Cocaine Use during Pregnancy and Intrauterine Growth Retardation: New Insights Based on Maternal Hair Tests

Louise Kuhn1,2, Jennie Kline1,2,3, Stephen Ng2, Bruce Levin2 and Mervyn Susser1,2

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.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Prenatal cocaine use is more accurately measured by maternal hair assay than by urine toxicology screening or self-report. To investigate the consequences of improved measurement, the authors ascertained cocaine use during pregnancy by maternal hair test, urine test, and self-report in a sample of 691 patients recruited from one New York City hospital in 1990–1992. Associations with intrauterine growth retardation, head circumference, and length of gestation were investigated. A positive hair test at delivery was not more strongly associated with birth weight (-38.1 g; 95% CI: -164, 88.3) or head circumference (-1.73 mm; 95% CI: -5.91, 2.44) than a positive urine test at delivery (-182 g (95% CI: -295, -69.8) and -6.11 mm (95% CI: -9.99, -2.24), respectively). Cocaine concentration in hair (which was higher if urine tests were positive) had a dose-response relationship with birth weight: a 27-g decrease (95% CI: -51.9, -1.04) with each log-unit increase in concentration. Birth weights were similar among infants of never users and infants of users who stopped using cocaine before delivery. Heavier use of cocaine, but not lighter use, was associated with intrauterine growth retardation, and exposure in late pregnancy was necessary to the association. Although maternal hair tests were instrumental in clarifying these relations, their clinical use is probably not warranted.

birth weight; cocaine; epidemiologic methods; infant, premature; pregnancy; pregnancy outcome; substance-related disorders


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Effects of prenatal cocaine use on the developing fetus are still poorly defined. In part, this stems from the difficulty of measuring cocaine use during pregnancy. Methods commonly applied for detection of cocaine use, self-reporting and urine toxicology screening, have very low sensitivity and may miss 60–80 percent of true users (1GoGoGo–4Go). Self-reporting is inadequate because pregnant women greatly underreport their drug use (1Go, 3GoGoGo–6Go), and urine toxicology screening can detect only use within the 2–3 days before the test (7Go). In light of these measurement deficiencies, it is often thought that associations based on self-reporting or urine testing may underestimate the "true" effects of cocaine use during pregnancy (8Go).

More sensitive measures of cocaine use now include radioimmunoassays of maternal or infant hair samples and meconium (9Go). 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 (10Go). In our data, hair tests detect three times more users than urine toxicology or self-reports (1Go). 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).


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
A stratified random sample of 400 women who were registered at prenatal care clinics in one New York City hospital between August 1990 and January 1992 were recruited, as well as all 352 consenting unregistered patients who had live births at the hospital over this period. The study sample was selected as shown in figure 1. This sampling scheme was intentionally designed to overrepresent cocaine users.



View larger version (38K):
[in this window]
[in a new window]
 
FIGURE 1. Sampling strategy employed in a study of cocaine use and growth retardation and availability of data on exposure and outcome measures, New York City, 1990–1992. (*187 women had at least one prenatal hair sample; 125 had a prenatal sample and a delivery sample. {dagger}307 women had at least one prenatal urine sample; 195 had a prenatal sample and a delivery sample. {ddagger}For 72 registered patients who were not interviewed at delivery, data from the prenatal interview were used for the analysis. All women had either a delivery interview or a prenatal interview.)

 
Measurement of cocaine use
Cocaine use was ascertained by hair test, urine test, and structured interview. For registered patients, all three measures were utilized at the first prenatal care visit and at delivery; another urine sample was sought 1 month after the first prenatal care visit. For unregistered patients, all measures were collected at the time of delivery. The number of women who consented to provide samples for each of these tests is shown in figure 1. All laboratory tests were performed blind to self-reports and other tests.

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 (10Go). 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) (11Go). 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.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
The analyses drew on data from 348 registered patients and 343 unregistered patients. Fifty-nine percent were Black and 34 percent were Hispanic. The mean age was 25 years. Forty-eight percent of the patients had not completed high school; 89 percent were covered by Medicaid. Registered patients who consented to hair testing were less likely to be Black; women who underwent hair testing did not differ from women without hair testing with regard to any other characteristic (table 1).


View this table:
[in this window]
[in a new window]
 
TABLE 1. Comparability of registered and unregistered patients included in an analysis of cocaine use and pregnancy outcome, by availability of results of hair testing at delivery, New York City, 1990–1992

 
Consistency of measures of cocaine ascertainment at delivery
Hair tests identified more women as cocaine users than either urine tests or self-reports. Of 168 women with positive hair tests at delivery (and available results of urine testing at delivery), 69 (41 percent) had positive urine tests and 47 (28 percent) reported using cocaine during pregnancy. Conversely, of 72 women with positive urine tests at delivery and available results of hair testing at delivery, 69 (96 percent) had positive hair tests. All 50 women who reported using cocaine during pregnancy had positive hair tests (table 2).


View this table:
[in this window]
[in a new window]
 
TABLE 2. Consistency of measures of cocaine use at delivery (ascertained by hair test, urine test, and self-report*) and geometric mean cocaine concentration in each category, New York City, 1990–1992

 
The cocaine users with positive hair tests but negative urine tests and self-reports tended to have lower concentrations in hair. When both the urine test and the hair test at delivery were positive (n = 69), the geometric mean cocaine concentration in hair was 568 ng/10 mg (93 percent of subjects had concentrations above the median); if the urine test was negative but the hair test was positive (n = 99), the geometric mean concentration was 30 ng/10 mg (27 percent of levels were above the median). Concentrations in hair were also lower with negative self-reports than with positive self-reports (table 2). Cocaine concentrations did not differ by hair length (mean = 8 cm).

