1 Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY.
2 Joseph L. Mailman School of Public Health, Columbia University, New York, NY.
3 Epidemiology of Developmental Brain Disorders Department, New York State Psychiatric Institute, New York, NY.
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ABSTRACT |
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birth weight; cocaine; epidemiologic methods; infant, premature; pregnancy; pregnancy outcome; substance-related disorders
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INTRODUCTION |
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More sensitive measures of cocaine use now include radioimmunoassays of maternal or infant hair samples and meconium (9). Hair samples permit detection of cocaine use over the widest time interval. The period measured is limited only by the length of the hair, since cocaine metabolites are permanently deposited in the protein matrix of hair (10
). In our data, hair tests detect three times more users than urine toxicology or self-reports (1
). An additional advantage with hair assays is that cocaine concentration can be quantified, thus permitting descriptions of dose-response relationships.
This study investigated associations between prenatal cocaine use and intrauterine growth retardation, head circumference, and length of gestation when measurement of cocaine use was improved with the inclusion of maternal hair tests. We hypothesized a priori that stronger associations between prenatal cocaine use and pregnancy outcomes would be observed when cocaine use was measured by hair assay than when it was measured by less sensitive methods (urine test and self-report).
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MATERIALS AND METHODS |
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For the hair test, a lock of scalp hair approximately 0.5 mm thick was cut such that its maximum length did not exceed the duration of pregnancy at the time of cutting (assuming hair growth to be 1.3 cm/month). Specimens, wrapped in aluminum foil inside a zipped plastic bag, were frozen at -20°C. Hair samples were analyzed in batches by a private laboratory (Psychemedics Corporation, Culver City, California); all of them were subjected to an extended washing procedure (to remove exogenous contamination) before testing (10). Cocaine concentration was quantified in ng/10 mg; levels of 2 ng/10 mg and above were considered positive.
For the urine test, specimens were analyzed using an enzyme-mediated immunoassay technique by a private laboratory (Bendiner and Schlesinger, Inc., New York, New York). The presence or absence of cocaine, opiate, barbiturate, methadone, amphetamine, and marijuana metabolites was ascertained. The threshold of the assay for a positive cocaine result is 300 ng/ml. Maternal or infant urine toxicology tests performed by the hospital were used if study results were unavailable.
A structured interview was administered by trained study staff. Women were assured of confidentiality and were told that no information would be disclosed to health care providers or included in their medical records. The interview included detailed questions about use of cocaine and other drugs during and before pregnancy, as well as frequency, recency, and mode of use. A positive self-report was defined as any reported use of cocaine (smoked, sniffed, or injected) since the date of the last menstrual period. We also asked about drug use by the father of the infant, exposure to drug-use situations, sociodemographic characteristics, cigarette smoking, alcohol consumption, and pregnancy history.
Assessment of pregnancy outcome
Birth weight and head circumference were measured by clinical staff who were unaware of the results of tests for cocaine use. Length of gestation was calculated from the reported date of the last menstrual period, elicited by study interview. Twenty-five women had missing and/or implausible dates (negative values or gestations of >45 weeks) and were excluded from analyses that required gestational age. Analyses of head circumference excluded 42 infants for whom this information was missing and one outlier. Other pregnancy outcome information was abstracted from neonatal and obstetric charts.
Statistical analysis
Cocaine use was classified dichotomously using the three measures obtained at delivery. Ordinary least squares regression analysis was used to model pregnancy outcomes as a function of each measure of cocaine use separately, adjusting for infant sex, sociodemographic characteristics, and pregnancy risk indicators. We included gestation as a covariate in all models when birth weight was the outcome in order to estimate intrauterine growth retardation. Potential confounders investigated included maternal age, parity, race, marital status, education, Medicaid coverage, cigarette smoking, and alcohol use, use of marijuana, heroin, and methadone (reported and indicated by urine toxicology), results of syphilis screening, registration status, prepregnancy weight, trimester of first prenatal care visit, and reported number of prenatal care visits. We screened all potentially confounding variables individually and in combination to investigate whether the magnitudes of cocaine-use associations with outcomes were modified with the inclusion of each covariate. The final models included variables which modified cocaine associations or which had independent associations (at p < 0.05) with the outcome.
Smoothed scatterplots of birth weight, gestation, and head circumference by hair cocaine concentration at delivery were generated using locally weighted regression (LOWESS) (11). Dose-response relationships were estimated using the natural logarithm of concentration plus 1 ng/10 mg, in addition to concentration categorized into quartiles. In registered patients with hair and urine tests during pregnancy and at delivery, we compared mean birth weights and cocaine concentrations by consistency of test results.
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RESULTS |
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Birth weight, head circumference, and gestation according to the three measures of cocaine use
Contrary to our study hypothesis, a positive hair test was not more strongly associated with birth weight and head circumference adjusted for gestation or with gestation alone than was a positive urine test or self-reported use (table 3).
