Central Stimulant
PREGNANCY RECOMMENDATION: Human and Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity Contraindicated (Nonmedical Use)
PREGNANCY SUMMARY
Although medicinal use of amphetamines appears to be low risk for embryo–fetal harm, abuse of the agent is associated with significant toxicity for the embryo, fetus, and newborn. Such use is contraindicated in pregnancy.
FETAL RISK SUMMARY
The amphetamines are a group of sympathomimetic drugs that are used to stimulate the central nervous system. Members of this group include amphetamine, dextroamphetamine, and methamphetamine. A number of studies have examined the possible relationship between amphetamines and adverse fetal outcome. Women were using these drugs for appetite suppression, narcolepsy, or illicit abuse purposes.
In near-term pregnant sheep administered IV doses at or below what is commonly regarded as abuse, methamphetamine rapidly crossed the placenta and accumulated in the fetus (1). Fetal blood pressure was increased 20%–37% with a decrease in fetal oxyhemoglobin saturation and arterial pH. Approximately similar results were reported in a 1993 abstract that also used pregnant sheep (2). Fetal concentrations of the drug were approximately the same as maternal levels during a 6-hour interval.
The question as to whether amphetamines are teratogenic in humans has been examined in a number of studies and single-patient case histories. Cardiac malformations and other defects were produced in mice injected with very large doses (about 200 times the usual human dose) of dextroamphetamine (3). These same investigators then retrospectively and prospectively examined human infants whose mothers had ingested the drug (4). In the retrospective portion of the study, 219 infants and children under 2 years of age with congenital heart disease were compared with 153 similar-age infants and children without heart defects. Neither maternal exposure to dextroamphetamine during pregnancy nor exposure during the vulnerable period differed statistically between the groups. However, a positive family history of congenital heart disease occurred in 31.1% of the infants with the defects compared with only 5.9% of the control group (p = 0.001). The prospective study compared 52 mothers with a documented exposure to dextroamphetamine during the vulnerable period with 50 nonexposed mothers. Neither group produced an infant with congenital heart disease, and the numbers of other congenital abnormalities were similar (nine vs. seven). Thus, this study found no evidence for an association between congenital heart defects and dextroamphetamine. However, in a follow-up study published 3 years later, the investigators reported a significant relationship between dextroamphetamine exposure and heart defects (5). Comparing 184 infants under 1 year of age with congenital heart disease with 108 control infants, significant differences were found for maternal exposure to dextroamphetamine (18% vs. 8%, p < 0.05), exposure during the vulnerable period (11% vs. 3%, p = 0.025), and positive family history of congenital heart disease (27% vs. 6%, p < 0.001). Infants who were both exposed during the vulnerable period and had a positive family history were statistically similar for the groups (5% vs. 1%).
In a fourth study by the above investigative group, 240 women were followed prospectively during their pregnancies to determine exposure to medicinal agents, radiation, and other potential teratogens (6). Thirty-one (13%) women consumed an appetite suppressant (usually dextroamphetamine) during the 1st trimester and an additional 34 (14%) were exposed later in pregnancy. Eight (3.3%) babies had a major congenital defect noted at birth, which is approximately the expected incidence in the United States. Three of the affected infants had been exposed during the 1st trimester to an appetite suppressant. Although the authors identified a wide range of maternal drug consumption during the 1st trimester, no conclusions as to the cause of the defects can be drawn from the data.
Four other reports have related various defects with amphetamine exposure (7–10). An infant with a bifid exencephalia was delivered from a mother who took 20–30 mg of dextroamphetamine daily throughout pregnancy (7). The infant died after an attempt was made at surgical correction. A second case involved a mother who ingested dextroamphetamine daily for appetite suppression and who delivered a full-term infant. The infant died 6 days later as a result of a congenital heart defect (8). Drug histories were obtained from mothers of 11 infants with biliary atresia and compared with the histories of 50 control mothers (9). Amphetamine exposure occurred in five women in the study group and in three of the controls. A 1966 report described a mother with two infants with microcephaly, mental retardation, and motor dysfunction (10). The mother had taken an appetite suppressant containing methamphetamine and phenobarbital during the 1st and 2nd trimesters of both pregnancies (pregnancy numbers 1 and 3). A spontaneous abortion occurred in pregnancy number 2, but no details were given of the mother’s drug intake. Her fourth pregnancy, in which she did not take the appetite suppressant, resulted in the delivery of a normal child. There was no family history of developmental disorders, congenital defects, mental retardation, cerebral palsy, or epilepsy.
