Neurotoxicologyand Teratology, Vol. 13, pp. 455--460. ©Pergamon Press plc, 1991. Printed in the U.S.A.
0892-0362/91 $3.00 + .00
Maternal and Neonatal Effects of Moderate Cocaine Use During Pregnancy I G A L E A. R I C H A R D S O N 2 A N D N A N C Y L. D A Y
Western Psychiatric Institute and Clinic, University o f Pittsburgh, Pittsburgh, PA 15213 R e c e i v e d 20 A u g u s t 1990 RICHARDSON, G. A. AND N. L. DAY. Maternal and neonatal effects of moderate cocaine use during pregnancy. NEUROTOXICOL TERATOL 13(4) 455-460, 1991.--Thirty-four women who reported using cocaine during pregnancy were compared to 600 women who reported no cocaine use during pregnancy and none for the year prior to pregnancy. Subjects were participants in a prospective, longitudinal study of prenatal substance use. The sample consisted of young, predominantly single, low-income women attending a public prenatal clinic. Women were interviewed at the end of their first, second and third trimesters regarding cocaine, alcohol, marijuana, tobacco and other drug use. The majority of the cocaine users were light to moderate users who decreased their use during pregnancy. The cocaine group was more likely to be white and to use alcohol, marijuana, tobacco and other illicit drugs more heavily than the comparison group. The cocaine users had more previous fetal losses but did not differ on other obstetrical complications. Infant growth, morphology and behavior were not affected. Prenatal cocaine use Obstetric complications Neonatal Behavioral Assessment Scale
Infant outcome
Growth and morphological characteristics
Of additional concern is the fact that cocaine use might cause intermittent fetal hypoxia. Cocaine can cause hypoxia through vasoconstriction, but the consequences for the fetus are not well understood. Potential negative effects might include damage to the central nervous system in the form of neonatal neurobehavioral effects. Chasnoff et al. (9) reported that infants exposed to cocaine or cocaine and methadone exhibited increased irritability, tremulousness and state lability during a Brazelton Neonatal Behavioral Assessment Scale (BNBAS) examination at three days of age compared to infants of women who used only methadone. Infants exposed to cocaine were also found to differ from a drug-free group on orientation, motor processes, state regulation and number of abnormal reflexes (11). Other indications of possible central nervous system dysfunction have been found on measures of neonatal EEG (19), fetal and infant state behavior (26) and reactivity to tactile stimulation (2). The potential teratogenicity of cocaine has also been assessed by comparing the morphological characteristics of the offspring of women who do and do not use cocaine. Cocaine use is reported to be associated with decreased birth weight, length and head circumference by some (5, 8, 36, 45), while others have found no relationship between cocaine use and neonatal growth (9,33). The results are similarly conflicting when the outcome is physical malformations (5, 10, 12, 18, 25, 33). The inconsistencies regarding the effects of prenatal cocaine use may result from a number of methodological problems. The lack of control or comparison groups precludes evaluation of the magnitude of the effect of drug exposure (19, 25, 26), Differences in the demographic composition of the various drug groups
COCAINE use is reported to be increasing in women of all socioeconomic levels in the United States (22,23). Cocaine use by women is most widespread during the childbearing years (14), yet there have been few prospective studies of the effects of cocaine use on the outcome of pregnancy. Recent research has shown that the potential exists for prenatal cocaine use to adversely affect pregnancy outcome. Single doses of cocaine increased maternal and fetal blood pressure and decreased uterine blood flow in pregnant ewes and resulted in fetal hypoxia and tachycardia (34,44). In addition, pregnant ewes showed greater cardiovascular responsivity to cocaine than nonpregnant ewes (43). Cocaine use in humans is associated with vasoconstriction, tachycardia and increased blood pressure (20), factors which have the potential to increase the risk of pregnancy complications such as spontaneous abortion, preterm labor, precipitous labor, and abruptio placentae (6). Reports with human samples are beginning to substantiate these obstetrical risks. Acker et al. (1) presented case studies of two women who experienced abruptio placentae shortly after using cocaine. Chasnoff (8,9) compared women using cocaine and other drugs to those on methadonemaintenance and to drug-free women. In both of Chasnoff's studies, cocaine users had an increased incidence of premature labor, precipitous labor and abruptio placentae. Bingol et al. (5) reported that women who abused only cocaine had a higher rate of stillbirths (all related to abruptio placentae) than drug-free women. In contrast, MacGregor et al. (32) and Neerhof et al, (35) found no significant differences in the rate of abrnptio placentae between polydrug cocaine-users and a comparison group.
lAn earlier version of this paper was presented at the Society for Research in Child Development, Baltimore, MD, April 1987. ZRequests for reprints should be addressed to Gale A. Richardson, Ph.D., Western Psychiatric Institute and Clinic, Program in Epidemiology, 3811 O'Hara Street, Pittsburgh, PA 15213.
