Drug Abuse

 

COCAINE AND PREGNANCY, HYPE OR SCIENCE?

A REVIEW OF THE LITERATURE.

Drs.E.Fromberg

Nederlands Instituut voor Alcohol en Drugs

Postbus 725

3500 AS Utrecht

The Netherlands

This paper is an update and extension of a presentation on a meeting of medical specialists, Erasmus University, Rotterdam, 30 May 1991 and has served as unpublished background paper for meeting of WHO's Global Advisory Committee on Cocaine, August 1992.

ABSTRACT

Cocaine has been considered a relatively harmless drug in the seventies, but its reputation changed in the eighties into that of a drug that makes the former devil drug heroin pale. This shift coincides with a growing number of publications, mostly from the U.S.A., about deleterious effects of cocaine use, among which the influence of maternal cocaine use on the course of pregnancy and neonati. This literature may convince many that cocaine is indeed a highly dangerous drug.

However under scrutiny, the literature shows a clear observational bias and analysis makes it at least very uncertain whether the described effects can really be attributed to maternal cocaine use. It is to be feared that the war on drugs rhetorics are the main cause of the crack-baby hype.

INTRODUCTION

Cocaine was considered a relatively harmless drug in the seventies, but its reputation changed in the eighties into that of a drug that makes the former devil drug heroin pale. This shift coincides with a growing number of publications, mostly from the U.S.A., about deleterious effects of cocaine use, among which the influence of maternal cocaine use on the course of pregnancy and neonati. This literature may convince many that cocaine is indeed a highly dangerous drug.

However under scrutiny, the literature shows a clear observational bias and analysis makes it at least very uncertain whether the described results can really be attributed to maternal cocaine use. This is not to prove cocaine's innocence, but to draw attention to the often biased nature of the medical literature on cocaine.

CHASNOFF'S FIRST EVIDENCE

Already in 1980 MAHALIK, GAUTIERI & MANN (1980) reported that cocaine in a dose of 60mg/kg administered subcutaneously to pregnant mice caused a range of congenital malformations in their offspring. So cocaine was understood to have teratogenic potential, although at a very high dose level: the dose administered equals the taking at once of 4 grams of cocaine in a 75 kg human being. This article drew little attention, possibly because it was published in a pharmaceutical journal, possibly because of lack of political interest in cocaine these days.

Moreover FANTEL and MacPHAIL reported in 1982 that at the same dose levels no teratogenicity could be detected in mice and rats. Their only finding was that of reduced birthweight which they associated with the reduced food intake of the mothers (maternal weight was also reduced in rats, not in mice).

It were ACKER et al (1983) who first drew attention to possible influences of maternal cocaine use on pregnancy outcome in humans. His article, two case histories involving abruptio placentae, was published in 1983 in a medical journal. It was followed in 1985 by an article of CHASNOFF and coworkers.

Chasnoff was and is director of a special program in Chicago: the Perinatal Addiction Project of Northwestern Memorial Hospital's Institute of Psychiatry and Prentice Women's Hospital and Maternity Center. The authors compared 23 women that were referred to this program with women from a methadon program and with drugfree women. From these 23, 12 used only cocaine ("C"), the other 11 used other drugs, particularly heroin, as well ("C+"). The authors reported a significantly higher frequency of spontaneous abortion among the C women and a significantly lower score of their neonates on the Neonatal Behavioral Assessment Scale with regard to interactive behaviour and "organizational response on environmental stimuli". Casuistically they drew attention to abruptio placentae, teratogenicity and SIDS. Birth weight, length, gestational age en head circumference did not differ significantly.

Although a highly questionable study, because of the selection of cases and the composition of the study groups, the study was reported in The U.S.Journal as front page news (KORCOK, 1985) without any critical note.

The publication of MADDEN, PAYNE and MILLER (1986) received no such attention. It contained 8 case histories of neonates of cocaine using women, four being perfectly normal while in the other four no evidence of potentially life threatening symptomatology could be found.

Chasnoff made a presentation for the 48th Annual Scientific Meeting of the Committee on Problems of Drug Dependence, Inc. (later published as Chasnoff 1987d), in which he repeated and extended his 1985 article.

A further article by CHASNOFF et al (1986) reported an infant developing cerebral infarction after delivery at term to a woman who used a large amount of cocaine in the 72 hours before delivery. The `post aut propter' is not discussed. Cocaine was implicated.