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Analyses carried out for registered and unregistered patients separately gave similar results. With a positive urine test, the estimated decrement in birth weight among registered patients was 223 g (95 percent CI: -510.3, 64.07), and among unregistered patients it was 171 g (95 percent CI: -294.04, -48.87). In the subset of registered patients with data on prepregnancy weight (n = 107), the estimated decrement in birth weight was 191 g (95 percent CI: -523.09, 141.40) after adjustment for gestation and the above covariates but not prepregnancy weight, and it was 173 g (95 percent CI: -506.30, 159.45) with adjustment for prepregnancy weight as well.
Similar results were obtained when analyses were limited to the 279 women with delivery hair tests. Among them, a positive urine test at delivery was associated with a significant decrement of 296 g (95 percent CI: -471, -122), and a positive self-report of use during pregnancy was associated with a decrement of 188 g (95 percent CI: -382, 7.08) after adjustment for gestation and the other covariates.
Head circumference. After adjustment for gestation, registration status, and infant sex, a positive hair test was associated with a nonsignificant decrement in head circumference of 1.73 mm (95 percent CI: -5.91, 2.44); a positive urine test was associated with a significant decrement of 6.11 mm (95 percent CI: -9.99, -2.24); and a positive self-report was associated with a significant decrement of 6.69 mm (95 percent CI: -11.0, -2.43).
Gestation. Unadjusted, length of gestation was associated with a positive hair test (ß = -1.48 weeks; 95 percent CI: -2.30, -0.66), a positive urine test (ß = -1.95 weeks; 95 percent CI: -2.73, -1.17), and a positive self-report (ß = -0.65 weeks; 95 percent CI: -1.09, -0.22). Of the covariates screened, only previous preterm birth and number of prenatal visits were related to length of gestation, accounting, together with cocaine use, for 16 percent of the variance in gestational age. Because previous preterm births might have been influenced by cocaine use and because number of prenatal care visits is constrained by early delivery, neither factor may be appropriate to include as a confounder. Adjustment for these variables decreased associations with cocaine measures by 50 percent or more.
Dose-response relationships
The LOWESS scatterplot of birth weight by cocaine concentration (figure 2) suggested no decline in birth weight at low cocaine concentrations but a marked gradient of decreasing birth weight with increasing cocaine dose at higher cocaine concentrations. A significant dose-response relationship was observed, with each log-unit increase in cocaine concentration being associated with an estimated 27-g decrement in birth weight (95 percent CI: -51.9, -1.04) after adjustment for gestation, registration status, infant sex, cigarette smoking, and alcohol consumption. Alternatively, when cocaine concentration was classified into quartiles, a gradient was also apparent. Mean birth weights were similar in women with negative hair tests and women with hair test results in the first quartile (210 ng/10 mg) and decreased thereafter (table 4). If a threshold in hair concentration was selected such that the geometric mean concentration in hair was the same as that in positive urine tests (>82 ng/10 mg), the estimated decrement in birth weight associated with a hair test result above that selected threshold (ßadj = -160.8; 95 percent CI: -315, -6.35) was similar to the association with positive urine tests. Each log-unit increase in cocaine concentration above 10 ng/10 mg was associated with an estimated 32-g decrement in birth weight (95 percent CI: -56.6, -7.72), after adjustment for the covariates listed above.
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Among 50 women who reported some cocaine use during pregnancy, the proportions who reported using cocaine at least once per week increased with increasing hair concentrations: 63 percent among 27 women with hair cocaine concentrations of >500 ng/10 mg, 47 percent among 15 women with concentrations of 90500 ng/10 mg, and 13 percent among eight with concentrations of 289 ng/10 mg (p = 0.01, 2 trend test).
Timing of cocaine use during pregnancy among registered patients
Among the 328 registered patients who underwent urine testing during pregnancy (mean length of gestation = 19 weeks), a positive urine test result during pregnancy was not associated with birth weight (ß = -26.5; 95 percent CI: -217, 164) after adjustment for gestation, infant sex, cigarette smoking, and alcohol consumption. Among the 202 registered patients who underwent urine testing at delivery, a positive urine test result was associated with decreased birth weight (ß = -223 g; 95 percent CI: -510, 64.1) after adjustment for the same covariates.
A total of 191 women had urine tests both prenatally and at delivery. When urine tests were positive prenatally but negative at delivery, mean birth weight was similar to that seen with two negative tests. Among 122 women with hair tests for both time points, mean birth weight with tests that were positive prenatally but negative at delivery was closer to mean birth weight following consistently negative results than to mean birth weight following positive results (table 5).
