EFFECTS OF COCAINE ONTHE HUMAN FETUS:

A REVIEW OF CLINICAL STUDIES

Paul L. Doering, Cheryl L. Davidson, Luann LaFauce, and Charles A. Williams

ABSTRACT. The abuse of cocaine in this country has reachedepidemic proportions and has generated great concern for the effectsof the drug on the fetus when used during pregnancy. Althougheducational campaigns cite adverse fetal effects as a deterrent tousing the drug, there are limited data on which to base a true riskassessment. This paper reviews the published studies of pregnancyoutcome in cocaine-abusing mothers, with special focus onstructural malformations and other neonatal risks.

DICP 1989;23:639-45.

THE PREVALENCE OF COCAINE ABUSE among women ofchildbearing age has caused special concern that thedrug might adversely affect fetal outcome. Much atten­tion has been given to case reports of fetal complica­tions, including malformations, related to the prenataluse of cocaine. Public information campaigns havevigorously discouraged use of cocaine, especially dur­ing pregnancy. Such programs are important but, ifcocaine-related fetal risks are not correctly understood,actual fetal risks might be over- or understated. Al­though nearly every practitioner would agree that prena­tal use of cocaine is harmful, it is important to under­stand the scientific data addressing risks to the fetus.Among other things, such data would be particularlyuseful in counseling expectant mothers who had alreadyused the drug, but who are now concerned about thechance of delivering an abnormal baby.

To have an adequate understanding of cocaine­related fetal risks, it is best to study maternal drug usesystematically, employing the necessary controls.Unless a fetal malformation is extraordinarily unique,case reports and other forms of anecdote usually do notdetect causal relationships between drug exposure andabnormal fetal outcome. Likewise, they do not allow

PAUL L. DOERING, M.S., is a Professor of Pharmacy Practice, College of Phar­macy, University of Florida; CHERYL L. DAVIDSON, Pharm.D., is a Resident inDrug Information Services, University of Colorado Health Science Center, Denver,CO; LUANN LAFAUCE, B.Sc., R.N., is the Coordinator, 'Ieratogen InformationService, Division of Genetics, Department of Pediatrics, University of Florida; andCHARLES A. WILLIAMS, M.D., is the Medical Director, Teratogen InformationService, and an Associate Professor, Division of Genetics, University of Florida,Gainesville, FL 32610. Reprints: Paul L. Doering, M.S.

1~1 1iI'-'-- This article has been selected for PhannaCE testing. ItE- may be used for continuing education credit in the UnitedStates and Canada. DICPlPharmaCE is a member of the

._._- Council on The Continuing Education Unit (CEU) and isapproved by the American Council on Pharmaceutical Education as a providerof continuing pharmaceutical education (provider number 180-407).

for identification of factors that would place certainpregnancies at special risk, nor do they control for thenumerous confounding factors known to accompanythe drug-abusing lifestyle. The purpose of this paper isto review the findings of recent clinical studies focusingon pregnancy outcome after prenatal cocaine exposure.

Pharmacology ofCocaineCocaine's pharmacologic effects on brain function

are mediated through its action on neurotransmitters.Cocaine alters the metabolism of norepinephrine,dopamine, serotonin, and acetylcholine by inhibitingreuptake of these neurotransmitters and by delaying theinactivation of norepinephrine and epinephrine. I Theresulting increase in catecholamines is responsible forthe feeling of euphoria and relief of fatigue associatedwith cocaine use. Other effects seen with cocaineinclude increases in blood pressure and heart rate, andintense vasoconstriction in key body organs.

When cocaine is used in toxic doses, convulsions mayoccur, followed by cardiovascular and respiratory fail­ure. Abrupt discontinuation of cocaine can produce asyndrome characterized by depression, social with­drawal, cravings, tremor, eating and sleeping distur­bances, and EEG changes. I

Cocaine may be abused through different routes ofadministration. Originally the drug was taken orally,but this route is not currently popular among drugabusers. Bioavailability via the oral and intranasalroute are the same (30-40 percent), as are the serumconcentrations one hour after administration.':" How­ever, initial uptake appears to be faster when cocaine isadministered intranasally, with onset of effect startingwithin one minute. Cocaine may also be injected intra­venously and subcutaneously. Subcutaneous injectionproduces a slower onset of action as a consequence ofthe local vasoconstriction it produces. Intravenous useproduces effects within 30 seconds and these effects lastapproximately 30 minutes." More recently a smokableform of cocaine base known as "crack" has becomepopular. Smoking cocaine can be considered a "bolusto the brain:' producing effects faster than even ivadministration. 4

.

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The distribution of cocaine into various tissues hasnot been well established. Studies in rats suggest thathigher concentrations occur in the brain but this has notbeen confirmed in humans. The half-life of cocaine isalso not firmly established and reported values haveranged from 19 to 168 minutes." Furthermore, half-lifedoes not correlate with duration of euphoric effect.

