Summary of Teratogenic Effects:

Cocaine is a topical anesthetic, local vasoconstrictor, and central nervous system (CNS) stimulant that is widely abused recreationally (Gay, 1981; Farrar & Kearns, 1989; Johanson & Fischman, 1989).

MAGNITUDE OF TERATOGENIC
RISK TO CHILD BORN AFTER
EXPOSURE DURING GESTATION

Placental Abruption and Other Serious Pregnancy Complications: MODERATE

Congenital Anomalies: SMALL TO MODERATE

QUALITY AND QUANTITY OF DATA
ON WHICH RISK ESTIMATE IS BASED

Placental Abruption and Other Serious Pregnancy Complications: FAIR TO GOOD

Congenital Anomalies: FAIR TO GOOD

COMMENTS
Vascular disruption in the fetus appears to be associated with maternal cocaine use and may be a particular hazard in the second or third trimester of pregnancy.

The extensive medical literature on the effects of maternal cocaine use in pregnancy must be interpreted with great caution. Confounding factors are present in human studies that often make it difficult to attribute abnormalities observed directly to a teratogenic effect of cocaine (Chasnoff, 1991, 1992; Lutiger et al., 1991; Gingras et al., 1992; Kain et al., 1992; Slutsker, 1992; Volpe, 1992; Coles & Platzman, 1993; Ellis et al., 1993; Frank et al., 1993; Hutchings, 1993; Holzman & Paneth, 1994; Neuspiel, 1994; Snodgrass, 1994). Documentation of the frequency, timing, and dosage of the mothers' use of cocaine, other illicit drugs, and alcohol is usually poor. Moreover, there appears to be a systematic publication bias in favor of studies that show an association between maternal cocaine use and untoward pregnancy outcomes and against studies that do not (Koren et al., 1989; Coles, 1993).

Increased frequencies of CNS infarction, disruption or malformations have been observed in neuroimaging studies of full-term infants, premature infants, infants with unexplained intrauterine growth retardation, and very-low-birth-weight infants born to women who had abused cocaine during pregnancy (Dixon & Bejar, 1989; Heier et al., 1991; Cohen et al., 1994; Dogra et al., 1994a, b; Singer et al., 1994). These studies each included between 19 and 43 exposed infants. No such association was seen in other studies respectively involving 86 very-low-birth-weight infants, 111 infants born at or before 37 weeks of gestation, or 39 term infants whose mothers had used cocaine during pregnancy (Dusick et al., 1993; McLenan et al., 1994; King et al., 1995). Similar brain lesions have been noted among infants of women who used cocaine during pregnancy in other series (Chasnoff et al., 1986; Sims & Walther, 1989; Kramer et al., 1990; Dominguez et al., 1991; Kapur et al., 1991; Volpe, 1992; Gieron-Korthals et al., 1994; Smit et al., 1994; Suchet, 1994). Such defects may represent residua of cocaine-induced CNS hemorrhage or ischemia at various gestational ages (Volpe, 1992). Cerebral infarction is a recognized complication of cocaine use in children and adults (Jacobs et al., 1989; Brown et al., 1992).

Other congenital anomalies thought to be due to vascular disruption have been reported among children of mothers who abused cocaine during pregnancy. These abnormalities include segmental intestinal atresia in at least six infants, gastroschisis in at least four, sirenomelia in at least two, limb-body wall complex in at least three, and limb reduction defects in more than a dozen (MacGregor et al., 1987; Chasnoff et al., 1988; Hoyme et al., 1990; Drongowski et al., 1991; Hannig & Phillips, 1991; van den Anker et al., 1991; Sarpong & Headings, 1992; Sheinbaum & Badell, 1992; Spinazzola et al., 1992; Viscarello et al., 1992; Hume et al., 1994; Martinez et al., 1994). No association with maternal cocaine use during pregnancy was seen in a case-control study of 110 infants with gastroschisis (Torfs et al., 1994). Moreover, the prevalence of cases with multiple vascular disruption defects seen in the Metropolitan Atlanta Congenital Defects Program did not change significantly between 1968 and 1989, a period marked by a substantial increase in cocaine abuse (Martin et al., 1992). This suggests that cocaine abuse did not produce a major increase in the overall frequency of such birth defects in this population.

The occurrence of neonatal necrotizing enterocolitis also seems to be associated with maternal cocaine use during pregnancy (Czyrko et al., 1991; Porat & Brodsky, 1991; Sehgal et al., 1993), and neonatal myocardial infarction has been reported in the infant of a woman who abused cocaine throughout pregnancy (Bulbul et al., 1994). Myocardial calcification, a rare finding that may be a residuum of in utero myocardial infarction, has also been observed in infants whose mothers abused cocaine during pregnancy (Yap et al., 1994). Such anomalies may be caused by the vasoconstrictive and hypertensive actions of cocaine.