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might contribute to differential outcomes. For example, Oro and Dixon (36) reported racial differences between cocaine users and amphetamine users but combined them into one group for analysis. Differences between groups in nutritional status and the amount of prenatal care also need to be evaluated. Identification of exposed and nonexposed groups on the basis of medical records, health registries or urinalysis yields no information regarding quantity, frequency or pattern of substance use (2, 18, 24, 27, 30). In addition, cocaine users are generally polydrug users. Analyses must control for other substance use such as alcohol, marijuana and tobacco when evaluating the effects of cocaine. There is also the problem of recall bias in those studies that rely on retrospective reporting at delivery, or even later in the postpartum period, of cocaine and other substance use over the entire pregnancy (5, 12, 13, 37). In conclusion, other studies have suggested effects of prenatal cocaine use but are inconclusive due to methodological problems. The current study attempts to overcome these shortcomings in the following ways: 1) the sample consists of women from a public prenatal clinic population who are not in drug treatment and have not been referred for drug abuse; 2) recall bias is minimized by interviewing the women regarding their substance use at the end of each trimester. Furthermore, all women are interviewed at the same time points; 3) the quantity and frequency of cocaine, alcohol, marijuana, tobacco and other drug use are assessed. Data are also collected on demographic factors, medical history and life-style of the mothers, thus allowing control of potential confounding variables. METHOD
Study Design The study sample consists of women and infants participating in a longitudinal investigation of the effects of prenatal alcohol and marijuana use. Written consent was obtained for both mothers and infants according to guidelines established by the University's Institutional Review Board for Biomedical Research and the Research Review and Human Experimentation Committee of Magee-Womens Hospital. Data collection began in May 1983; delivery interviews were completed by February 1986. Women who were at least 18 years of age were initially interviewed during their fourth prenatal month. Cocaine, alcohol, marijuana, tobacco and other drug use were assessed for the year prior to pregnancy and for the first trimester. A more detailed description of the methods used for measuring substance use, along with the development and reliability of the measures, has been presented elsewhere (17,39). Women were interviewed again at seven months about their substance use during the second trimester and again at 24 hours postdelivery, when they were asked about third trimester substance use. Demographic, life-style and psychological characteristics were also assessed at each phase. Information regarding maternal medical history, pregnancy, labor and delivery conditions was abstracted from the medical charts by study nurses. All newborns underwent comprehensive physical examination, generally within 24 to 48 hours of delivery, by study nurse clinicians who were blind to prenatal exposure status. The infants' length, head and chest circumference were measured. Birth weight and Apgar scores were transcribed from the medical records. Gestational age, as measured by a modification of the Dubowitz assessment (3), was also assessed by the study nurses. Morphological abnormalities were recorded during the physical examination and later classified as major or minor physical anomalies (41). The Brenner et al. (7) standards were
used to define small-for-gestational age. A subsample of fullterm infants was assessed with the Brazelton NBAS, generally on the second postpartum day (38).
Subjects Thirty-four women who reported using cocaine during pregnancy were compared to 600 women who reported no cocaine use during pregnancy and none for the year prior to pregnancy. At the time these data were collected, cocaine was being snorted in its powder form. The majority (58.8%; N =20) of the cocaine group reported use only during the first trimester; 11.8% (N =4) and 2.9% ( N = 1) reported use only during the second or third trimester, respectively; 14.7% ( N = 5 ) reported use through the first and second trimesters; 2.9% ( N = 1) used cocaine first and third trimesters; and 8.8% ( N = 3 ) reported use during all three trimesters. The quantity of cocaine use was reported in grams or lines. An equivalence of one line = 1/30 gram was used to convert all quantities to grams. Frequency of use was reported in days, weeks or months. Overall, women in the cocaine group were light users with most of the use occurring in the first trimester. They reported using an average of 2 to 3 grams per month during the first trimester (range= 1/30 gram used once to 1 gram used daily), During the second and third trimesters, the average use was 0.4 and 0.2 grams per month, respectively. Seven women who used cocaine more than once per week were compared to the rest of the cocaine group who used once per month or less often. The two groups did not differ on any of the maternal demographic, obstetrical or substance use variables or the infant outcome variables. All results, therefore, are reported for the combined group.