Once in the plasma, cocaine is rapidly metabolized bycholinesterase enzymes to its major metabolites,ecgonine and benzoylecgonine. The rate of conversionis dependent on cholinesterase activity which can varyamong individuals and species. Cholinesterase activityhas been shown to be high in humans, horses, and chim­panzees and low in sheep, cats, dogs, and rats: Thesedifferences in cholinesterase activity may help explainthe variability seen in pharmacokinetic parameters.Cholinesterase activity is also decreased in humanfetuses, infants, elderly males, and to a lesser degree,pregnant females. 1 Once formed, cocaine metabolitesare excreted primarily by the kidneys.

Anima/Data

The teratogenic effects of cocaine were investigatedby Mahalik et al. by treating pregnant mice with a large(60 mg/kg), single subcutaneous dose on either day 7,8,9, 10, 11, or 12of gestation. The offspring ofthese micewere compared with those of a drug-free controlmouse. From their observations, the authors concludedthat cocaine has teratogenic potential, producing soft­tissue abnormalities when taken on any day of gesta­tion. Cocaine also caused significant skeletal abnor­malities when taken on days 7, 8, or 9 of gestation. Asignificant number of mice were born with exencephaly,cryptorchidism, hydronephrosis, anophthalmia, mal­formed or missing lenses, extra ribs, malformed sterne­brae, and split xiphoid processes. The authors furtherconcluded that these defects (e.g., exencephaly) are simi­lar to defects elicited by hypoxic conditions, suggestingcocaine may produce teratogenic effects by decreasingplacental transfer of oxygen."

It is important to note that this study employed a doseof cocaine that the authors felt would produce mildexcitatory response without producing convulsions ordeath. However, 60 mg/kg is much larger than the usualrecreational dose of cocaine in humans, which rangesfrom 0.2-2.0 mg/kg. 1

Two studies add further evidence that cocaine'sadverse effect on the fetus is mediated through its vaso­constrictive properties. Both Moore et al." and Woodset al. 7 studied uterine blood flow and fetal cardiovascu­lar effects in response to a single dose of intravenouscocaine. Moore et al. produced a significant increase infetal blood pressure and decrease in uterine blood flowwith a 0.5 mg/kg dose of cocaine in pregnant ewes.Fetal plasma cocaine levels were generally one-eighththat of maternal levels. The authors detected no changein fetal heart rate."

In the Woods et al. study, also with ewes, theresearchers gave doses similar to those used in humansrecreationally (0.5, 1.0, and 2.0 mg/kg), although theydid not monitor blood levels. They demonstrated adose-dependent decrease in uterine blood flow ranging

from 24 to 47 percent, as well as a significant increase infetal blood pressure and heart rate at the two higherdoses. Fetal blood gases were also monitored in thisstudy. A significant decrease in fetal oxygen contentand oxygen tension was detected with doses of 1.0-2.0mg/kg, These decreases were observed within 5 minutesof administration and returned to baseline after 15-30minutes.'

These two studies demonstrate the effects that a doseof cocaine can have on the sheep fetus. When extrapo­lating these effects to the human fetus it should be notedthat the ewe placenta provides a greater barrier thanthat of the human placenta due to its differing anatomi­cal structure. The vasoconstrictive effects of cocainedecrease blood flow to the uterus (as confirmed by fetalblood gases) subjecting the fetus to hypoxic conditions.The effects of repeated fetal hypoxic events, as wouldoccur with recurrent cocaine abuse in the humanmother, cannot be conclusively established throughthese animal studies.

Human Studies

As early as 1983, cocaine use during the perinatal per­iod had been associated with abruptio placentae," andpremature labor and prune-belly syndrome" werereported in 1985. Subsequently, case reports havedescribed intrauterine growth retardation," cerebralinfarction," rupture of intracranial aneurysm," fetaldeath;" ischemic bowel infarction," and neonatalretinopathy. 15 We identified 14 clinical studies thatassessed groups of newborns subjected to in uterococaine exposure. These reports are reviewed belowwith attention to the design of the studies and themethod and extent to which newborn babies were evalu­ated for birth defects.

In 1985Chasnoff et al. reported the results of a studyof 23 babies born to 23 cocaine-using women in Chi­cago. All women were enrolled in a drug treatment pro­gram. Twice-weekly maternal urine samples wereobtained to screen for illicit drug use and alcohol breathtests were employed at the discretion of program staff.The 23 women were divided into two groups and twoadditional groups were added as controls. Group I (12women) used cocaine at conception but did not use opi­ates. Group II (11 women) used cocaine and opiates atthe time of conception but were placed on methadonemaintenance in later pregnancy. Three women in groupI and four women in group II also used cocaine intra­venously. Sixty percent of women in groups I and IIused cocaine after conception, consuming 0.5-5 g ofcocaine per use at a frequency of two to five times perweek. Group III (15 women) used only heroin at thetime of conception but were maintained on methadonethereafter. Group IV (15 women) had no history ofillicit drug use and was selected from the general prena­tal care clinic. All groups had some women who period­ically used alcohol, cigarettes, and marijuana duringpregnancy. Neonates were examined at birth and theBrazelton Neonatal Behavioral Assessment Scale wasalso administered. 9