Fetal structural defects have been associated with maternal abuse of drugs in a large volume of literature (see also Ethanol, Cocaine, Heroin, Lysergic Acid Diethylamide [LSD], Marijuana, and Methadone). For example, in a 1972 case, multiple brain and eye anomalies were observed in an infant exposed in utero to amphetamines, LSD, meprobamate, and marijuana (11). In this and similar cases, the cause of the structural abnormalities is probably multifactorial, involving drug use, life-styles, infections, poor maternal health, and other factors.
In a retrospective study, 458 mothers who delivered infants with major (N = 175) or minor (N = 283) abnormalities were compared with 911 matched controls (12). Appetite suppressants were consumed during pregnancy by significantly more mothers of infants with anomalies than by controls (3.9% vs. 1.1%, p < 0.01). Dextroamphetamine consumption accounted for 13 of the 18 maternal exposures in the anomaly group. During the first 56 days of pregnancy, dextroamphetamine-containing compounds were used by 10 mothers in the anomaly group compared with only 5 of the controls (2.2% vs. 0.5%; p < 0.05). The abnormalities (3major and 7 minor) observed in the 10 infants were urogenital system defects (4 cases), and 1 case each of congenital heart disease, cleft lip, severe limb deformity, accessory auricles, congenital dislocation of hip, and pilonidal sinus. Although statistically significant results were found in this study, the results must be interpreted cautiously due to the retrospective collection of drug histories and the lack of information pertaining to past and present maternal medical and obstetric histories.
A prospective study of 1824 white mothers who took anorectic drugs (primarily amphetamines) during pregnancy compared with 8989 white mothers who did not take such drugs measured rates of severe congenital defects of 3.7% and 3.4%, respectively, in infants with a gestational age of at least 37 weeks (13). When children of all known gestational ages were included, amphetamine usage occurred in 85% (1694 of 1992) of the group consuming anorectic drugs. The incidence of severe congenital defects in the amphetamine group was 3.4%. Fourteen infants were exposed in the first 84 days after the last menstrual period, and except for three infants with cleft lip and/or palate, no pattern of malformations was observed.
The effects of amphetamine abuse on fetal outcome and subsequent development were described in a series of reports from Sweden (14–18). Twenty-three women who ingested amphetamine during the 1st trimester were divided into two groups: 6 who claimed that they stopped use of the drug after they became aware of their pregnancy or after the 1st trimester, and 17 who continued use of the drug throughout gestation (14). Two of the infants (group not specified) had congenital defects: a stillborn infant had myelomeningocele, and one had extensive telangiectasis (considered to be an inherited disorder). The outcome of the infants exposed throughout gestation included six preterm (<37 weeks), three small-for-gestational-age (all with poor prenatal care), one of whom had a seizure on the first day, and two full-term but extremely drowsy infants. In a later report, 66 infants born to amphetamine-addicted mothers were followed during their first year of life (16). Except for temporary drowsiness in the first few months, all children had normal somatic and psychomotor development at 12 months of age. In the final report from these investigators, the fetal outcome of 69 amphetamine-addicted women who delivered 71 children (1 delivered twice and 1 delivered twins) was described (17). Seventeen of the women claimed to have stopped amphetamine ingestion as previously described, and 52 continued use of amphetamines throughout pregnancy. Three women in the first group and 17 in the second group were alcoholics (18). Four infants had congenital defects: intestinal atresia (two cases—both died and one also had hydrocephalus), congenital heart defect (one case), and epidermolysis bullosa without known heredity (one case). In one of the four cases, the mother was an alcoholic, but the particular case was not specified. Drowsiness was observed in 8 infants and jitteriness in 11 infants; 4 full-term infants required tube feedings. The four studies (14–17) were combined into a single article published in 1980 (18).