Statistical Analysis The alcohol and marijuana variables were expressed as average number of drinks or joints per day and tobacco as packs per day. Chi-square analyses and t-tests were used to test the differences between the cocaine and comparison groups for categorical and continuous variables, respectively. In evaluating infant outcome, analysis of covariance was used to test the difference between groups while controlling for confounding variables. RESULTS
Women in the cocaine and comparison groups were 22 to 23 years old on average, predominantly single, reported an income of $300 to $399 per month and had approximately 12 years of education (Table 1). Women in the cocaine group were significantly more likely to be white (p
0892-0362/91 $3.00 + .00
Maternal and Neonatal Effects of Moderate Cocaine Use During Pregnancy I G A L E A. R I C H A R D S O N 2 A N D N A N C Y L. D A Y
Western Psychiatric Institute and Clinic, University o f Pittsburgh, Pittsburgh, PA 15213 R e c e i v e d 20 A u g u s t 1990 RICHARDSON, G. A. AND N. L. DAY. Maternal and neonatal effects of moderate cocaine use during pregnancy. NEUROTOXICOL TERATOL 13(4) 455-460, 1991.--Thirty-four women who reported using cocaine during pregnancy were compared to 600 women who reported no cocaine use during pregnancy and none for the year prior to pregnancy. Subjects were participants in a prospective, longitudinal study of prenatal substance use. The sample consisted of young, predominantly single, low-income women attending a public prenatal clinic. Women were interviewed at the end of their first, second and third trimesters regarding cocaine, alcohol, marijuana, tobacco and other drug use. The majority of the cocaine users were light to moderate users who decreased their use during pregnancy. The cocaine group was more likely to be white and to use alcohol, marijuana, tobacco and other illicit drugs more heavily than the comparison group. The cocaine users had more previous fetal losses but did not differ on other obstetrical complications. Infant growth, morphology and behavior were not affected. Prenatal cocaine use Obstetric complications Neonatal Behavioral Assessment Scale
Infant outcome
Growth and morphological characteristics
Of additional concern is the fact that cocaine use might cause intermittent fetal hypoxia. Cocaine can cause hypoxia through vasoconstriction, but the consequences for the fetus are not well understood. Potential negative effects might include damage to the central nervous system in the form of neonatal neurobehavioral effects. Chasnoff et al. (9) reported that infants exposed to cocaine or cocaine and methadone exhibited increased irritability, tremulousness and state lability during a Brazelton Neonatal Behavioral Assessment Scale (BNBAS) examination at three days of age compared to infants of women who used only methadone. Infants exposed to cocaine were also found to differ from a drug-free group on orientation, motor processes, state regulation and number of abnormal reflexes (11). Other indications of possible central nervous system dysfunction have been found on measures of neonatal EEG (19), fetal and infant state behavior (26) and reactivity to tactile stimulation (2). The potential teratogenicity of cocaine has also been assessed by comparing the morphological characteristics of the offspring of women who do and do not use cocaine. Cocaine use is reported to be associated with decreased birth weight, length and head circumference by some (5, 8, 36, 45), while others have found no relationship between cocaine use and neonatal growth (9,33). The results are similarly conflicting when the outcome is physical malformations (5, 10, 12, 18, 25, 33). The inconsistencies regarding the effects of prenatal cocaine use may result from a number of methodological problems. The lack of control or comparison groups precludes evaluation of the magnitude of the effect of drug exposure (19, 25, 26), Differences in the demographic composition of the various drug groups
COCAINE use is reported to be increasing in women of all socioeconomic levels in the United States (22,23). Cocaine use by women is most widespread during the childbearing years (14), yet there have been few prospective studies of the effects of cocaine use on the outcome of pregnancy. Recent research has shown that the potential exists for prenatal cocaine use to adversely affect pregnancy outcome. Single doses of cocaine increased maternal and fetal blood pressure and decreased uterine blood flow in pregnant ewes and resulted in fetal hypoxia and tachycardia (34,44). In addition, pregnant ewes showed greater cardiovascular responsivity to cocaine than nonpregnant ewes (43). Cocaine use in humans is associated with vasoconstriction, tachycardia and increased blood pressure (20), factors which have the potential to increase the risk of pregnancy complications such as spontaneous abortion, preterm labor, precipitous labor, and abruptio placentae (6). Reports with human samples are beginning to substantiate these obstetrical risks. Acker et al. (1) presented case studies of two women who experienced abruptio placentae shortly after using cocaine. Chasnoff (8,9) compared women using cocaine and other drugs to those on methadonemaintenance and to drug-free women. In both of Chasnoff's studies, cocaine users had an increased incidence of premature labor, precipitous labor and abruptio placentae. Bingol et al. (5) reported that women who abused only cocaine had a higher rate of stillbirths (all related to abruptio placentae) than drug-free women. In contrast, MacGregor et al. (32) and Neerhof et al, (35) found no significant differences in the rate of abrnptio placentae between polydrug cocaine-users and a comparison group.
lAn earlier version of this paper was presented at the Society for Research in Child Development, Baltimore, MD, April 1987. ZRequests for reprints should be addressed to Gale A. Richardson, Ph.D., Western Psychiatric Institute and Clinic, Program in Epidemiology, 3811 O'Hara Street, Pittsburgh, PA 15213.
