrawal,28,227 and possibly carcinogenesis.156 Infants may be irritable or hypertonic and may have problems with habituation and arousal. Long-term behavioral and intellectual effects include decreased IQ, learning disabilities, memory deficits, speech and language disorders, hyperactivity, and dysfunctional behavior in school.206,295,301
Brain autopsies of children with FAS demonstrate malformations of gray and white matter, a failure of certain regions such as the corpus callosum to develop, a failure of certain cells such as the cerebellar astrocytes to migrate, and a tendency for tissue in certain regions to die.97 The mechanisms of ethanol-induced teratogenesis are not fully elucidated.29,121 Much of the work in animals has focused on the developing nervous system, where ethanol adversely affects nerve cell growth, differentiation, and migration, particularly in areas of the neocortex, hippocampus, sensory nucleus, and cerebellum.117,303
Several mechanisms are potential contributors to the effects of ethanol.114 Ethanol interferes with a number of different growth factors, which may affect neuronal migration and development.331 In addition, ethanol interferes with the development and function of both serotonin and N-methyl-d-aspartate (NMDA) receptors. Ethanol, or its metabolite acetaldehyde, may also cause cell necrosis directly or through the generation of free radicals and excessive apoptosis.64,97,125 In particular, craniofacial abnormalities may be related to apoptosis of neural crest cells through the formation of free radicals, a deficiency of retinoic acid, or the altered expression of homeobox genes that regulate growth and development.303
One integrative model of ethanol-induced teratogenesis proposes that sociobehavioral risk factors, such as drinking behavior, smoking behavior, low socioeconomic status, and cultural or ethnic influences, create provocative biologic conditions, such as high peak blood ethanol concentrations, circulating tobacco constituents, and undernutrition. These provocative factors exacerbate fetal vulnerability to potential teratogenic mechanisms, such as ethanol-related hypoxia or free radical-induced cell damage.5
Opioid use in pregnancy remains a significant cause of both maternal and neonatal morbidity. In past month surveys, approximately 0.2% of pregnant women report heroin use, 0.9% report the illicit use of prescription pain relievers, and 0.1% report the use of oxycodone (OxyContin).269 Up to 75,000 babies per year may be exposed to methadone or heroin in utero.222 Most clinical research regarding opioid toxicity during pregnancy relates to the use of heroin or methadone.
Pregnant opioid users are at increased risk for many medical complications of pregnancy, such as hepatitis, sepsis, endocarditis, sexually transmitted infections, and AIDS, and may be at increased risk for obstetric complications, such as miscarriage, premature delivery, or stillbirth.100,113 Some of the obstetric complications may be related to associated risk factors in addition to the opioid use. Maternal opioid use most commonly affects fetal growth.100,113,337 There is an increased incidence of low birth weight in babies born to opioid-using mothers compared with control participants, and the effect is greater for heroin than for methadone.