This assumption is not surprising. Cocaine has potent vasoconstrictive properties and freely passes across the placenta. Therefore effects on pregnancy and the fetus may be expected. Even if vasoconstriction in the placental vessels were to prevent fetal contact with cocaine, the resulting hypoxia might cause damage. Thus, it is not surprising that Chasnoff c.s. claimed cocaine to be the causal factor, especially when taking their observational bias into account. In the meantime basic research was performed on the hemodynamic effects of cocaine and published by MOORE et al. (1986). They demonstrated that cocaine administered in doses that produce plasma levels as observed in humans significantly decreases uterine blood flow for approximately 15 minutes and induces a hypertensive response in the pregnant ewe and the fetus. So a possible mechanism for all the signs and symptoms observed is available. In the same vein, WOODS, PLESSINGER and CLARK (1987) reported the negative influence of cocaine on uterine blood flow and fetal oxygenation.

Then CHASNOFF (1987a) went on to write an extensive article in Contemporary Ob/Gyn on the effects of cocaine: how to identify the substance abuser, which laboratory data should be collected for evaluation and reports about his experience with cocaine using pregnant women. He reports a survey of 600 obstetricians (response 20%) which indicates that at least the respondents strongly dissuade their patients to use cocaine, and urge them only to take drugs prescribed by their physician.

Thereafter, CHASNOFF, LEWIS and SQUIRERS (1987b) published a case history. This report described the case of a two weeks old baby that was brought to the hospital by the mother because of increased irritability. Minor signs of intrauterine exposure to alcohol were found, corresponding with the heavy alcohol use of the mother during pregnancy. Both mothers milk and baby urine contained cocaine and benzoylecgonine. The baby was hospitalised without treatment and the symptoms disappeared spontaneously. The increased irritability was ascribed to maternal cocaine use.

SUPPORT AND DISSENT

ORO and DIXON (1987) from San Diego published a study that compared maternal and neonatal variables of a group of neonati that had been exposed to cocaine and/or methyl-

amphetamine, a group that was exposed to opioids (heroin and/or methadone) and a drugfree group. Due to the fact that they do not discriminate between cocaine and methamphetamine their data are questionable. They however reported that use of cocaine and/or methamphetamine is negatively influencing gestational age, birth weight, length, occipitofrontal circumference and placental hemorrhage.

In the same year BINGOL et al. (1987) published a comparison between the neonati of 50 cocaine-using women © and 110 polydrug-users (C+) and 340 drugfree women. These authors found a significant decrease of birth weight, an increase in stillbirth due to abruptio placentae and a significantly increased malformation rate. The population researched was again non random, the C women being identified by urinalysis upon admission. Therefore only very recent cocaine use was the inclusing criterion. In response BAUCHNER et al.(1987) wrote a letter to the editor, claiming that the study may misleading, because it did not account for variables known to affect birth weight such as alcohol consumption and the nutritional state of the women.

Chasnoff's Chicago group published a further report, with MacGREGOR (1987) as first author. They described a prospective cohort study of 70 cocaine using pregnant women (only 24 or 34% had only used cocaine), the others were poly drug users. The control group was from the general hospital population, matched on maternal age, parity, socioeconomic class, tobacco use and medical complications. The use of cocaine during pregnancy was associated with lower gestationalage at delivery, an increase in preterm labor and delivery, lower birth weights and delivery of small for gestational age infants. The most remarkable finding however was that no significant differences could be found between the cocaine only and the polydrug users. The authors failed to find statistically significant differences in the frequency of abruptio placentae, but state that the difference clinically is alarming. HOWARD (1989) reported on a study published by CHASNOFF (1987c) which is partly retrospective, partly prospective with a study group of 52 and a control group of 78 women and reports in which an increase of SIDS is reported. Other authors (RYAN, EHRLICH and FINNEGAN, 1987) reported an increased number of spontaneous abortions and fetal deaths among poly-drug using women that also have cocaine as one of their drugs of use.

BAUCHNER et al. (1988), in reaction to Chasnoff's 1985 case reports, undertook a study in Boston City Hospital to determine whether a relation could be found between SIDS and maternal cocaine use. This study prospectively compared 175 babies of cocaine using women, among which there were polydrugusers (with 15% of them reportedly used opioids) and 821 babies of women that were not using cocaine, although some of them used other drugs (15% opioids too). The study population was randomly obtained, drawn from a much larger research project that included all women who applied for prenatal care in a large hospital over a period of two years and spoke either English or Spanish, provided they agreed to participate. 69% of the total applicants participated, the languages being the most important reason of non-participation. A reasonable picture was obtained of their drug use and after interviews urine was taken for analysis. This study found no significant differences in the incidence of SIDS.

The British started contributing to the literature (CRITCHLEY et al, 1988) with a case report of fetal death in utero in a 17 year old mother. Fetal blood turned out to contain 1 mg/l cocaine.