In the pregnancies under study, two patients in groupI and two in group II had onset of labor with abruptio

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placentae in the third trimester immediately after a sin­gle intravenous self-injection of cocaine, but there wereno occurrences of abruptio placentae in the othergroups. One infant in group I was born with prune-bellysyndrome, a major malformation of the genitourinarytract, bilateral hydronephrosis, and bilateral crypt­orchidism. Birth weights, Apgar scores, and head cir­cumferences were similar in all groups. Significantneurobehavioral differences detected by the Brazeltonscale showed "depressed interactive abilities and signif­icant impairment in organizational abilities in infantsexposed to cocaine.' '9

The authors concluded that the increased rate ofspontaneous abortions found in the cocaine-usingwomen was consistent with the known vasoconstrictiveproperties of cocaine. They also concluded that themalformation observed in the infant of the cocaine­using mother was "consistent" with the report ofMahalik et al., who found the increased incidence ofcryptorchidism and hydronephrosis described above."

Madden et al. (1986) reported the results of a study ofeight babies born to mothers with a history of cocaineuse. The mothers' urines tested positive for cocaine atthe time their babies were admitted to the hospital. Nocontrol groups were assessed. Ethnic backgrounds ofthe mothers were: Hispanic (67 percent), Asian (10 per­cent), white (22 percent), and black (1 percent). Cocainewas most frequently smoked and doses varied consider­ably; three women reported no exposure during the firsttrimester. Twowomen reporting concurrent exposure toalcohol delivered babies small for gestational age, 2140and 2460 grams, respectively. No physical anomalieswere observed except for one infant with a sacral exos­tosis and two infants having capillary hemangiomas.The authors concluded that there was no evidence ofteratogenicity and no commonality of facial features orother stigmata in their small series. 16

Bingol et al. (1987) reported the results of a study ofthe effects of cocaine use among pregnant women intwo hospitals in New York City. The ethnic groupsinvolved were approximately 50 percent black and 50percent Hispanic. Mothers were questioned by a geneticcounselor upon being admitted for delivery. Threegroups were identified: group I had 50 mothers whoonly used cocaine (60 percent consumed about 1-5 g/wkintranasally; 30 percent smoked cocaine, about 1-1.5g/d; 10percent injected cocaine, about 10-30 mg/injec­tion); group II had 110 polydrug users (includingcocaine), and group III had 340 drugfree control moth­ers. Urine toxicology screening of the babies confirmedsolitary cocaine residuals in group I and the absence ofdrug products in group III. In general, both groups Iand II had an increased incidence of stillbirths due toabruptio placentae and had babies of lower birthweights (group I, 2275.8 ± 689g; group 11,2469.4 ± 698g; group III, 3121.8 ± 614 g) and smaller head circum­ferences (group I, 32 ± 1.8 cm; group II, 33 ± 2.0 ern;group III, 34 ± 2.2 em), Differences in all three observa­tions were statistically significant when the cocaine­only group (group I) was compared with control (groupIII). Finally, group I had an increased rate of malforma­tions, 10 percent versus 5 percent and 2 percent ingroups II and III, respectively. The group I malforma-

Fetal Effects of Cocaine

tions were a stillborn with exencephaly, an infant withan "interparietal encephalocele:' an infant with a"parietal bone defect" without herniation of meningesor cerebral tissue, an infant with hypoplastic right heartsyndrome, and one with transposition of the great ves­sels. Skull defects were observed only in group I. Inter­estingly, there was no difference in the frequency ofminor anomalies in the three groups. 17

The authors concluded that the skull defects may, infact, resemble teratogenic effects seen by Mahalik etal. 5 in experiments using CF-l mice exposed to cocaine.The authors also speculated that the abruptio placentaewas related to the known vasoconstrictive properties ofcocaine. They believed the study demonstrated thatcocaine abuse by pregnant women significantly reducedbirth weight, increased the stillbirth rate related toabruptio placentae, and was associated with anincreased congenital malformation rate. 17

MacGregor et al. (1987) studied cocaine-exposedinfants from the same Chicago program involved inChasnoff's 1985 study. The pregnancy outcomes of 70cocaine-exposed women were compared with 70 controlwomen. Of the exposed women, 34 percent usedcocaine, 29 percent cocaine and marijuana, 31 percentcocaine and opiates, and 6 percent cocaine and otherillicit substances. The mean gestational age was lower inthe cocaine-exposed group (37.1 ± 3.6 wk vs. 39.5 ± 2.0wk for controls). The mean birth weight was signifi­cantly less in the cocaine-exposed group (2853± 698 gvs. 3382 ± 551 g for controls). Four congenital anoma­lies were seen in the cocaine-exposed group (prune-bellysyndrome (1]; transverse distal limb reduction (1]; jeju­nal atresia and bowel infarction (1]; and imperforateanus, horseshoe kidney, clubfoot, and amniotic banddefect [1]). One unspecified congenital anomaly wasseen in the control group but there was no statisticalsignificance between the rate of anomalies in the twogroups."

