Objective
To review systematically maternal antenatal cocaine exposure and adverse perinatal outcomes.
Study Design
Medline, Embase, CINAHL and secondary references in relevant studies were searched. English language studies of antenatal cocaine exposure and pregnancy outcomes published from 1966 to July 2009 were included. Metaanalyses were performed using the random effects model.
Results
Thirty-one studies were included. Cocaine use during pregnancy was associated with significantly higher odds of preterm birth (odds ratio [OR], 3.38; 95% confidence interval [CI], 2.72–4.21), low birthweight (OR, 3.66; 95% CI, 2.90–4.63), and small for gestational age infants (OR, 3.23; 95% CI, 2.43–4.30), as well as shorter gestational age at delivery (−1.47 week; 95% CI, −1.97 to −0.98 week) and reduced birthweight (−492 g; 95% CI, −562 to −421 g).
Conclusion
Prenatal cocaine exposure is significantly associated with preterm birth, low birthweight, and small for gestational age infants.
Birthweight (BW) and gestational age (GA) at birth are important determinants of perinatal, neonatal, childhood, and adult health. Factors thought to be associated with low birthweight (LBW) and preterm birth (PTB) include, but are not limited to maternal, paternal, fetal, societal, environmental, life style-related, infectious, nutritional, genetic, and psychosocial factors. An association between maternal antenatal use of cocaine and adverse pregnancy outcome has been suggested. The high prevalence of cocaine use during pregnancy has become a major health concern. Approximately 15-17% of regular users of cocaine are women of childbearing age. Cocaine is a central nervous system stimulant. Because of its sympathomimetic-driven vasoconstrictive effects, it can lead to hypertension in the mother and fetus, which may result in placental infarcts or hemorrhages at any time in gestation. Because of its high water content, lipid solubility, low molecular weight, and low ionization at physiologic pH, cocaine is believed to cross the placental barrier by simple diffusion. Exposure to cocaine has been reported to be associated with a shorter gestation, premature birth, abruptio placenta, and other adverse maternal and neonatal outcomes.
Reports of fetal cocaine effects have been controversial, as the interpretation of results is hampered by the fact that cocaine use is commonly accompanied by other confounding maternal lifestyle factors. Some of these confounding factors include cigarette smoking, other drug use (heroin, cannabis, methadone, alcohol, and others), lower socioeconomic status, and lack of adequate prenatal care, all of which may combine to contribute to poor pregnancy outcome. Therefore, we believe that a thorough and current review of the literature will help elucidate and quantify the effects of maternal antenatal cocaine use on perinatal outcomes thereby providing up-to-date information. Our objective was to review systematically the effect of cocaine consumption during pregnancy on various neonatal outcomes (LBW, PTB, and small-for-gestational age [SGA] neonates).
Materials and Methods
The Meta-analysis of Observational Studies in Epidemiology (MOOSE) criteria were followed for this systematic review. The methods of review by our group have been described previously. The medical literature published between 1966 through July 2009 was searched in Medline, Embase, CINAHL databases, and bibliographies of identified articles for papers reporting on gestational cocaine exposure and pregnancy outcome. A search strategy using a combination of “pregnancy,” “cocaine,” “preterm birth,” “premature,” “intrauterine growth restriction,” “low birthweight,” “small-for-gestational age,” “birthweight,” “gestational age,” “outcome,” “complications,” “intervention,” and “cessation” keywords (MeSH) was used. Retrieved articles were hand searched for additional references. Non-English papers, comments, letters, editorials, and reviews were excluded. However, references of excluded publications were searched.
English language studies reporting on cocaine exposure in pregnancy and outcomes of interest: LBW (defined as BW <2500 g), PTB (defined as birth before 37 completed weeks of gestation), SGA (defined as BW <10th percentile for GA), BW in grams, and GA in weeks were reviewed. The criteria for inclusion of articles were as follows: human exposure to any amount of cocaine during any or all the trimesters of pregnancy, as evidenced by drug history, maternal or neonate urine test or neonate meconium test, and report of pregnancy outcome of interest. Prospective and retrospective cohort studies, as well as case-control studies of cocaine exposure were included. Polydrug use is common in this population and was not an exclusion criterion. We excluded studies that reported duplicate populations, exposure that was ambiguous and those that did not report on the outcomes of interest. Studies fulfilling all inclusion criteria were included for detailed review. Two reviewers (K.G. and K.M.) independently assessed eligibility, risk of bias, and extracted information using predetermined standardized data collection forms. Risk of bias for observational studies was evaluated using criteria for selection bias, exposure assessment bias, confounder adjustment, analytic bias, outcome assessment bias, and attrition bias according to our previously reported criteria ( Appendix 1 ).