CHOUTEAU, NAWEROW and LEPPERT (1988) compared 124 neonati of mothers that had cocaine positive urines at admission with 218 whose mothers had negative urines. Thus they discriminated only on recent cocaine use, nor do they mention what other drug use was shown at urinalysis. Only women that had not had any prenatal care were included in the samples. They found a significant reduction in birth weight and gestational age.

However the authors commented that care was necessary in the interpretation of the reduced gestational age because of the subjectivity in its determination given the lack of prenatal care. Explicitly the authors mention not to have found any difference with regard to abruptio placentae.

CHERUKURI et al. (1988) reported a retrospective study among 55 crack using women and used 55 women matched on age, socioeconomic status, parity and alcohol use as a control group. The study group consisted of women that admitted crack use, so non random again. Gestational age, length and head circumference were significantly reduced and the frequency of premature breaking of the membranes (PROM) was increased. The authors commented that the differences shown were probably underrated due to their research design. However they statet that this design did not allow for tem to assign with certainty the differences found to the pharmacological action of crack as the influence of the related lifestyle might explain it as well.

The Boston group published a further report, FRANK (1988) being the first author. In their publication they drew first attention to the fact that, as already mentioned, most authors obtained their target groups in a non-random way and did not control for other possible causative factors such as maternal demographic characteristics, previous obstetric history, maternal nutritional state and the use of tobacco, alcohol, Cannabis or other drugs. To avoid these problems they studied 679 women during and after pregnancy and compared cocaine using women with non-using women on the influence of all these variables. Selection was random: all women admitted to the hospital were taken into the study, with exception of 14% because of language difficulties, 5% due to administrative loss and 7% due to refusal to consent. However the medical records of non-participants did not differ from those of participants with regard to drug use. Significant differences were found between the cocaine using group and the non using group with regard to the following obstetrical risk factors: worse nutritional status, more sexually transmitted diseases, more premature babies with low birthweight, more abortions, more use of other drugs (alcohol and tobacco included). Finally the authors stated that not only urinalysis, but self-report as well should be used as an inclusion criterion.

In the meantime Chasnoff had continued to research the deleterious effects of cocaine. In his first study (1985) he described two cases of teratology: one prune belly syndrome and one hypospadias. Although this was statistically non-significant, taking into account Mahalik's 1980 data indicating teratogenicity in mice, he tried to prove it in humans. He studied prospectively 50 cocaine using women (some being poly drug users) and 30 polydrug non-cocaine using women and published in 1988 (CHASNOFF, CHISUM and KAPLAN, 1988). In the first group 7 babies were delivered with genitourinary abnormalities, in the second group one case of Fetal Alcohol Syndrome (FAS). Again, this difference was statistically non significant.

The possible detrimental effect of cocaine exposure on the developing brain, as already suggested by Chasnoff's (1985) neurobehavioural findings, were further analysed by DOBERCZAK et al. (1988). In this study 39 infants that had been exposed to cocaine were examined for neurologic and electroencephalographic abnormalities. Clinically 34 of them were assessed as having increased muscle tone, deep tendon reflexes, irritability and tremors, that disappeared without therapy in a few days in 32 of the infants. Two had to be sedated for two days. The others were normal. The EEG's of 17 neonates were abnormal in the first week, 5 of which normalized in the second week (3 did not turn up for the second EEC) and 9 normalized within 3-12 month. In one of these patients the first EEC abnormalities appeared on day 13 of life. After 12 months only one infant still had an abnormal EEC. The authors called the symptoms mild, selflimited and transient.

Chasnoff's group (MITCHELL et al 1988) publicized the data of ultrasound studies performed on 67 fetuses of cocaine using mothers and compared these with the measurements of 'non-addicted' fetuses. The results suggest abnormal growth of 'addicted' fetuses can occur, however no statistically significant differences in birth weight could be demonstrated.

At about the same time LITTLE et al (1988) publicized in Dallas. The records of 102 women that delivered consecutively were reviewed with regard to cocaine use as well as other drug use, legal or illegal. The occurrence of abruptio placentae was noted as were congenital malformations. Only 10 women used cocaine, either only or in combination with other drugs. No significant differences could be detected. This article was quickly followed by a second (LITTLE et al, 1989) which described the study of the neonati of 53 self-reporting cocaine-users which were compared with 100 neonati that had not been exposed to cocaine in utero. The control group was comprised of the next two birth's within the hospital after any cocaine-birth (unless these were also cocaine positive). The mothers of cocaine exposed babies used significantly more tobacco, marihuana, alcohol and methamphetamines than the non-C mothers, as well were different with respect to age and ethnicicty. However this time a significantly lower birthweight and excess congenital malformations were reported among the babies of cocaine using mothers.