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).


View this table:
[in this window]
[in a new window]
 
TABLE 3. Pregnancy outcomes (birth weight, head circumference, and gestational age) according to maternal cocaine use, as measured by hair testing and urine toxicology screening in samples taken at delivery and by self-report, New York City, 1990–1992

 
Birth weight. A positive hair test at delivery, adjusted for gestation, registration status, infant sex, cigarette smoking, and alcohol consumption, was associated with a nonsignificant decrement in birth weight of 38 g (95 percent CI: -164, 88.3); a positive urine test at delivery was associated with a significant decrement of 182 g (95 percent CI: -295, -69.8), and a positive self-report of use during pregnancy was associated with a decrement of 135 g (95 percent CI: -262, -7.74) (table 3). The associations were almost unchanged (e.g., for a positive urine test, ß = -186 g; 95 percent CI: -320, -51.7) after adjustment for all variables screened for confounding.

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 (2–10 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.



View larger version (16K):
[in this window]
[in a new window]
 
FIGURE 2. Smoothed scatterplot of birth weights (g) by cocaine concentration (ng per 10 mg) in the mother's hair at delivery among 339 women, New York City, 1990–1992. The plot was generated using locally weighted regression (LOWESS).

 

View this table:
[in this window]
[in a new window]
 
TABLE 4. Relations between pregnancy outcomes (birth weight, head circumference, and gestational age) and cocaine concentrations in maternal hair samples collected at delivery,* New York City, 1990–1992

 
Head circumference decreased with increasing cocaine concentration in hair in univariate models and after adjustment for length of gestation and infant sex (ß = -1.02 mm/log concentration; 95 percent CI: -1.77, -0.27). With adjustment for registration status as well, the association was reduced (ß = -0.51 mm/log; 95 percent CI: -1.33, 0.30). Length of gestation was not consistently reduced with increasing cocaine concentration in a dose-related pattern.

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 90–500 ng/10 mg, and 13 percent among eight with concentrations of 2–89 ng/10 mg (p = 0.01, {chi}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).


View this table:
[in this window]
[in a new window]
 
TABLE 5. Mean birth weights and measured cocaine concentrations among births to registered patients with two urine tests or two hair tests (one given during pregnancy and one given at delivery), New York City, 1990–1992

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Improved detection of cocaine use during pregnancy with the more sensitive hair testing method did not strengthen measures of association between prenatal cocaine use and pregnancy outcomes. Rather, positive hair test results showed weaker associations than positive urine tests or self-reports. This finding reflected the fact that cocaine use was related to pregnancy outcomes in a dose-dependent manner, and the more sensitive hair test captured light users missed by the less sensitive tests.

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 (9Go). 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 (4Go, 12Go). 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 studies—namely, the inclusion of prenatal patients in Boston versus prenatal (registered) patients plus unregistered patients in New York—seems 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 (13Go, 14Go) 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.


    ACKNOWLEDGMENTS
 
This work was supported in part by a grant from the National Institute of Drug Abuse (R01 DA 05730).

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.


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Kline J, Ng SK, Schittini M, et al. Cocaine use during pregnancy: sensitive detection by hair assay. Am J Public Health 1997;87:352–8.[Abstract]
  2. Frank DA, Zuckerman BS, Amaro H, et al. Cocaine use during pregnancy: prevalence and correlates. Pediatrics 1988;82:888–95.[Abstract]
  3. Chiriboga CA, Vibbert M, Malouf R, et al. Neurological correlates of fetal cocaine exposure: transient hypertonia of infancy and early childhood. Pediatrics 1995;96:1070–7.[Abstract]
  4. Zuckerman B, Frank DA, Hingson R, et al. Effects of maternal marijuana and cocaine use on fetal growth. N Engl J Med 1989;320:762–8.[Abstract]
  5. Sackoff J, Kline J, Kinney A, et al. Cocaine use in obstetric patients underreported. (Letter). Am J Public Health 1992;82:1043.
  6. Grant T, Brown Z, Callahan C, et al. Cocaine exposure during pregnancy: improving assessment with radioimmunoassay of maternal hair. Obstet Gynecol 1994;83:524–31.[Abstract]
  7. Hamilton HE, Wallace JE, Shimek EL Jr, et al. Cocaine and benzoylecgonine excretion in humans. J Forensic Sci 1977;22:697–707.[ISI][Medline]
  8. Volpe JJ. Effect of cocaine use on the fetus. N Engl J Med 1992;327:399–407.[ISI][Medline]
  9. Mirochnick M, Frank DA, Cabral H, et al. Relation between meconium concentration of the cocaine metabolite benzoylecgonine and fetal growth. J Pediatr 1995;126:636–8.[ISI][Medline]
  10. Baumgartner WA, Hill VA, Blahd WH. Hair analysis for drugs of abuse. J Forensic Sci 1989;34:1433–53.[ISI]
  11. Cleveland WS. Robust locally weighted regression and smoothing scatterplots. J Am Stat Assoc 1979;74:829–36.[ISI]
  12. Shiono PH, Klebanoff MA, Nugent RP, et al. The impact of cocaine and marijuana use on low birth weight and preterm birth: a multicenter study. Am J Obstet Gynecol 1995;172:19–27.[ISI][Medline]
  13. Gibbs RS, Romero R, Hillier SL, et al. A review of premature birth and subclinical infection. Am J Obstet Gynecol 1992;166:1515–28.[ISI][Medline]
  14. Goldenberg RL, Iams JD, Mercer BM, et al. The Preterm Prediction Study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births. Am J Public Health 1998;88:233–8.[Abstract]
Received for publication April 26, 1999. Accepted for publication August 27, 1999.