The third reviewer (P.S.) acted as an arbitrator. Metaanalyses were performed using the random effects model and unadjusted odds ratio (OR) or weighted mean difference and 95% confidence interval (CI). A priori planned sensitivity and subgroup analyses were planned for recent publications vs older publications, dividing studies into 2 equal divisions based on year of publication (before or after 1991), whether objective vs self-reported use of cocaine exposure was reported in the studies, whether study was prospective or retrospective, whether studies had minimal/low risk of overall bias compared with studies with moderate risk of biases and whether matched or unmatched controls were used for analyses. Clinical heterogeneity was assessed and reported in the table of included studies ( Table 1 ). Statistical heterogeneity was assessed using the I-squared (I 2 ) values.
| Author | Year of study | Type of study | Setting of study | Population | Exposure assessment (when, how) | Outcomes assessed | Confounders adjusted for | Results | Quality assessment (risk of bias) |
|---|---|---|---|---|---|---|---|---|---|
| Bingol et al | 1984-85 | Prospective cohort with unmatched controls (similar for MA, SES, tobacco, ethnicity) | 2 large inner-city hospitals in New York City (Harlem, Bronx) | Poor inner-city women at delivery | Neonate urine at birth | PTD, BW | Low | ||
| MacGregor et al | 1983-86 | Retrospective cohort with matched controls (MA, parity, SES, tobacco, med complications) | Single center, Chicago | Pregnant women receiving care at the Perinatal Center for Chemical Dependence of Northwestern University | NS ? Maternal self-report antenatally | LBW, PTD, SGA, BW, GA | Low | ||
| Cherukuri et al | 1986 | Retrospective cohort with matched controls (MA, parity, PNC, SES, race, ROH) | Single center Brooklyn NYC | Patient delivering at Kings County Hospital, on public assistance | Maternal self-report at delivery | LBW, PTD, SGA, BW, GA | Low | ||
| Chouteau et al | 1986 | Retrospective cohort with unmatched controls | Single center, large teaching hospital, NYC | Pregnant at L+D who did not receive ANC | Maternal urine toxicology at admission | BW, GA | Low | ||
| Fulroth et al | NS | Prospective cohort with unmatched controls | Single center, Oakland | All infants delivered at Highland General Hospital, Oakland | Maternal self-report or urine at admission and neonate urine | PTB | Moderate | ||
| Hadeed, Siegel | 1984-87 | Prospective cohort with matched controls (MA, parity, tobacco, SES, ethnicity) | Single center, Hollywood Presbyterian Center in Los Angeles, California | Pregnant women receiving government subsidized medical care | Maternal and infant urine immediately after birth | BW, GA | Low | ||
| Little et al | 1987 | Retrospective cohort with unmatched controls | Single center, Dallas, Texas | Mother of infant born at Parkland Memorial Hospital | Self-report (SW) and chart review | PTD, SGA, BW, GA | Low | ||
| Neerhof et al | 1986-88 | Prospective cohort with unmatched controls | Single center, Chicago | All patients admitted to L+D (screening policy) | Maternal urine at admission and neonate urine | PTD, SGA, BW, GA | Moderate | ||
| Zuckerman et al | 1984-87 | Prospective cohort with unmatched controls | Single center, Boston | Recruited at women’s and adolescent prenatal clinic (52% Medicaid, low income) | Interview and maternal urine antenatally and PP | BW, GA | Low | ||