Then CHASNOFF et al (1989a) compared 23 women that only used cocaine during the first trimester of their pregnancy with 52 women that used during the whole of their pregnancy and 40 non-using women. The first and the third group did not differ with respect to preterm delivery, low birthweight and intrauterine growth retardation. In group 2 the frequency of these conditions was increased. Abruptio placentae occurred asfrequently in group 1 as group 2 and was considered to be a consequence of damage to the placenta and placental bloodvessels that were caused in early pregnancy and not due to acute hypertension . Neonatal Behavior Assessment Scale-scores were significantly different in both groups.

In the Journal of the American Medical Association SILVERMAN (1989) states that a picture of effects on the fetus begins to emerge, citing both NIDA and Chasnoff. This interpretation of the studies however is highly questionable, with the above mentioned studies being highly contradictory.

As an Annotation in "Developmental Medicine and Child Neurology", HOWARD (1989) of the Intervention Program for Handicapped Children raised the issue and came to the conclusion that cocaine causes spontaneous abortions, fetal deaths and SIDS, based on Chasnoff (1987c), RYAN (1987) and ORO & DIXON (1987). Other publications reporting "negative" findings are simply ignored.

Then another first author of the Chicago group published: NEERHOF at al.(1989). In this study 138 pregnant women that were cocaine positive at urinalysis at admission (among them 24 that were positive on other drugs also) were compared with a control group of 88 pregnant women that were randomly selected (except when they admitted to cocaine use or had a positive urine).

The target group differed from the control group with regard to age, gravidity and parity so the real significance of the statistically significant findings (PROM, reduced birthweight, -length and gestational age) was not very great. Neither of the non-significant differences: abruptio placentae, perinatal death. Casuistically they again note congenital malformations. There was a significant difference between the frequency of congenital malformations among the pure cocaine users (4%) and the poly-drug users (21%).

In a review of the literature published by ROLAND & VOLPE (1989) it was concluded that "the recent epidemic (...) has caused increasing concern about the potential hazards of prenatal cocaine exposure on the developing fetus and newborn. Although large-scale epidemiologic studies and long term data are lacking, a review of the literature suggests strongly that (...) maternal cocaine abuse during pregnancy may be associated with increased perinatal morbidity and mortality."

Then MERCADO et al (1989) published a case description of a woman that had a cerebral hemorrhage after taking crack. As this happened 4 days post partum, this has nothing to do with pregnancy, however the title of this report suggests a relationship.

The next publication was from the Boston group: ZUCKERMAN et al.(1989) studied prospectively the effects of maternal cocaine (and/or marihuana) use on fetal growth in 1226 women. It was reported that 114 of them used cocaine during pregnancy, which was either self-reported or shown in urinalysis. Significant differences existed between cocaine using and non using women with regard to alcohol and tobacco use. The authors concluded that without a causal relationship can be postulated, cocaine use is associated with intrauterine growth retardation (IUGR): significant differences were found in weight, length and head circumference. Moreover congenital malformations occurred significantly more freqently among babies of cocaine using women. A remarkable fact was however that no significant signs of IUGR could be found in the children of women that self-reported cocaine use but were negative at urinalysis.

Then CHASNOFF, HUNT & KAPLAN (1989b) published again, this time to associate prenatal cocaine exposure with respiratory pattern abnormalities leading to SIDS. A prospective study of 32 cocaine exposed babies, compared with 18 opiate exposed ones as controls, showed 12 from the study group and 1 of the control group as having an abnormal cardiorespiratory pattern.

The Journal (LEE, 1989), in a sensational report, report: "Cocaine babies on the rise in US", quoted an ex-addict Florida based addictions consultant: "some US hospital units are almost exclusively occupied by newborn babies addicted to cocaine, and thousands of such infants are putting a strain on some cities' social and welfare services". This seems in striking contrast to the small numbers of pregnancies and babies studied by all the authors mentioned.

Next JAMA published a study by CHAVEZ, MULINARE and CORDERO (1989) which compared 7133 baby's with congenital genito-urinary malformations with 4246 without malformations, that were matched on ethnicity, hospital, and birth trimester. From the first group 4929 mothers (69%) were questioned, from the second 3029 (71%), about cocaine use in the month before and in the first trimester of the pregnancy. A statistically significant relationship was found between maternal cocaine use and congenital malformations in the urinary tract. No relationship was found between cocaine use and genital malformations.

In the same JAMA issue, GOLDIN (1989) warned in a letter to the editor that in CHASNOFF (1989a) results may be confounded by self-selection, as one of the stated goals of Chasnoff's center is to facilitate the mothers' stopping of their cocaine use. Those who might have stopped in the first trimester, might as well have stopped or reduced smoking of tobacco, marihuana and other drugs and might have had better prenatal care. Chasnoff's answer does not elucidate the matterof changing use patterns, but agrees that better prenatal care might influence results.