Data suggesting an association between maternal cocaine use during pregnancy and the occurrence of congenital anomalies of the genitourinary system in infants have been reported. Several infants with the rare prune belly anomaly have been born to women who used cocaine during pregnancy (Chasnoff et al., 1985, 1989; Bingol et al., 1986). A small but statistically significant increase in the frequency of congenital anomalies of the urinary, but not of the genital, tract was found in one case-control study (Chavez et al., 1989). Nine of 52 infants born to women who chronically abused cocaine had genitourinary tract anomalies in another study (Chasnoff et al., 1988, 1989). In contrast, congenital urogenital anomalies were no more frequent than expected in a cohort of 1324 children of women who abused cocaine during pregnancy (Rajegowda et al., 1991). Several other investigations also have found no increase in the frequency of urinary tract anomalies among the children of women who used cocaine during pregnancy (Bingol et al., 1987; Little et al., 1989; Neerhof et al., 1989; Rosenstein et al., 1990; Hurt et al., 1995), but the sample sizes involved (50 to 105 exposed infants) are too small to rule out even a substantial increase in the rate.

An increased frequency of cardiovascular malformations was observed among 214 infants with neonatal toxicology screens showing the presence of cocaine in one study (Lipshultz et al., 1991), but meta-analysis of six other epidemiological studies revealed no significant association between maternal cocaine use in pregnancy and fetal cardiovascular malformations (Lutiger et al., 1991).

Significantly increased frequencies of congenital anomalies in general have been reported in studies of 138, 53, and 50 infants of women who abused cocaine during pregnancy (Bingol et al., 1987; Little et al., 1989; Neerhof et al., 1989), but not in other studies of similar or larger size (Hadeed & Siegel, 1989; Gillogley et al., 1990; Handler et al., 1991; Slutsker, 1992; Eyler et al., 1994; Hurt et al., 1995).

A distinctive pattern of minor anomalies (i.e., a "fetal cocaine syndrome") has been recognized among infants born to women who used cocaine during pregnancy (Fries et al., 1993; Robin & Zackai, 1994). Frequent features include low birth weight, prematurity, irritability, microcephaly, large fontanelles, prominent glabella, marked periorbital and eyelid edema, low nasal bridge, short nose, and small toenails. The clinical importance of this syndrome is currently unclear; further delineation of the characteristics and natural history is necessary.

Growth retardation involving weight, length, and head circumference has consistently been noted among infants born to women who abused cocaine during pregnancy, but this effect appears to be due largely, if not entirely, to concomitant exposure to alcohol or cigarette smoking (Doering et al., 1989; Rosenak et al., 1990; Bateman et al., 1993; Behnke & Eyler, 1993; Singer et al., 1993; Weathers et al., 1993; Burkett et al., 1994; Eyler et al., 1994; Jacobson et al., 1994a, b; Kliegman et al., 1994; Knight et al., 1994; Holzman & Paneth, 1994; Richardson & Day, 1994; Hurt et al., 1995; Miller et al., 1995; Mirochnick et al., 1995; Shiono et al., 1995). Few differences were observed by three years of age between 93 infants whose mothers used cocaine and a group of infants whose mothers did not use cocaine but had similar use of alcohol, cigarettes, and marijuana during pregnancy (Azuma & Chasnoff, 1993; Griffith et al., 1994). Weight and head circumference were lower in a group of 111 children of women who abused cocaine during pregnancy than in control children up to 30 months of age in another study, but no difference in these measurements was found at 36 months (Hurt et al., 1995). In a study of 59 infants born to women who abused cocaine and other drugs during pregnancy, catch-up growth was observed for weight but not for length or head circumference at 6.5 and 13 months of age after correcting for the effects of maternal smoking, alcohol use and opiate use during pregnancy (Jacobson et al., 1994a, b). Similarly, the average weight but not the average length of 31 well-nourished children who had been born to women who abused cocaine during pregnancy had caught up to normal at six months of age (Harsham et al., 1994). No effect of maternal use of cocaine during pregnancy was observed on the height, weight, or head circumference of 668 inner city African-American children evaluated at six years of age (Day et al., 1994).

Lower than expected scores on the Bayley Scales of Infant Development were achieved at a corrected gestational age of about 17 months in a series of 30 children born to women who used cocaine during pregnancy, (Singer et al., 1994). Lower than expected Bayley motor but not mental scores and differences in reaction to novel stimuli were observed among 61 infants whose mothers had abused cocaine during pregnancy in another study (Mayes et al., 1995). No difference in cognitive or language development scores but differences in reported emotional and behavioral status were observed among 20 three- to five-year-old children of women who abused crack cocaine during pregnancy in another study (Hawley et al., 1995). Interpretation of these findings is confounded by possible effects of maternal prenatal alcohol abuse and other differences in lifestyle that distinguish women who abuse cocaine during pregnancy from other women.