| Gillogley et al | 1987-88 | Retrospective cohort with matched controls (race, discharge date) | Single center, Perinatal unit, University of California, Davis, Sacramento | Admission Ob service of UCDMC, urban, 93% Medicaid or no insurance, diverse ethnicity (routine testing) | Maternal urine at admission ± neonate urine | LBW, PTB, BW, GA | Multiple regression with smoking | −129g associated with tobacco use | Low |
| Calhoun, Watson | 1987-88 | Prospective cohort with matched controls (parity, SES, MA) | Single center, L+D, Portland | Indigent, low rate of ANC, no insurance, | Maternal and infant urine at admission | PTB, SGA, BW, GA | Moderate | ||
| Cohen et al | 1986-87 | Retrospective cohort with matched controls (MA, race, parity) | Single center, San Francisco General hospital | Toxic screen from L+D or nursery, 88% black | Maternal and/or neonatal urine at admission | LBW, PTB, BW, GA | Minimal | ||
| Kelley et al | NS | Retrospective cohort with controls matched (age of infant, race, sex, SES) | Single center, pediatric well-child clinic, large urban teaching hospital, Boston | Infant 1wk-26 mo, 80% black, 96% Medicaid | Maternal self-report at delivery or neonate urine | LBW, PTB, SGA, BW, GA | Moderate | ||
| McCalla et al | 1988-89 | Cross-sectional cohort with unmatched controls | Single center, municipal hospital, NYC | Inner-city | Maternal urine at admission ± neonate urine | LBW, GA | Regression analysis for: PNC, MA, parity, tobacco, ROH | For smoking, −125.0g ( P = .04) for BW and −0.37 wks ( P = .18) for GA | Low |
| Richardson, Day | 1983-86 | Prospective cohort with unmatched controls | Single center, Magee-Womens Hospital, interview each trimester | Young, single, low income women attending public prenatal clinic | Maternal self-report antenatally | BW, GA, LBW, SGA | Moderate | ||
| Spence et al | NS | Prospective cohort with unmatched controls | Single center, Hahnemann University Hospital, Philadelphia | Consecutive admission in L+D, routine screen | Maternal urine at delivery | PTB, BW | Low | ||
| Bateman, et al | 1985-86 | Prospective cohort with unmatched controls | Single center, Harlem Hospital, NYC | Inner-city | Maternal self-report or infant urine | LBW, PTB, BW, GA | GA, MA, gravidity, race, sex, PNC, syphilis, tobacco, ROH, marijuana, PCP, opiates | Regression coefficient −121g ( P < .005) | Low |
| Forman et al | 1990-91 | Prospective cohort with unmatched controls | 3 centers, Toronto | Mother-infant pairs in 3 nurseries, 69% white | Neonate urine and hairs | BW | Tobacco – LBW BW | LBW: 50% of smokers vs 8% of nonsmokers 2899 ± 750g (C+T) 3423 ± 612g (C only) 3414 ± 564 (No exp) | Low |
| Rosengren et al | 1990 | Prospective cohort with unmatched controls | 2 urban centers, Hartford, Connecticut | Consecutive newborns, urban and suburban population | Neonate meconium | LBW, PTB, BW | Moderate | ||
| Eyler et al | 1987-88 | Retrospective cohort with matched controls (race, MA, parity, GA at PNC, ROH, tobacco) | Single center, regional hospital (referral center), Florida | Women using rural county public health unit (min access rehab), Medicaid, low income | Maternal history or urine or neonate urine | LBW, PTB, GA, BW | Low | ||
| Kliegman et al | 1990-91 | Prospective cohort with unmatched controls | Single center, large urban university-based maternity hospital, Cleveland | Anonymous screen, unselected population | Maternal urine at delivery or postpartum | LBW, PTD | Race, MA, ROH, marijuana, tobacco, PNC, primiparous, history of PTB | Multivariate logistic models adjusted OR, 9.90 (0.53-1.84) | Low |
| Neuspiel et al | 1992 | Retrospective cohort with unmatched controls | Single center, public hospital, Bronx, NYC | NS | Maternal urine at admission and neonate cord blood | BW, GA | Cotinine, smoking history | −204g ( P = .15) | Moderate |