From Los Angeles came a publication of HADEED and SIEGEL (1989). They performed a retrospective study on neonati that had cocaine positive urine immediately postpartum. If the mothers had no history of other drug use they were included in the study group (N = 56). The control group were neonati with negative urines and no history of drug exposure, matched on maternal variables (N = 56). Growth retardation and microcephaly were significantly more frequent among cocaine exposed babies. No signs of teratogenicity were found. DIXON and BEJAR (1989) of the San Diego team published an echoencephalographic study into central nervous system injuries. Again the study group comprized cocaine exposed and methamphetamine exposed neonates. She concluded that antenatal exposure to stimulants is associated with a significant risk for cerebral injury, even among seemingly normal term neonates.

A case report (REZNIK et al. 1989) incriminates maternal cocaine use for arterial thrombosis and hypertension in a neonate that had an umbilical artery catheter. Although aortal thrombosis is a well known complication of such catheter, the cocaine exposure was claimed to be an added risk factor.

The earlier mentioned question of GOLDIN (1989) clearly gave CHASNOFF an idea. His group retrospectively compared pregnancy outcome of 1) cocaine using women in his program receiving prenatal care; 2) cocaine using women without prenatal care and 3) a control group from the general obstetric population. Group 1 was worse than 3, but better than 2 (MacGREGOR et al. 1989).

PROOF OF BIAS

A completely different approach is published in the Lancet by a Toronto based group. KOREN c.s. (1989) analysed all abstracts submitted to the Society of Pediatric Research. All abstracts that are submitted are published, included those that are not accepted for presentation or publication of the complete paper, those being selected for presentation being marked with a symbol. The researchers analysed all abstracts on fetal outcome after gestational exposure to cocaine and concluded that there was a significant difference. If no adverse effects were reported the chance for acceptance was only 11%, if adverse effects were reported the chance for acceptance was 57%. Now, this might have been the result of no effects found due to poor research methodology and effects found due to well performed research. However, further scrutiny made clear that the negative ( = no effect) studies were scientifically equivalent or superior to the positive ones, and when comparing the refused negative and positive abstracts, that the negative abstracts were superior in almost every variable studied, for example in verifying cocaine use, and in not confusing cocaine use and use of other drugs. The finding of a negative effect of cocaine had more influence then the quality of the research, although the latter should be the factor that decides publication or not. The authors concluded that this clear bias against the null hypothesis is the result of the public reputation of cocaine being an evil drug, which has to have these effects. Moreover, the authors stated, the effects described occurred in samples of heavy cocaine using women and these data cannot be applied on mild, recreational users that often discontinue use during pregnancy.

THE FLOOD GOES ON..

These observations did however nothing to stem the flood of publications. BURKETT, YASIN & PALOW (1990) reported from Florida of significant lower birth weight, small size for gestational age (SGA), neurologic problems and syphilis in cocaine exposed babies. Congenital malformations seemed to be multifactorial. The authors stated that this consistent pattern of poor outcome reflected the lifestyle of their patients. PETITTI et al. (1990) showed in a population study based on birth certificates that 10% of the cases of low birthweight (<2500 gr) in Alameda County should be attributed to cocaine use. The Journal (McCANN, 1990) reported a speech by Dr.Little at a science writers seminar sponsored by the American Heart Association in which he reported his finding (LITTLE,1989) that heart defects are the most common birth defects among cocaine exposed fetuses (8% of 53 neonates).

DATTEL (1990) reported retrospectively from San Francisco General Hospital a significant increase of abruptio placentae, preterm labor, low birth weight and fetal distress requiring cesarean section, however without presenting all thedata. No significant differences were found between cocaine only and cocaine plus other drugs.

MASTROGIANNIS et al. (1990) divided the babies born to mothers with a history of cocaine use into two groups: those tested negative on cocaine and its metabolites in their first voided urine and those tested positive. In the last group preterm labor, meconium stained amniotic fluid and PROM were significantly more frequent. Lower birth weight, abruptio placentae and growth retardation were also more frequent than in the general population, but did not differ sifnificantly between the two study groups. Maternal variables differed however significantly between the two groups with regard to smoking and polydrug use.

GINGRAS, O'DONNELL & HUME (1990a) and GINGRAS & WEESE-MAYER (1990b) go even as far as suggesting that in utero cocaine exposure in rabbits may be a useful model for the study of SIDS, so convinced he is SIDS can be caused by intrauterine exposure to cocaine.