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DISCUSSION |
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Our initial hypothesis that improved ascertainment of cocaine use would yield stronger estimates of association followed from the well-known epidemiologic dictum that nondifferential misclassification tends to bias associations towards the null value. However, misclassification was not nondifferential, because hair cocaine concentration was related to both the urine test and self-report results as well as to pregnancy outcomes. While previous studies using urine toxicology (or other insensitive tests) may have underestimated the prevalence of cocaine use during pregnancy, they most likely correctly estimated associations with heavier use and overestimated associations with "any" cocaine use, i.e., when lighter and heavier users were combined.
The hair testing allowed us to quantify cocaine concentration, and it demonstrated a clear dose-response gradient of increasing intrauterine growth retardation with increasing cocaine exposure. This observation strengthens the argument for the importance of cocaine (in high doses) in restricted fetal growth. Cocaine quantified in meconium has also been found to be related to intrauterine growth retardation in a dose-dependent manner (9). Furthermore, our data point to a threshold below which cocaine use during pregnancy appears to have minimal or no harmful consequences for intrauterine growth.
Given the low sensitivity of urine tests, it may seem preferable to use the more sensitive hair test in clinical practice. However, our results suggest that little is gained from the use of hair tests to predict risk of intrauterine growth retardation. Those who are most at risk can be identified by a urine test; most of the additional users identified using the more expensive hair test have no substantial risk over true nonusers.
A limitation of hair testing (and of our study) is that women may be reluctant to consent to providing a hair sample. Although we cannot rule out selection bias, it did not appear to be relevant: Women who did not consent to hair testing were similar to consenting women, and associations with other cocaine measures were similar in these two groups.
Since few women reported prenatal cocaine use, we had only a limited capacity to define heavy and light cocaine use in behavioral terms, and we relied on the observed distribution of cocaine concentrations in hair to estimate dose. Most (70 percent) women with high cocaine concentrations (>90 ng/10 mg) had positive urine tests at delivery, indicating use within the last 2 days; this suggests that recent users are frequent users, an inference made previously (4, 12
). Hair cocaine concentration may also reflect host metabolism and the purity of the drug used.
Infants of women with positive prenatal cocaine tests but negative tests at delivery (suggesting that the women had stopped using cocaine in later pregnancy) had birth weights similar to those of infants of nonusers. These results, although they are based on small numbers, suggest that third trimester exposure is necessary for growth to be affected. Thus, cessation of drug use, even if it is only achieved during pregnancy, may reduce or eliminate the increased risk of growth retardation. In this light, access to drug treatment for pregnant women takes on added importance. Further study using segmental analysis of hair samples to establish more precisely the timing and dose of cocaine use over the duration of pregnancy would be helpful in confirming this inference.
We estimate that if urine tests are positive at delivery, indicating recent and probably frequent use during pregnancy, birth weight is decreased by 182 g (95 percent CI: -295, -69.8). This estimate is comparable to that obtained in a similarly designed large Boston, Massachusetts study, which estimated an adjusted 93-g decrement in birth weight associated with urine test positivity. The somewhat lower estimate in the Boston sample may reflect differences in the timing of urine tests used to define use. In Boston, women were classified as urine test-positive if they had a positive test either during pregnancy or at delivery; in our study, women were classified as urine test-positive based on their test at delivery only. Another difference between the studiesnamely, the inclusion of prenatal patients in Boston versus prenatal (registered) patients plus unregistered patients in New Yorkseems an unlikely explanation, since, in our study, associations with intrauterine growth were similar among registered patients and unregistered patients.
We consider our findings for growth and head circumference to be more secure than those for gestation. Associations with intrauterine growth retardation and head circumference persisted after adjustment for maternal characteristics and exposures associated with growth in other samples. In contrast, associations with gestation may be confounded by unmeasured risk factors, such as genital tract infections, including Mycoplasma or bacterial vaginosis, which may influence preterm delivery (13, 14
) and which may occur at increased frequencies in drug-using women. Poor measurement of gestation, particularly among women interviewed late in pregnancy or at delivery, may limit interpretation.
In this study, use of maternal hair testing offered new insights into the effects of prenatal cocaine use. Higher concentrations of cocaine were associated with increased risk of intrauterine growth retardation and reduced head circumference; concentrations below a threshold level had little or no detectable consequences for fetal growth. Exposure late in pregnancy appeared to be necessary for fetal growth retardation. Paradoxically, although the maternal hair test was instrumental in clarifying these relations, use of hair testing in clinical practice is probably not warranted.
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ACKNOWLEDGMENTS |
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The authors thank Drs. L. Cooper, A. Grunebaum, R. Neuwirth, R. Kairam, and F. Shahrivar and their staffs for facilitating this research at their hospital. They thank Drs. M. Schittini and P. Murphy, J. Silverstein, and G. Rodriquez for assistance in the development and implementation of the field work.
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REFERENCES |
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