| Singer et al | NS | Retrospective cohort with matched controls (race, SES) | NS | AA, low SES, public assistance | Maternal urine and self-report antenatally | LBW, BW, GA | Low | ||
| Miller et al | 1990 | Retrospective cohort with matched controls (race, age, parity, month of delivery) | Single center, New Orleans | Large urban center, inner-city, indigent population | Maternal urine at delivery | BW, GA, PTB, SGA | Tobacco PNC | BW/Tobacco + :2759 ± 462 (45) for cocaine vs 2824 ± 876 (75) for controls BW/Tobacco –:3051 ± 602 (17) for cocaine vs 3078 ± 853 (167) for controls GA/Tobacco+: 38.4 ± 2.5 (45) for cocaine vs 37.6 ± 4.4 (75) for controls GA/Tobacco-: 39.0 ± 1.6 (16) for cocaine vs 38.4 ± 4.3 (164) for controls | Minimal |
| Shiono et al | 1984-89 | Prospective cohort with unmatched controls | Multicenter (7 centers) university-based prenatal clinics in US (Oklahoma, Louisiana, Texas, Tulane, Washington, Harlem) | Multiethnic, from Vaginal Infections and Prematurity study | Maternal serum or self-report antenatally or at delivery | LBW, PTB | Frequency use Blood concentration Tobacco ROH Marijuana | Logistic regression for smoking LBW OR, 1.1 (0.6-2.2) PTB OR, 1.5 (0.9-2.6) | Low |
| Kistin et al | 1988 | Retrospective cohort with unmatched controls | Multicenter (12 centers) Univ Illinois hospital perinatal network | Patient delivering in a hospital of the network | Self-report or maternal or neonate urine at delivery | LBW, PTB, SGA | Race Age Gravidity | Low | |
| Sprauve et al | 1992 | Retrospective cohort with unmatched controls | Single center, Atlanta | Inner-city, indigent, routine voluntary urine drug screening | Maternal urine at any time during pregnancy or within 1 wk of delivery | LBW, PTD, SGA | ROH, tobacco, weight, age, PNC, PTB | LBW: 1.59 (1.03-2.43) PTB: 0.88 (0.63-1.22) SGA: 1.7 (1.24-2.32) | Low |
| Richardson et al | 1988-93 | Prospective cohort with unmatched contols | Single center, PNC clinic Magee-Women’s hospital, Pittsburgh | Inner-city, low income | Maternal self-report antenatally and PP | PTB, LBW, SGA | PNC | Low | |
| Bandstra et al | 1990-93 | Retro and prospective cohort with unmatched controls | Single center, Miami prenatal cocaine study | AA, inner-city, low SES | Maternal self-report and urine, infant urine and meconium | LBW, BW, GA | Tobacco | BW −0.006 (−0.012-0.000) P = .038 GA 0.008 (0.002-0.014) P = .10 | Moderate |
| Ogunyemi, Hernandez-Loera | 1991-2000 | Retrospective cohort with matched controls | Single center, Los Angeles | All deliveries at this institution | Maternal toxicology screen PP | BW, GA, PTB, SGA | Tobacco | PTB coefficient regression 0.045(0.06) (−0.08 to −0.17) | Moderate |
| Bada et al | NS | Retrospective cohort with unmatched controls | Multicenter (4 centers) Providence, Miami, Memphis, Detroit | Database Maternal Lifestyle Study | Maternal self-report or neonate meconium | LBW, PTB, SGA | Tobacco | LBW 5.57 (3.06-7.91) PTB 3.66 (0.87-6.53) SGA 13.79 (10.08-17.33) | Low |
Results
Assessment of effects of cocaine exposure
Four hundred seventy-seven citations were identified. After review, 55 reports were retrieved for detailed evaluation. Thirty-one studies met inclusion criteria and were included in this systematic review ( Figure 1 ). Characteristics of included studies are described in Table 1 . The risk of bias and quality of the studies are reported in Appendix 2 .
- 1
LBW: cocaine use during pregnancy was significantly associated with LBW births as compared with women who did not use cocaine during pregnancy (19 studies, 38,796 participants, unadjusted pooled OR, 3.66; 95% CI, 2.90–4.63; I 2 = 72%) ( Figure 2 ).