SKOLNICK (1990) reported in the JAMA about Chasnoffs presentation to the annual meeting of the American College of Obstetricians and Gynecologists, based on his study (Chasnoff, 1990) performed in Florida, where mothers known to have used drugs during pregnancy, must be reported to health authorities. Urines of all women enrolling for prenatal care in Pinellas county, were analysed for drugs. The main conclusion was a clear underreporting to health authorities and a strong bias towards reporting of black, and/or poor women. On the basis of these findings Chasnoff urged obstetricians always to take a drug history, as drug use is so wide spread. COLMORGEN et.al. (1990) even proposed screening of urine to become a routine part of all medical examinations given at the time of enrollment in prenatal care, as he found that 15.9 % of female patients screened used one or more substances.

WEBSTER & BROWN-WOODMAN (1990) investigating the teratogenicity of cocaine in rats, found a dose related effect: none at 40 mg/kg, the strongest at 70 mg/kg while 80 mg/kg turned out to be lethal for most dams. The malformations found following cocaine administration in mid-pregnancy, that period being after organogenesis, were found to be due to hemorrhage and edema in developing limbs, genital tubercle, tail and sometimes the upper lip and adjacent part of the nose. It is suspected that these are the result of cocaine induced vasoconstriction and hypoxia. They note the effects to be very significant, however not very frequent.

It has to be noted as well that the dosages used are extremely high when compared with the dosage level used by humans. The no effect dose, 40 mg/kg, is equivalent to a single dose of 3 grams in humans.

CHURCH, OVERBECK & ANDRZEJCZAK (1990a,b) reported a dose dependent effect on the litters of rats with regard to decrease of litter size, birth weight and post natal weight gain, increase of stillbirths and dose dependent behaviour disturbances in offspring, but all this again at the same extremely high dosages.

HOYME et al (1990) described ten children with congenital malformations ascribed to intrauterine cocaine exposure and proposed vascular disruption as the mechanism. This article is accompanied by an editorial comment from BRENT (1990) in "Teratology" about the relationship between uterine vascular clamping (a simple technique to produce congenital malformations), the vascular disruption syndrome and cocaine teratogenicity. He concluded that epidemiological, as well as embryological, studies have been both positive and negative and that many questions need to be answered. Cocaine, the author states, causes no specific diagnostic syndrome as by example the FAS caused by alcohol. On the other hand, cocaine exposure is associated with a very diverse range of vascular disruptive phenomena, that are serious, although rare.

WIGGINS & RUIZ (1990a) stating that the range of differences between control and test subjects (rats) is within the range of normal variation between litters and sets of dams, tried to 1) determine the amount of cocaine that pregnant rats can tolerate without outward signs of sickness or death; 2) having established such a sublethal dose, to determine the effects of cocaine exposure on the outcome of pregnancy and on the unborn and suckling offspring; and 3) to estimate how much of any cocaine effects can be attributed to any associated undernourishment, by using a very large population: over 175 dams, producing 1280 pups. The sublethal dose was established to be 60 mg/kg/day orally administered in one dose; this is about 4.5 grams for a human. The survival of the dams was normal at this dose, but at dosages of 80 or 90 mg/kg/day there was a high mortality rate.

Prematurity and litter size were not influenced, even at the highest dosages. Cocaine treatment however gave an increased mortality in the neonatal period due to poor maternal care, especially as the result of cannibalism. The authors concluded from pair-fed dams that the undernourishment of the dams is the greatest contributor to the growth retardation observed in cocaine exposed fetuses, as the differences between the litter of cocaine treated dams and dams that were artificially kept at the same weight by food restriction were small. In a second article (WIGGINS & RUIZ, 1990b) a significant hypomyelination is reported in the offspring which they consider to be a direct toxic effect of cocaine.

Then the Southern Medical Journal published a quite demagogic special article (GIACOIA, 1990) "Cocaine in the cradle: a hidden epidemic" in which all alleged effects of intrauterine cocaine exposure are taken for granted. The list of references (38) omits all articles that could doubt the alleged effects. Immediate action is considered necessary to stem the epidemic. The same demagogy is in the title of a case report (APPLE & ROE, 1990): "Cocaine associated fetal death in utero", describing a 16 year old female found dead by suffocation by homicide. Her blood contained cocaine. Upon autopsy she turned out to have been pregnant (approximately 16 weeks).....

A possible explanation for the often contradictory findings is given by ROE et al. (1990) who established that cholinesterases in the normal human at term placenta metabolise about 20 % of the cocaine that passes it into less active metabolites, thus protecting to some degree the fetus. It is however known that large individual differences exist with regard to cholinesterase activity and low activity is associated with increased toxicity. Adverse effects due to cocaine exposure might be associated more with low cholinesterase activity, than by cocaine exposure. It therefore may be of interest to determine the cholinesterase activity in mothers that give birth to babies that show anomalies ascribed to intrauterine cocaine exposure.