There is extensive clinical experience with methadone maintenance during pregnancy. Compared with untreated heroin use, methadone maintenance during pregnancy is associated with better obstetric care, decreased risk of maternal withdrawal, increased fetal growth, decreased fetal mortality, decreased risk of HIV infection, and increased likelihood that a child will be discharged home with his or her parents.146 Women who receive low-dose methadone and good prenatal care are at increased risk for pregnancy-related complications but have birth outcomes similar to nonusers.100 For these reasons, methadone maintenance has become the standard opioid replacement therapy during pregnancy.135
Nonetheless, alternatives to methadone are being explored. Just as alternative opioid replacement strategies with buprenorphine have been introduced for opioid users in general, new strategies using buprenorphine in pregnancy are being tested. In one large trial, obstetric outcomes were similar after buprenorphine treatment compared with methadone, although more women in the buprenorphine arm dropped out of the study because they did not feel well during the induction of therapy.146,147 One group in Australia is using implantable naltrexone in pregnant patients after opioid detoxification.137,138
The most significant acute neonatal complication of opioid use during pregnancy is the neonatal withdrawal syndrome (NWS), which is characterized by hyperirritability; GI dysfunction; respiratory distress; and vague autonomic symptoms, including yawning, sneezing, mottling, and fever.135 Myoclonic jerks or seizures may also signify neurologic irritability. Withdrawing infants are recognizable by their extreme jitteriness despite efforts at consolation; ecchymoses and contusions may be found on the tips of their fingers or toes as a result of trauma from striking the sides of the bassinet. Approximately 50% to 90% of methadone, heroin, buprenorphine, and probably other chronic opioid-exposed newborns show some signs of withdrawal.100,146
Opioid withdrawal symptoms typically occur within one week of birth. Heroin withdrawal usually occurs within the first 24 hours, but methadone and buprenorphine withdrawal usually occur within 2 to 3 days of age. The onset of methadone withdrawal is delayed because methadone has a larger volume of distribution and slower metabolism in the neonate and therefore an increased half-life. The onset and severity of methadone withdrawal may be related to absolute neonatal serum concentration or the rate of decline in concentration.83,168 In one study, methadone withdrawal occurred when the plasma concentration fell below 0.06 mg/mL.262
The onset and severity of symptoms may also be related to which opioid(s) as well as other licit and illicit substances were used; how much was used chronically; how much was used near the time of delivery; the character of the labor; whether analgesics or anesthetics were used; and the maturity, nutrition, and medical condition of the neonate.80 Acute neonatal withdrawal symptoms generally last from days to weeks, but as many as 80% of infants have been reported to have recurrence of some symptoms such as restlessness, agitation, tremors, wakefulness, hyperphagia, colic, or vomiting for 3 to 6 months.58 In general, the incidence and severity of withdrawal are thought to be greater from methadone than from either heroin or buprenorphine.135 When methadone was compared with buprenorphine, buprenorphine-exposed infants required lower total doses of morphine to control symptoms, had shorter courses of treatment, and had shorter hospitalizations overall.146,147
From 5% to 7% of babies showing signs of withdrawal experience seizures, generally by 10 days after birth.127 Seizures may be more likely after methadone withdrawal than after heroin withdrawal. These seizures do not necessarily predispose to idiopathic epilepsy; in one small study, children who had withdrawal seizures were without seizures and had normal neurologic examination findings and psychometric testing at one-year follow-up.84
Treatment of withdrawal begins by providing a comforting environment: swaddling or tightly wrapping the infant, minimal handling or stimulation, and demand feeding. More severe symptoms may require pharmacologic therapy. The severity of withdrawal as measured by a standardized scoring scale determines the need for therapy; several scales are in use.100,185 In general, babies who are extremely irritable; have feeding difficulties, diarrhea, or significant tremors; or cry continuously are candidates for pharmacologic therapy.135
Opioid agonists such as morphine, methadone, tincture of opium, and paregoric; sedative–hypnotic agents such as diazepam and phenobarbital; and clonidine have all been used both individually and in various combinations to treat withdrawal symptoms. Few well-controlled trials have evaluated the relative efficacy of the different interventions or examining long-term effects of therapy.234,235 Oral morphine is preferred to treat withdrawal symptoms because it is a short-acting pure opioid agonist, and the formulation has no additives.244 Clonidine and phenobarbital are beneficial as adjunctive therapies.
Opioid agonists may be more effective at preventing withdrawal seizures from heroin or methadone than from phenobarbital or diazepam.127,151 However, sedative–hypnotic agents are commonly used by heroin users or adults maintained on methadone, and sedative–hypnotic withdrawal seizures may contribute to the overall neonatal abstinence symptomatology. In this setting, there may be a role for phenobarbital.