Oro and Dixon (1987) evaluated 110 neonates inwhich the baby or the mother had confirmed exposureto either cocaine, methamphetamine, heroin, or metha­done at the time of birth. Patterns of maternal drug usewere identified, presumably by retrospective interviewor questionnaire. The Finnegan scheme was used toassess newborn behaviors. Over an 18-month period104 exposed mothers and their infants were identified:users of cocaine only (13), cocaine and methampheta­mine (5), methamphetamine only (28), heroin only (17),methadone and heroin (32), and narcotic and cocaine ormethamphetamine (9). Forty-five mothers served ascontrols matched for age, ethnicity, and prenatal carebut not matched for alcohol exposure. 19

An analysis of variance showed no differencesamong infants exposed to cocaine, methamphetamine,or both with respect to gestational age, occipitofrontalhead circumference (OFC) and birth weight. The studyfound that gestational age, birth weight, length, andOFC were significantly lower in both the cocaine/amphetamine and narcotic groups than in the drug-freecontrols. Both of these drug-exposed groups had a sig­nificantly higher incidence of prematurity and a higherincidence of intrauterine growth retardation. Bothgroups also had more prenatal complications such as

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fetal bradycardia and retroplacental hemorrhages. Onecase of neonatal anemia was due to peripartum hemor­rhage. The Finnegan withdrawal scoring scheme dem­onstrated that infants exposed to cocaine, metham­phetamine, or both drugs had altered neonatal behav­ioral patterns characterized by abnormal sleep, poorfeeding, tremors and hypertonia, and other behaviors. 19

The authors concluded that neonates with prenatalexposure to cocaine or methamphetamine or both havemore adverse perinatal outcomes than controls. Thebehavioral abnormalities observed were believed to rep­resent direct drug effects rather than withdrawal.Small-for-gestational-age infants and prematureinfants were thought to represent the outcome of pla­cental insufficiency. The incidence of malformationswas not mentioned and presumably none occurred ineither the control or drug-exposed infants."

Chasnoff et al. (1988) reported on the frequency ofmalformations found in 50 infants exposed in utero tomultiple drugs, including cocaine, compared with 30infants born to women using multiple drugs that did notinclude cocaine. Mothers from both groups wereenrolled during the first trimester of pregnancy into achemical dependency treatment program. All heroinusers were converted to methadone maintenance. Theprevalence of heroin, marijuana, alcohol, and cigaretteuse was frequent and similar in both groups. Urine toxi­cologies were performed regularly throughout the preg­nancies. All neonates were examined at birth. At two tofour days of age, renal ultrasound was performed on allinfants by examiners unaware of the baby's history.Nine babies in the cocaine group had malformations(two had ileal atresia and seven had a malformation ofthe genitourinary tract) and one in the non-cocainegroup had a malformation (fetal alcohol syndrome). Ofthe seven with genitourinary malformations, three hadhydronephrosis with normal physical examinations;one had hydronephrosis in addition to two absent digitson one hand, second-degree hypospadias and unde­scended testes; one had hydronephrosis with two absentdigits on one hand, ambiguous genitalia, absent uterusand ovaries, anal atresia, deficient abdominal muscula­ture, and unilateral talipes equinovarus (features con­sidered compatible with pseudohermaphroditism); andtwo had second-degree hypospadias only. Although theseven babies with genitourinary tract malformationsdid not represent a statistically significant increase inmalformations when compared with the non-cocainegroup, the authors concluded that the observation wasan important finding and could be explained by theknown vasoconstrictive effects of cocaine. This groupis part of an ongoing malformation study by Chasnoffet al. in a large population of exposed pregnancies."For example, an increase in sudden infant death syn­drome has also been reported in an evaluation of thissame group of women," although a recent prospectivestudy of 175cocaine-exposed pregnancies failed to con­firm any increased risk for sudden infant death syn­drorne."

Ryan et al. (1987) reported their experience withpolydrug-using women in a drug rehabilitation pro­gram in Philadelphia. Fifty women using cocaine andother illicit drugs were compared with 50 polydrug-

using women not using cocaine and to 50 non-drug­dependent women. Urine toxicology testing was used toestablish cocaine exposure. Neonatal gestational andgrowth parameters were measured but it is unclearwhether examiners specifically evaluated for dys­morphia. The results indicated that infants born tococaine-abusing women had decreased birth weight,head circumference, length, and Apgar scores. Infantsborn to drug-dependent women, both cocaine users andnon-cocaine users, had a poorer general outcome thanthose born to drug-free women;"

Chouteau et al. (1988) studied 343 urban motherswho lacked prenatal care; 143 had positive urine testsfor cocaine and 218 did not. Alcohol and tobacco usewas not controlled for and it appears that both groupswere polydrug-users. Thus, use of other illicit agents areprobably confounding factors. Significantly morecocaine-exposed mothers had babies with birth weights< 2500 g and gestational ages ~ 34 weeks. No signifi­cant difference was noted in frequency of abruptio pla­centae or premature rupture of membranes. Frequencyof congenital anomalies was not discussed;"