TABOR, SMITH-WALLACE & YONEKURA (1990) compared PCP exposed neonati with matched cocaine exposed neonati. The differences with regard to IUGR and precipitate labor were non significant. Cocaine babies tended to be born more prematurely, while PCP babies had more meconium stained amniotic fluid.

DOMBROWSKI et al (1991) draw attention to the fact that many cocaine using women in the USA believe that cocaine quickens the delivery and makes the experience more intense. They studied the records of 592 cocaine using women (urinalysis plus history) and compared these with 4687 women, not being identified as cocaine users. Duration of delivery was after correction for multiparity, birthweight, maternal age and gestational age not significantly related to cocaine use. A relation existed between use, decreased birth weight and prematurity. Abruptio placentae was significantly (P<.05) related with cocaine use, but its frequency was much lower than found by other authors.

DOWNING, HORNER & KILBRIDE (1991) suggest that perinatal cocaine exposure be considered a risk factor for neonatal necrotizing enterocolitis and so one can go on. With time more effects are being described or attributed to cocaine.

META-ANALYSIS

Although the studies reviewed here generally establish negative consequences of cocaine use by the mother on the pregnancy and the fetus, all observed effects are somewhere denied by other studies. This is not remarkable, these kind ofstudies have to meet several methodological complications to

be acceptable. Some of the methodological problems are:

• the unreliability of the data on drug use: urinalysis gives only information which regards to drug use within a few days, drug history is unreliable (HINGSON et al. 1986, COLMORGEN et al. 1992);
• the lack of comparability of study and control groups. Many factors that are related to illegal drug use may cause effects that seem to be attributable to the drug itself but are actually the result of the social situation. Comparison between cocaine users and non users is not likely to control for associated risk factors such as STDs, poor prenatal care etc.
• Comparison with other drug users who do not use cocainedoes not adress this problem either because it will introduce other problems: cocaine users might be expected to use significantly more alcohol and tobacco than other drug users (GRAHAM & KOREN, 1991).

To adress such problems the technique of meta-analysis was developed, which pools the data of different studies with similar design to arrive at an overall quantitative estimate of the effect studied. It does not change the limitations of the individual studies, but as random errors tend to cancel out, gives a clearer view of the trends. This technique was applied by LUTIGER c.s. (1992) on the existing literature on cocaine and pregnancy. Their literature search identified 45 articles on cocaine and pregnancy of which 20 met the inclusion criteria for this study:

• exposure to cocaine during pregnancy in humans,
• report of outcome,
• case control or cohort study
• control group present.

These studies were combined and comparisons were made 1) between cocaine alone and non drug users and 2) between cocaine plus polydrug users and non drug users and 3) between polydrug users with and without cocaine on their menu.

The first comparison showed no significant differences for small for gestational age (SGA), low birth weight, prematurity, premature rupture of membranes (PROM), abruptio placentae, meconium staining, SIDS, and cardiac malformations. The only statistically significant differences were for genitourinary malformations and intrauterine death.

The comparison between cocaine/polydrug and drug free controls gave the same tendencies; in addition there was a greater likelyhood of spontaneous abortion. In the third comparison only the genitourinary malformations showed up with significance.

The overal conclusion of Lutiger c.s. is that lower head circumference, gestational age, birth weight and length are a consistent feature present in babies exposed to drugs. "The likelyhood of spontaneous abortion and congenital genitourinary malformations is significantly increased for the drug exposed babies.", write the authors, "considering the clustering of other reproductive risk factors in the cocaine users when compared to non drug users, one should be extremely careful before attributing these adverse effects to cocaine only". Controlling for confounding factors results in the disappearance of most of the effects, leaving only the genitourinary malformations and SGA as consistent findings. All other adverse effects as abruptio placentae, SIDS, cardiac malformations fail to show up in the analysis. The authors suggest that this could be related to the fact that more positive studies (i.e. in which effects are found) than negative studies (where no effects are found) are published, as has already been established by KOREN (1989).

CONCLUSION

Since the first mention of possible negative influences of cocaine on pregnancy, an impressive stream of publications has "erupted". Many of them were just suggestive case histories, the type of publications that seem to draw at lot of attention and interest, but which are scientifically of very limited value. In other studies cocaine is not separated from other drugs or are control groups missing. The present paradigm being "cocaine -crack- is the devils drug" bias on all levels starts playing a more and more important role, as has been shown by Koren et al. When meta analysis reduces all the suggested adverse effects to just a few, however serious they may be at an individual level, and where these effects may not even be attributed to cocaine itself but to the lifstyle/social circumstances of the women studied, this should be a warning to us to be extremely careful when judging existing literature on other aspects of cocaine use.

Acknowledgements.