In contrast, no difference in Bayley scores was found between 101 children whose mothers had abused cocaine during most or all of their pregnancies and control infants tested repeatedly between six and 30 months of age (Hurt et al., 1995). No difference in Bayley scores in comparison to controls was found among 51 children whose urine at birth contained cocaine metabolites and who underwent developmental testing every six months up to two years of age (Chiriboga et al., 1995). Development at about 20 months of age was also similar to controls in a group of 30 children born to women who used cocaine "socially" during the first trimester of pregnancy (Graham et al., 1992). No difference in global IQ but significantly decreased language development was found in comparison to controls within a group of 23 children born to women who abused cocaine during pregnancy (Nulman et al., 1994). The children, who had all been adopted into other families, were studied at a mean age of 34 months.

Prematurity, abnormal neonatal cardiorespiratory function, and transient abnormalities of neurological function are often observed among infants born to women who used cocaine during pregnancy (Chasnoff et al., 1985, 1989; Neuspiel & Hamel, 1991; Plessinger & Woods, 1991; Scanlon, 1991; Black et al., 1993; Dusick et al., 1993; Forman et al., 1993; Mayes et al., 1993; Singer et al., 1993; Eyler et al., 1994; Frassica et al., 1994; Gingras et al., 1994; Kliegman et al., 1994; Chiriboga et al., 1995; King et al., 1995). Structural and functional abnormalities of the eyes have been described in these infants in some studies but not others (Dominguez et al., 1991; Good et al., 1992; Stafford et al., 1994). Persistent arterial hypertension may be relatively frequent among children born to women who abuse cocaine during pregnancy (Horn, 1992).

An increased frequency of SIDS was observed in a cohort study of almost 1000 infants whose mothers had used cocaine during pregnancy (Durand et al., 1990) and in a population-based cohort study that included 8868 births to women reported to have used cocaine during pregnancy (Kandall et al., 1993). The rate of SIDS among the infants of women who had used cocaine during pregnancy was 4.6 per 1000 in the latter study, but very much higher rates (10/66 and 4/71) were reported in two series of infants born to women who chronically abused cocaine during pregnancy (Chasnoff et al., 1988; Cordero & Custard, 1990). Other investigations have found no association between maternal cocaine use during pregnancy and SIDS (Bauchner et al., 1988; Silvestri et al., 1991).

Abruptio placentae, often with fetal death, has been associated with cocaine use during pregnancy (Acker et al., 1983; Chasnoff et al., 1985; Bingol et al., 1987; Keith et al., 1989; Cohen et al., 1991; Dombrowski et al., 1991; Handler et al., 1991; Slutsker, 1992; Dusick et al., 1993; Burkett et al., 1994; Holzman & Paneth, 1994; Miller et al., 1995; Shiono et al., 1995). The occurrence of abruption in these cases is probably due to the vasoconstrictive and hypertensive effects of the drug.

A dose-dependent increase in the frequency of limb and tail reduction defects was observed among the offspring of pregnant rats treated with 2.5-4 times the usual human dose of cocaine (Webster & Brown-Woodman, 1990). Some of the fetuses with limb defects were also found to have CNS anomalies of a type associated with vascular disruption (Webster et al., 1991). In another study, urinary tract anomalies were observed with increased frequency among the offspring of rats injected with cocaine in doses similar to those used recreationally in humans (El-Bizri et al., 1991). Increased frequencies of congenital anomalies, including brain, eye, urinary tract, and cardiovascular defects, have been observed among the offspring of mice given <1-3 times the usual human recreational dose of cocaine during pregnancy (Mahalik et al., 1980; Finnell et al., 1990; Gressens et al., 1992; Mahalik & Hitner, 1992; Fisher et al., 1994). This was not seen in other studies using similar doses in mice, rats, or rabbits (Fantel & MacPhail, 1982; Church et al., 1988; Henderson & McMillen, 1990; Weese-Mayer et al., 1991). Various behavioral abnormalities and other alterations of brain structure and function have been noted among the offspring of rats, mice, and rabbits treated with cocaine during pregnancy (Hutchings et al., 1989; Smith et al., 1989; Spear et al., 1989; Kunko et al., 1993; Heyser et al., 1994; Johns et al., 1994; Kosofsky et al., 1994; Molina et al., 1994; Wood et al., 1994, 1995; Johns & Noonan 1995; Murphy et al., 1995; Olsen, 1995; Salo et al., 1995; Sobrian et al., 1995; Tan & Costa, 1995; Tonkiss et al., 1995; Vorhees et al., 1995).

Key References:
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