Cherukuri et al. (1988) performed a retrospectivematched cohort study of 55women who admitted to theuse of crack during pregnancy. The control group wascomprised of 55 non-drug-using women who deliveredduring the same period. Urine toxicologic testing wasnot performed and recall history of drug abuse was themethod used to assign mothers into control and studygroups; thus correct assignment into groups is subjectto errors or biases due to recall. All neonates wereexamined at birth and gestational age was estimated byphysical and neurologic examination. The mean gesta­tional age of crack-exposed infants was significantlylower than that of nonusers (37.4 vs. 39.2 wk; p =0.02).The mean birth weight of the crack-exposed group was2528 g versus 3056 g in the controls (p =0.04). Therewere no gross congenital malformations among crack­exposed infants. There was one case of diaphragmatichernia in the control group. One fetal death occurred ina crack user, but there was no evidence of abruption oranomalies. The authors concluded that crack-exposedinfants were 3.6 times more likely to have intrauterinegrowth retardation and 2.8 times more likely to have ahead circumference less than the tenth percentile forgestational age. Finally, premature rupture ofthe mem­branes was 1.8 times more common in the crackgroup."

Mitchell et al. (1988) reported the results of ultra­sound study of fetuses of 83 pregnant women exposedto cocaine as determined by retrospective medicalrecord review. The use of other addictive drugs couldnot be excluded. Complete ultrasound data wereavaila­ble for 43 pregnancies and fetal dating was determinedusing a combination of maternal history of menstrualperiods and use of ultrasound data. The results of fetalstudy were compared with established norms for fetalgrowth at different gestational ages. The results did notshow any statistical difference for the following param­eters: birth weight, biparietal diameter, abdominal cir­cumference, head circumference, and femur length.There was a tendency, however, for cocaine-exposedfetuses to have biparietal diameters less than the 50th

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percentile and to have abdominal circumference valuesless than the 25th percentile. The authors concludedthat the study suggested but did not prove that someaspects of fetal growth were abnormal in cocaine­exposed infants."

Doberczak et al. (1988) evaluated electroencephalo­gram (EEG) abnormalities in 39 infants exposed inutero to cocaine. Maternal history and maternal andneonatal toxicology screening were used to confirm thatcocaine was the only illicit drug exposure. No congeni­tal malformations occurred in the infants. Thirty-fourinfants had increased muscle tone, brisk deep tendonreflexes, irritability, or tremors. The EEGs were abnor­mal in 17 of 38 infants during the first week of life;abnormalities were characterized as showing centralnervous system irritability. By 3 to 12 months of age, 9of 10previously abnormal tracings had normalized andone was pending further study. The authors concludedthat the EEG abnormalities were transient and might bethe result of changes in neurotransmitter availabilityand function."

In 1989 Chasnoff et al. reported on 75 cocaine­exposed pregnancies evaluated between 1986and 1988.Twenty-three mothers using cocaine only in the first tri­mester (group I) were compared with 52 who usedcocaine throughout pregnancy (group II) and 40 con­trols (group III). Alcohol, marijuana, and tobacco usewas similar in groups I and II. Forty percent snortedcocaine, 40 percent used freebase, and the remainderused cocaine intravenously. Infants exposed to cocainethroughout pregnancy (group I) had a significantdecrease in mean birth weight (2829 ± 708 g vs.3436± 628 g for controls), length and head circumfer­ence (32.7 ± 2.3 em vs. 34.6 ± 1.6 em for controls).Groups I and II demonstrated, using the NeonatalBehavioral Assessment Scale, impairments in orienta­tion, and motor and state regulation behaviors. Twoinfants in group I had ileal atresia and six infants ingroup II developed seizures of unknown cause; theyhad normal metabolic studies and brain scans, althoughtwo had abnormal EEGs. Two additional infants ingroup II had cerebral infarctions. Genitourinaryanom­alies were seen in three infants in group I and six ingroup II. Among those nine, two had prune-belly syn­drome. The authors noted in the study that the interac­tive effects of alcohol, marijuana, and tobacco couldnot be completely evaluated. 28

Zuckerman et al. (1989) evaluated a group of 1226mothers (predominantly young, low-income, urban,black or Hispanic) to assess the fetal outcome ofcocaine and marijuana-exposed pregnancies. Exposednewborns were grouped according to whether expo­sures were ascertained by maternal interview or by urineassay. Alcohol and tobacco use were determined bymaternal interview. Infants born from mothers withpositive urine assays for cocaine (114babies) had signif­icantly smaller birth weight (93g lighter), length (0.7 emshorter), and head circumference (0.43 em smaller)than matched controls. Similar differences were foundfor marijuana-exposed pregnancies having positiveurine tests. No fetal outcome differences were foundfor either marijuana or cocaine when maternal inter­view was relied upon to identify cocaine or marijuana-

FetalEffects ofCocaine

exposed pregnancies. The authors concluded thatcocaine and marijuana are independently associatedwith impaired fetal growth and that clinical studiesevaluating fetotoxicity of such agents should employuse of biologic markers to identify exposures. 29