The author wishes to thank Prof.Dr.D.Lindhout, Dept. of Clinical Genetics, Erasmus University Rotterdam, for providing him with most of the literature reviewed, and Dr.A.Ball, WHO, Project on Substance Abuse, for critically reviewing the text.

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ZUCKERMAN,B., FRANK,D.A., HINGSON,R., AMARO,H., LEVENSON,S.M., KAYNE,H, PARKER,S., VINCI,R., ABOAGYE,K., FRIED,L.E., CABRAL,H., TIMPERI,R. & BAUCHNER,H. (1989) Effects of maternal marijuana and cocaine use on fetal growth. New England Journal of Medicine, 320(12) pp. 762-768

The main abnormalities associated with cocaine use during pregnancy are: IUGR, Abruptio, teratogenicity and SIDS.

INTRAUTERINE GROWTH RETARDATION.

All studies report retardation of growth. However the populations researched are composed in such a way that it is difficult, if not impossible, to decide whether this is the result of a direct effect of cocaine on the unborn, or the result of maternal malnutrition whether or not due to the anorexigenic action of cocaine.

ABRUPTIO PLACENTAE

The first mentioning a case in which there was a possible association between abruptio placentae and cocaine use was ACKER (1983). CHASNOFF (1985) reported from his highly non-random study population 4 cases of abruption after just one injection with cocaine. He considers this to be the result of cocaine's direct effect on the utero-placental bloodvessels. When he later (1989a) fails to observe a difference in frequency of abruptio between women that only used cocaine in the first trimester of pregnancy and those that used during the whole pregnancy, he changes opinion and deems cocaine to damage the bloodvessels at their laying out early in pregnancy.

However in seven studies involving large numbers of patients, four (CHOUTEAU,1988; NEERHOF,1989; LITTLE,1988 and LITTLE 1989) found no relationship, while two others (DATTEL, 1990, and MASTROGIANNIS, 1990) found a significant increase in incidence and one an increase with low significance (DOMBROWSKI, 1990: P<.05).

Where in other studies a relationship was found, is the study group non-random (CHASNOFF, 1989a and BINGOL, 1987).

TERATOGENICITY

The indications for teratogenicity of cocaine in humans are weak too at scrutiny. The study groups of CHASNOFF are so non-random that the value of his papers is no more than of case histories. This might be acceptable for physicians, but from a scientific point of view it has no importance.

SUDDEN INFANT DEATH SYNDROME.

Methodical question about this research (CHOUTEAU) is again that the only selection has been on urinalysis, so on recent cocaine use, and that no data are available about the use of other drugs in both the target and the controlgroup.

overige literatuur

*BAUCHNER,H., ZUCKERMAN,B. (1990) Cocaine, sudden infant death syndrome, and home monitoring. Journal of Pediatrics, 117(6) pp. 904-906

*BINGOL,N., FUCHS,M.,HOLIPAS,N., HENRIQUEZ,R., PAGAN,M. & DIAZ,V. (1986) Prune belly syndrome associated with maternal cocaine abuse. American Journal ofHuman Genetics, 39(3) pp. A51

BRENT;R.L. (1990) Relationship between uterine vascular clamping, vascular disruption syndrome and cocaine teratogenicity, Teratology, 41 pp. 757-760

*COLLINS,E., HARDWICK,R.J. & JEFFERY,H. (1989) Perinatal cocaine intoxication. Medical Journal of Australia, 150 pp. 331-334

*DAVIDSON WARD,S.L., BAUTISTA,D., CHAN,L., DERRY,M., LISBIN,A., DURFEE,M.J., MILLS,K.S.C. & KEENS,T.G. (1990) Sudden infant death syndrome in infants of substance-abusing mothers, Journal of Pediatrics, 117(6) pp. 876-881

*DURAND,D.J., ESPINOZA,A.M. & NICKERSON,B.G. (1990)

Association between prenatal cocaine exposure and sudden infant death syndrome, Journal of Pediatrics, 117(6) pp. 909-911

*FULROTH,R., PHILLIPS,B. & DURAND,D.J. (1989) Perinatal outcome of infants exposed to cocaine and/or heroin in utero. American Journal of Diseases of Children, 143 pp. 905-910

*KEITH,L.G., MacGREGOR,S., FRIEDELL,S., ROSNER,M., CHASNOFF,I.J. & SCIARRA,J.J. (1989) Substance abuse in pregnant women; recent experience at the Perinatal Center for Chemical Dependence of Northwestern Memorial Hospital. Obstetrics and Gynecology 73(5) pp. 715-720

*MILLER,B.M., ROSARIO,P.G., PRAKASH,K., PATEL,H.K. & GERST,P.H. (1990) Neonatal intestinal perforation: the "crack" connection.

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