Infants of opioid-using mothers have a two to three times increased risk for SIDS compared with control participants.152,153 The mechanism may be related to a decreased medullary responsiveness to CO2, or the effect may be related to some condition of the postnatal environment.100
Although young children born to opioid users do not seem to have significant differences in behavior compared to control participants, older children have increased learning problems and school dysfunction particularly related to behavior difficulties.337
Approximately 1% of pregnant women in the United States use cocaine at some time during their pregnancy.222 The rate may be as high as 15% in certain populations,77 and it is estimated that more than 100,000 infants born in the United States each year may be exposed to cocaine in utero.56 The consequences of cocaine use during pregnancy have been extensively reviewed.131,241,283
The incidence of abruptio placentae may be significant when related to acute cocaine use.287 Some uncommon perinatal problems include seizures, cerebral infarctions, and intraventricular hemorrhage.61,241
Cocaine use is significantly related to decreases in gestational age, birth weight, length, and head circumference, although these growth parameters generally correct by several years of age.283 In addition, these growth effects are exacerbated by concomitant alcohol, tobacco, and opioid use.283 Good prenatal care can mitigate many of these adverse effects of cocaine.193,252,337
Significant congenital malformations were reported among some infants who were exposed to cocaine in utero, specifically genitourinary malformations, cardiovascular malformations, and limb-reduction defects.49,104 However, in one large population-based study, there was no increase in the incidence of malformations.203
Teratogenic effects are observed in animal models of in utero cocaine exposure. Decreased maternal and fetal weight gain and an increased frequency of fetal resorption were demonstrated in rats96; sporadic physical anomalies are also observed.63 Teratogenic effects similar to those observed in humans were reported in mice, including bony defects of the skull, cryptorchidism, hydronephrosis, ileal atresia, cardiac defects, limb deformities, and eye abnormalities.101,194,195,213 Cocaine caused hemorrhage and edema of the extremities, and, subsequently, limb-reduction defects in rats when administered during midgestation in the postorganogenic period.324
The perinatal effects of cocaine are probably mediated through a vascular mechanism. Cocaine administration in the pregnant ovine model causes increased uterine vascular resistance, decreased uterine blood flow, increased fetal heart rate and arterial blood pressure, and decreased fetal PO2 and O2 content.22,333 Similar effects are reported in rats.237 Fetal hypoxia may cause rupture of fetal blood vessels and infarction in developing organ systems such as the genitourinary system60,213,293 or the CNS.57,82,325 Hyperthermia or direct effects of cocaine in the fetus may exacerbate these effects.40 Limb-reduction defects similar to those attributed to cocaine can be produced after mechanical clamping of the uterine vessels.40,326 A developing concept is that after vasospasm and ischemia, reperfusion occurs with the generation of oxygen free radicals and subsequent injury.333,334
Despite the reported malformations and a possible mechanism, neither the human epidemiology nor the effects observed in animal models suggest a specific teratogenic syndrome. The risk of a significant malformation from prenatal cocaine exposure is low, but the effect, if one occurs, may be severe.41,89,104
One of the greatest concerns about prenatal cocaine exposure is the potential adverse effect on the developing child, and this is an intensive area of epidemiologic research. The most common findings in early infancy are lability of behavior and autonomic regulation; decreased alertness and orientation; and abnormal reflexes, tone, and motor maturity; however, many studies show no effect, especially after controlling for confounding variables.95,283 For some children, effects may manifest in later infancy as difficulty with information processing and learning. For school-age children, observed cognitive deficits may also be related to the home environment even for children who showed some of the typical neonatal behaviors.102,283 Nonetheless, there is evidence of impairment in modulating attention and impulsivity, which makes handling unfamiliar, complex, and stressful tasks more difficult,209,283 and these effects are also observed in animal models of prenatal cocaine exposure.89,123,182,296
The mechanism of neurotoxicity has not been specifically elucidated. As described earlier, for many of the maternal and fetal physical defects, cocaine may have direct toxicity or, alternatively, effects may be mediated through hypoxia or oxygen free radicals. Because cocaine interferes with neurotransmitter reuptake, it is likely that cocaine also disrupts normal neural ontogeny by interfering with the trophic functions of neurotransmitters on the developing brain, in particular dysfunction of signal transduction via the dopamine D1 receptor.123,182,199,208 These mechanisms may be more important in the etiology of neurobehavioral effects.