Fifty-three cocaine-exposed infants were reported byLittle et al. (1989), but identification of cocaine use wasby self-report and thus biases the study. The mothersalso used other illicit drugs such as tobacco and alcohol.A control group of 100randomly sampled women fromthe same hospital was not matched for other drug use.Infants were also examined by physicians aware of thedrug history and thus not blinded. Cocaine-exposedinfants had significantly lower birth weight, length, andhead circumference than did infants of controls. Thefrequency of any anomaly (nine in cocaine, six in con­trol group), of major congenital anomalies (five incocaine, two in control group), and specifically of con­genital cardiac anomalies (four in cocaine, zero in con­trol group) was increased in the cocaine-exposed group.Confounding factors of other drug effects as wellas theuse of self-report makes interpretation of the fetaleffects of cocaine difficult in this report. 30

Finally, we should make note of recent (1989)reportsthat have been published as abstracts but await publica­tion and review in refereed journals. The implicationsof these reports are sufficient to warrant a brief review.First, Chavez et al. examined the relationship of peri­conceptional cocaine use on malformations in a popu­lation-based study of 4929 babies enrolled in themetropolitan Atlanta Birth Defects Case-ControlStudy (directed by the Centers for Disease Control).The periconceptional period includes the time from onemonth prior to three months after conception. Datawere based on retrospective self-reporting and are thussubject to biases of ascertainment. A group of 3029ran­domly selected babies without malformations was usedas case controls. The analysis controlled for the effectsof maternal age, education, alcohol use, smoking, andother illicit drug use. The estimated relative risk for uri­nary tract malformations for cocaine exposure was 4.8and 2.3 for defects of the genitalia." Second, Kobori etal. reported 11 cases of fetal malformations in which 6of 11 mothers used cocaine alone and the other 5 usedother street drugs in addition to cocaine. Central ner­vous system malformations were severe and includedhydranencephaly (1), porencephaly (2), hypoplasticcorpus callosum with unilateral parietal lobe cleft andheterotopias (1), intraparenchymal hemorrhage (5),unilateral three-vessel hemispheric infarction (1), andencephalomalacia (1). Three infants had arthrogryposismultiplex congenita of central origin, four infants died,and the remaining seven had serious neurodevelopmen­tal disabilities. A variety of facial dysmorphia was alsoobserved. The authors concluded that cocaine was apotent teratogen. 32 Finally, Hoyme et al. reported eightchildren born to women abusing cocaine, with or with­out additional substance abuse. Three children hadintestinal disruptions: one with midcolonic atresia, onewith ileal atresia, and one with widespread infarction ofthe bowel distal to the duodenum (previously reportedby Telsey et al. 14). Six children also had limb anomalies:three had unilateral terminal transverse defects, one

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child had the Poland sequence and bilateral upper limbanomalies including ulnar ray deficiencies, and two hadbilateral radial ray defects. The authors concluded thatcocaine is a human teratogen and that the nature of theobserved malformations imply that vascular disruptionor hypoperfusion is the primary mechanism of fetalinjury,"

Summary ofHuman Studies

In the clinical studies reported in refereed journals, atotal of 260 babies were reportedly exposed to cocaineonly (not also exposed to other illicit drugs) duringsome phase of prenatal development. There are addi­tional polydrug-exposed babies as outlined in Table 1. Itis clear that cocaine-exposed pregnancies are at anincreased risk for an abnormal birth outcome althoughthis risk is heavily related to the suboptimal prenatalconditions of women who ultimately come to usecocaine during pregnancy. These suboptimal conditionsinclude low socioeconomic class, poor education,absence of prenatal care, use of other illicit drugs, alco­hol and cigarette use, malnutrition, and other factors.Not only do these conditions contribute to suboptimalfetal outcome" but they serve as enormous confound­ing variables that usually cannot be effectively sortedfrom the effects of solitary cocaine exposure." Thus,although the literature appears to report on manybabies with prenatal "cocaine exposure:' the fetalexposures are surely not solitary risk factors regardingimpairment of fetal development. These aspects makethe assessment of human teratogenicity of cocaineexceedingly difficult regarding evaluation of clinicalstudies.

Nevertheless, the studies in aggregate indicate thatcocaine-exposed pregnancies are at increased risk for amildly decreased birth weight and for some degree ofsmall-for-gestational-age size. Abruptio placentaeappears often as a complicating feature as do someinstances of prematurity. The growth anomalies or pla­cental problems can be explained on the basis ofcocaine's known vasoconstrictive properties and itspotential deleterious effect on normal placental func­tion.