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might contribute to differential outcomes. For example, Oro and Dixon (36) reported racial differences between cocaine users and amphetamine users but combined them into one group for analysis. Differences between groups in nutritional status and the amount of prenatal care also need to be evaluated. Identification of exposed and nonexposed groups on the basis of medical records, health registries or urinalysis yields no information regarding quantity, frequency or pattern of substance use (2, 18, 24, 27, 30). In addition, cocaine users are generally polydrug users. Analyses must control for other substance use such as alcohol, marijuana and tobacco when evaluating the effects of cocaine. There is also the problem of recall bias in those studies that rely on retrospective reporting at delivery, or even later in the postpartum period, of cocaine and other substance use over the entire pregnancy (5, 12, 13, 37). In conclusion, other studies have suggested effects of prenatal cocaine use but are inconclusive due to methodological problems. The current study attempts to overcome these shortcomings in the following ways: 1) the sample consists of women from a public prenatal clinic population who are not in drug treatment and have not been referred for drug abuse; 2) recall bias is minimized by interviewing the women regarding their substance use at the end of each trimester. Furthermore, all women are interviewed at the same time points; 3) the quantity and frequency of cocaine, alcohol, marijuana, tobacco and other drug use are assessed. Data are also collected on demographic factors, medical history and life-style of the mothers, thus allowing control of potential confounding variables. METHOD
Study Design The study sample consists of women and infants participating in a longitudinal investigation of the effects of prenatal alcohol and marijuana use. Written consent was obtained for both mothers and infants according to guidelines established by the University's Institutional Review Board for Biomedical Research and the Research Review and Human Experimentation Committee of Magee-Womens Hospital. Data collection began in May 1983; delivery interviews were completed by February 1986. Women who were at least 18 years of age were initially interviewed during their fourth prenatal month. Cocaine, alcohol, marijuana, tobacco and other drug use were assessed for the year prior to pregnancy and for the first trimester. A more detailed description of the methods used for measuring substance use, along with the development and reliability of the measures, has been presented elsewhere (17,39). Women were interviewed again at seven months about their substance use during the second trimester and again at 24 hours postdelivery, when they were asked about third trimester substance use. Demographic, life-style and psychological characteristics were also assessed at each phase. Information regarding maternal medical history, pregnancy, labor and delivery conditions was abstracted from the medical charts by study nurses. All newborns underwent comprehensive physical examination, generally within 24 to 48 hours of delivery, by study nurse clinicians who were blind to prenatal exposure status. The infants' length, head and chest circumference were measured. Birth weight and Apgar scores were transcribed from the medical records. Gestational age, as measured by a modification of the Dubowitz assessment (3), was also assessed by the study nurses. Morphological abnormalities were recorded during the physical examination and later classified as major or minor physical anomalies (41). The Brenner et al. (7) standards were
used to define small-for-gestational age. A subsample of fullterm infants was assessed with the Brazelton NBAS, generally on the second postpartum day (38).
Subjects Thirty-four women who reported using cocaine during pregnancy were compared to 600 women who reported no cocaine use during pregnancy and none for the year prior to pregnancy. At the time these data were collected, cocaine was being snorted in its powder form. The majority (58.8%; N =20) of the cocaine group reported use only during the first trimester; 11.8% (N =4) and 2.9% ( N = 1) reported use only during the second or third trimester, respectively; 14.7% ( N = 5 ) reported use through the first and second trimesters; 2.9% ( N = 1) used cocaine first and third trimesters; and 8.8% ( N = 3 ) reported use during all three trimesters. The quantity of cocaine use was reported in grams or lines. An equivalence of one line = 1/30 gram was used to convert all quantities to grams. Frequency of use was reported in days, weeks or months. Overall, women in the cocaine group were light users with most of the use occurring in the first trimester. They reported using an average of 2 to 3 grams per month during the first trimester (range= 1/30 gram used once to 1 gram used daily), During the second and third trimesters, the average use was 0.4 and 0.2 grams per month, respectively. Seven women who used cocaine more than once per week were compared to the rest of the cocaine group who used once per month or less often. The two groups did not differ on any of the maternal demographic, obstetrical or substance use variables or the infant outcome variables. All results, therefore, are reported for the combined group.
Statistical Analysis The alcohol and marijuana variables were expressed as average number of drinks or joints per day and tobacco as packs per day. Chi-square analyses and t-tests were used to test the differences between the cocaine and comparison groups for categorical and continuous variables, respectively. In evaluating infant outcome, analysis of covariance was used to test the difference between groups while controlling for confounding variables. RESULTS
Women in the cocaine and comparison groups were 22 to 23 years old on average, predominantly single, reported an income of $300 to $399 per month and had approximately 12 years of education (Table 1). Women in the cocaine group were significantly more likely to be white (p