The Collaborative Perinatal Project monitored 50,282 mother–child pairs, 671 of whom had 1st trimester exposure to amphetamines (19, pp. 346–347). For use anytime during pregnancy, 1898 exposures were recorded (19, p. 439). In neither group was evidence found to suggest a relationship to large categories of major or minor malformations. Two case reports failed to observe any neonatal effects from the treatment of narcolepsy with large doses of amphetamine (20,21). A 1988 report described a mother who had used amphetamines, barbiturates, cocaine, LSD, alcohol, and marijuana during pregnancy who delivered a female infant with bilateral cerebrovascular accident and resulting porencephaly (22). The infant expired at 2.5 months of age. The fetal injury was thought to be caused by cocaine (see also Cocaine).
A 1992 case report described the use of dextroamphetamine and lovastatin in a human pregnancy (23). A woman was treated for 5 weeks with the combination, starting approximately 6 weeks from her last menstrual period, for progressive weight gain and hypercholesterolemia. Therapy was discontinued when her pregnancy was diagnosed at 11 weeks’ gestation. A female infant was delivered by cesarean section at 39 weeks’ gestation. Gestational age was confirmed by an ultrasound examination at 21 weeks’ gestation and the Dubowitz score at birth. The infant had a constellation of malformations termed the VATER association (vertebral anomalies, anal atresia, tracheoesophageal fistula with esophageal atresia, renal and radial dysplasias). Specific anomalies included an asymmetric chest, thoracic scoliosis, absent left thumb, foreshortened left forearm, left elbow contracture, fusion of the ribs on the left, butterfly vertebrae in the thoracic and lumbar spine, left radial aplasia, and a lower esophageal stricture. Chromosomal analysis was normal, and the family history was noncontributory (23).
The effects of IV methamphetamine abuse on the fetus were evaluated in a 1988 report (24). Maternal use of the drug was identified by self-reporting before delivery in 52 women, and an equal number of controls were selected for comparison. Although self-reporting of illegal drug use is prone to underreporting, the drug histories were validated by social worker interviews and were thought to represent actual drug use in the study population. Other drugs used in the study and control groups were tobacco (24 vs. 6), marijuana (20 vs. 1), cocaine (14 vs. 0), and one each in the study group for alcohol, lorazepam, dextroamphetamine, heroin, opium, LSD, and diazepam. No statistical differences were measured between the groups in the rate of obstetric complications (12% vs. 27%) or neonatal complications (21% vs. 17%). The latter category included meconium (10% vs. 12%), fetal heart rate decelerations (4% vs. 0) and tachycardia (2% vs. 0%), tachypnea (4% vs. 2%), and withdrawal symptoms (2% vs. 0%). Mean birth weight, length, and head circumference were all lower in the study infants compared with controls (p = 0.001). Six (12%) of the infants in the study group had a congenital defect compared with seven (14%) of the controls. Statistically, however, the investigators could only conclude that methamphetamine abuse does not cause a ≥12-fold increase in congenital anomalies (24).
A 1992 abstract described the effects of methamphetamine abuse in 48 newborns in comparison to 519 controls (25). Offspring of women positive for opiates, cocaine, alcohol, and toluene were excluded from both groups. Except for a significantly lower birth weight, 3173 vs. 3327 g (p = 0.03), all other parameters studied were similar, including birth length, head circumference, Apgar scores, gestational age at delivery, and the incidence of both major and minor malformations.
Intrauterine death occurred at 34 weeks’ gestation in the fetus of a 29-year-old amphetamine addict who had injected 500 mg of amphetamine (26). The mother was exhibiting toxic signs and symptoms of amphetamine overdose when she was brought to the hospital. An initial fetal bradycardia of 90–100 beats/minute worsened over the next 50 minutes when the heart sounds became inaudible. Approximately 24 hours later, a 3000-g female stillborn infant without congenital abnormalities was delivered.