A more problematic concern is whether cocainecauses structural birth defects as opposed to its effect ofgeneralized growth impairment. A number of casereports indicate that disruptive events such as vascularinfarctions can cause structural fetal injuries. But thegeneral conclusion from the studies reviewedis that thegreat majority of cocaine-exposed pregnancies do notresult in structural fetal abnormalities. Even the often­quoted study by Chasnoff et al. of urogenital anomaliesin cocaine-exposed pregnancies" could not find statisti­cal significance although the frequency of such anoma­lies was "noteworthy." Because these anomalies areoften frequent in the normal population (such as hypo­spadias or hydronephrosis) a large series of exposedpregnancies may be needed before true associated risksare proven. In this regard, the 1989 report from theCenters for DiseaseControl does suggest that there maybe an increased risk for urogenital malformations incocaine-exposed pregnancies." More disturbing are therecent reports of structural, severe central nervous sys­tem anomalies and intestinal and extremity malforma­tions. The case reports suggest that a disruption ofnormal fetal tissues (as opposed to a malformationevent that impairs early tissue migration and forma­tion":") may be a mechanism for a teratogenic effectfrom cocaine. These observations are in keeping withvasoconstrictive capabilities of cocaine and thus fit intoa tenable pathogenetic model. Recent reports, togetherwith previous isolated case reports, provide evidencef?r a unique fetal injury from cocaine due to disrup­nons, Such fetal injury is to be distinguished from thefetal malformations seen in, for example, the fetal alco­hol syndrome where primary fetal morphogenesis isimpaired and no disrupting injuries are observed.

Finally, exposed infants are at risk for behavioral andcognitive abnormalities in the newborn period but it isunclear to what extent these abnormalities will affectlong-term developmental outcome.

Summary

Given the limitations of studying any drug in preg­nant women, we may never know the absolute risk ofmaternal cocaine intake.

Table 1. Summary of Clinical Studies of Human Fetal Outcome in Cocaine-Exposed Pregnancies

Reference 9 16 17 18 19 20 23 24 25 26 27 28 29 30Yearof report 1985 1986 1987 1987 1987 1987 1987 1988 1988 1988 1988 1989 1989 1989Patients (n) 23 8 50 70 18 50 50 143 55 43 39 75 114 53Determination of exposureby history + + + + + + + + + + + +by toxicology screen + + + + + + + + + ? + + +

Drug exposurecocaine only 12 8 50 24 13 0 0 0 0 0 39 0 114 0polydrug 11 0 0 36 5 50 50 124 55 43 0 75 0 53

Increased incidence of + + + + + + + + NA +abnormal fetal outcome"

+ +

Increased incidence of or + + ? ? + ? ? + ?noteworthy occurrence of

+

structural birth defects

·Inc~ud~s nonstructural defects suc~ as.growth retardation, prematurity, low birth weight, or decreased gestational age.(+) indicates presence of event; (-) indicates absence of event; NA = not applicable.

644 • DICp, The Annals ofPharmacotherapy • 1989 September, Volume 23 at PENNSYLVANIA STATE UNIV on May 11, 2016aop.sagepub.comDownloaded from

Nevertheless, we can make some meaningful conclu­sions about the fetal risks associated with maternalcocaine use. First, placental dysfunction due to vascu­lar compromise probably increases the fetal risk forgrowth retardation or prematurity. Fetal loss due toabruptio placentae may occur. Also, cocaine-inducedneuroexcitation (increased startle response, abnormalsleep patterns, jitteriness) can cause neonatal behav­ioral abnormalities, but it is not clear if these behavioraleffects are lasting. Finally, there may be an increasedrisk for fetal structural anomalies due to disruption ofin utero events, possibly related to the vasoactive prop­erties of cocaine. Larger epidemiologic studies areneeded before this risk for structural fetal anomalies ismore precisely defined. ~

ReferencesI. JONES R. The pharmacology of cocaine. NIDA Res Monogr

1984;50:34-53.2. WILKINSON P, VANDYKEC, lATLOW P, BRASH P, BYRK R. Intra­

nasal and oral cocaine kinetics. Clin Pharmacol Ther 1980;27:386-94.

3. lAVAID 11,MUSA MN, FISCHMAN M, SCHUSTER CR, DAVIS 1M.Kinetics of cocaine in humans after intravenous and intranasaladministration. Biopharm Drug Dispos 1983;4:9-18.

4. SEIGEL RK. Cocaine smoking. J Psychoactive Drugs 1982;14:271-325.

5. MAHALIK MP, GAUTIERI RF, MANN DE. Teratogenic potential ofcocaine hydrochloride in CF-I mice. J Pharm Sci 1980;68:703­6.

6. MOORE TR, SORG 1, MILLER L, KEY TC, RESNIK R. Hemody­namic effects of intravenous cocaine on the pregnant ewe andfetus. Am J Obstet GynecoI1986;155:883-8.

7. WOODS lR lr, PLESSINGER MA, CLARK KE. Effect of cocaine onuterine blood flow and fetal oxygenation. JAMA 1987;257:957­61.

8. ACKER D, SACHS BP, TRACEY Kl, WISE WE. Abruptio placentaeassociated with cocaine use. Am J Obstet Gynecol 1983;146:220-1.

9. CHASNOFF IJ, BURNS W1, SCHNOLL SH, BURNS FA. Cocaine usein pregnancy. N Engl J Med 1985;313:666-9.

10. LEBLANC PE, PAREKH Al, NASO B, GLASS L. Effects of intra­uterine exposure to alkaloidal cocaine ("crack"). Am J DisChild 1987;141:937-8.

II. CHASNOFF IJ, BUSSEY ME, SAVICH R, STACK CM. Perinatal cere­bral infarction and maternal cocaine use. J Pediatr 1986;108:456-9.

12. HENDERSON CE, TORBEY M. Rupture of intracranial aneurysmassociated with cocaine use during pregnancy. Am J Perinatol1988;5:142-3.

13. CRITCHLEY HO, WOODS SM, BARSON Al, RICHARDSON T,LIEBERMAN BA. Fetal death in utero and cocaine abuse. Casereport. Br J Obstet GynaecoI1988;95: 195-6.

14. TELSEY AM, MERRIT TA, DIXON SD. Cocaine exposure in a termneonate. Necrotizing enterocolitis as a complication. ClinPediatr 1988;27:547-50.

15. TESKE MP, TRESE MT. Retinopathy of prematurity-like fundus

FetalEffects ofCocaine

and persistent hyperplastic primary vitreous associated withmaternal cocaine use. Am J OphthalmoI1987;103:719-20.

16. MADDEN 10, PAYNE TF, MILLER S. Maternal cocaine abuse andeffect on the newborn. Pediatrics 1986;77:209-11.

17. BINGOL N, FUCHS M, DIAZ N, STONE RK, GROMISCH DS. Terato­genicity of cocaine in humans. J Pediatr 1987;110:93-6.

18. MACGREGOR SN, KEITH LG, CHASNOFF 11,et al. Cocaine useduring pregnancy: adverse perinatal outcome. Am J ObstetGynecoI1987;157:686-90.

19. ORO AS, DIXON SD. Perinatal cocaine and methamphetamineexposure: maternal and neonatal correlates. J Pediatr 1987;111:571-8.

20. CHASNOFF 11, CHISUM GM, KAPLAN WE. Maternal cocaine useand genitourinary tract malformations. Teratology 1988;37:201-4.

21. CHASNOFF 11,BURNS KA, BURNS W1. Cocaine use in pregnancy:perinatal morbidity and mortality. Neurotoxicol Terato11987;9:291-3.

22. BAUCHNER H, ZUCKERMAN B, MCCLAIN M, FRANK D, FRIEDLE, KAYNE H. Risk of sudden infant death syndrome amonginfants with in utero exposure to cocaine. J Pediatr 1988;113:831-4.

23. RYAN L, EHRLICH S, FINNEGAN L. Cocaine abuse in pregnancy:effects on the fetus and newborn. Neurotoxicol Teratol 1987;9:295-9.

24. CHOUTEAU M, NAMEROW PB, LEPPERT P. The effect of cocaineabuse on birth weight and gestational age. Obstet Gynecol1988;72:351-4.

25. CHERUKURI R, MINKOFF H, FELDMAN 1, PAREKH A, GLASS L.A cohort study of alkaloidal cocaine ("crack") in pregnancy.Obstet GynecoI1988;72:147-51.

26. MITCHELL M, SABBAGHA RE, KEITH L, MACGREGOR S, MOTA1M, MINOQUE 1. Ultrasonic growth parameters in fetuses ofmothers with primary addiction to cocaine. Am J Obstet Gyne­col 1988;159:1104-9.

27. DOBERCZAK TM, SHANZER S, SENIE RT, KANDALL SR. Neona­tal neurologic and electroencephalographic effects of intrauter­ine cocaine exposure. J Pediatr 1988;113:354-8.

28. CHASNOFF 11, GRIFFITH DR, MACGREGOR S, DIRKES K, BURNSKA. Temporal patterns of cocaine use in pregnancy: perinataloutcome. JAMA 1989;261:1741-4.

29. ZUCKERMAN B, FRANK DA, HINGSON R, et al. Effects of mater­nal marijuana and cocaine use on fetal growth. N Engl J Med1989;320:762-8.

30. LITTLE BB, SNELL LM, KLEIN VR, GILSTRAP LC III. Cocaineabuse during pregnancy: maternal and fetal implications.Obstet GynecoI1989;73:157-60.

31. CHAVEZ GF, MULINARE 1, CORDERO lE Maternal cocaine useand the risk for genitourinary tract defects (abstract). Clin Res1989;37:A43.

32. KOBORI lA, FERRIERO DM, GOLABI M. CNS and craniofacialanomalies in infants born to cocaine abusing mothers(abstract). Clin Res 1989;37:196A.

33. HOYME HE, JONES KL, DIXON SD, et al. Maternal cocaine useand fetal vascular disruption (abstract). Clin Res 1989;37:196A.

34. DOBERCZAK TM, THORNTON rc, BERNSTEIN 1, KANDALL SR.Impact of maternal drug dependency on birth weight and headcircumference of offspring. Am J Dis Child 1987;141:1163-7.

35. FRANK DA, ZUCKERMAN BS, AMARO H, et al. Cocaine use dur­ing pregnancy: prevalence and correlates. Pediatrics 1988;82:888-95.

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