Amphetamine withdrawal has been described in newborns whose mothers were addicted to amphetamines during pregnancy (27–29). In a report of four mothers using methamphetamine, symptoms consisting of shrill cries, irritability, jerking, and sneezing were observed in two infants (27). One of the infants was evaluated at 4 months of age and appeared normal except for small size (weight 3rd percentile, head circumference 10th percentile). The author speculated that the symptoms in the newborns may have been caused by hidden narcotic addiction (27). Another report of four women with methamphetamine dependence described one newborn with marked drowsiness lasting for 4 days (28). The mother had not been taking narcotics. The third report of neonatal withdrawal involved an infant delivered from a mother who was a known amphetamine addict (29). Beginning 6 hours after birth, the female infant had diaphoresis, agitation alternating with periods of lassitude, apnea with feedings, a seizure on the 6th day, vomiting, miotic pupils, and a glassy-eyed stare. Her first 3 months were marked by slow development, but at 2.5 years of age, there was no evidence of neurologic disability and intelligence was considered above normal.
Methamphetamine withdrawal characterized by abnormal sleep patterns, poor feeding, tremors, and hypertonia was reported in a 1987 study (30). Infants exposed to methamphetamine or cocaine, either alone or in combination, were combined into a single group (N = 46) because of similar maternal and neonatal medical factors. Mothers in the drug group had a significantly greater incidence of prematurity compared with drug-free controls (28% vs. 9%), and a significantly greater incidence of placental hemorrhage and anemia compared with narcotic-using mothers and controls (13% vs. 2% vs. 2.2%, and 13% vs. 2% vs. 0%). Maternal methamphetamine abuse was significantly associated with lower gestational age, birth weight, length, and occipitofrontal circumference (30).
Echoencephalography (ECHO) was performed within 3 days of birth on 74 term (>37 weeks) infants who had tested positive for cocaine or methamphetamine, but who otherwise had uncomplicated perinatal courses (31). The infants had no other known risk factors for cerebral injury. The 74 newborns were classified into three groups: 24 (32%) exposed to methamphetamine, 32 (43%) exposed to cocaine, and 18 (24%) exposed to cocaine plus heroin or methadone, or both. Two comparison groups were formed: a group of 87 term, drug-free infants studied by ECHO because of clinical concerns for hypoxic–ischemic encephalopathy, and a normal group of 19 drug-free term newborns. Both groups of comparison infants were also studied by ECHO within 3 days of birth. Only one structural anomaly, consisting of an absent septum pellucidum, was observed in the infants examined. The affected newborn, exposed to methamphetamine, was also found to have bilateral optic nerve atrophy and diffuse attenuation of the white matter. Twenty-six (35.1%) of the drug-exposed infants had cranial abnormalities detected by ultrasonography, which was similar to the 27.6% (24 of 87) incidence in the group suspected of encephalopathy (p = 0.7). The normal controls had an incidence of 5.3% (1 of 19) (p < 0.01 in comparison to both of the other groups). The lesions observed in the drug-exposed infants were intraventricular hemorrhage, echodensities known to be associated with necrosis, and cavitary lesions. Lesions were concentrated in the basal ganglion, frontal lobes, and posterior fossa (31). The ECHO abnormalities were not predicted by standard neonatal clinical assessment and were believed to be consistent with those observed in adult abusers of amphetamines and cocaine (31).
Amphetamines do not appear to be human teratogens (32–34). Mild withdrawal symptoms may be observed in the newborns, but the few studies of infant follow-up have not shown long-term sequelae, although more studies of this nature are needed. Illicit maternal use of amphetamines, on the other hand, presents significant risks to the fetus and newborn, including intrauterine growth restriction, premature delivery, and the potential for increased maternal, fetal, and neonatal morbidity. These poor outcomes probably reflect several factors, including multiple drug use, lifestyles, and poor maternal health. However, cerebral injuries occurring in newborns exposed in utero appear to be directly related to the vasoconstrictive properties of amphetamines (31).
BREASTFEEDING SUMMARY
Amphetamine, the racemic mixture of levo—and dextroamphetamine, is concentrated in breast milk (21). After continuous daily dosing of 20 mg, milk concentrations ranged from 55 to 138 ng/mL with milk:plasma ratios varying between 2.8 and 7.5. Amphetamine was found in the urine of the nursing infant. No adverse effects of this exposure were observed over a 24-month period. In a second study, no neonatal insomnia or stimulation was observed in 103 nursing infants whose mothers were taking various amounts of amphetamine (35). The American Academy of Pediatrics classifies amphetamines as contraindicated during breastfeeding because of irritability and poor sleeping pattern (36).
References
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