The Effects of Intrauterine Cocaine Exposure on the Respiratory Status of the Very Low Birth Weight Infant

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Original Article &&&&&&&&&&&&&& The Effects of Intrauterine Cocaine Exposure on the Respiratory Status of the Very Low Birth Weight Infant

Ivan L. Hand, MD Lawrence Noble, MD CONCLUSION: Perinatal cocaine exposure appears to have some significant short-term Tammy J. McVeigh, MD effects on the need for surfactant replacement therapy and need for initial MaeHee Kim, MD intubation in respiratory distress syndrome (RDS) but no overall effect on Jing Ja Yoon, MD the development of BPD. Journal of Perinatology 2001; 21:372 – 375.

OBJECTIVES: This study examined the effects of intrauterine cocaine exposure on very low INTRODUCTION birth weight infants with respect to their surfactant requirement and need for ventilatory support. Use of cocaine has increased dramatically since the 1980s among various segments of the population. Specifically, its use has increased STUDY DESIGN: among pregnant women1 and is particularly prevalent among inner- A retrospective cohort study was conducted on infants with birth weight city women. Approximately 17% of inner-city women have taken between 750 and 1500 g admitted to the neonatal intensive care unit cocaine at least once during their pregnancy.2 Due to this increased between January 1992 and January 1995. cocaine use among pregnant women, numerous studies have been RESULTS: done to assess the effect of in utero cocaine exposure on pregnancy Of the 149 infants studied, 48 infants were exposed only to cocaine and 101 outcome, the developing fetus, and neonatal complications. infants had no drug exposure. There were no significant differences between Cocaine use during pregnancy has been associated with the two groups for gestational age, sex, abruptio placenta, prolonged rupture younger gestational age at delivery, lower birth weight, increased of membranes, and antenatal steroid usage. The cocaine-exposed group incidence of preterm labor and delivery, and small for gestational had a significantly greater birth weight (1190 vs. 1109, p<0.02), less age infants.3 These clinical outcomes are consistent with animal prenatal care (48% vs. 14%, p<0.00007), older maternal age (30 vs. 24, data that have demonstrated an increase in maternal blood p<0.00002), more black race (79% vs. 57%, p<0.01), and more rapid pressure and a decrease in uterine blood flow due to the plasma reagin (RPR) positivity (25% vs. 2%, p<0.00006). There were no vasoconstrictive properties of cocaine.4,5 By reducing uterine blood significant differences in median APGAR scores, or incidence of necrotizing flow, cocaine impairs the transfer of oxygen and nutrients to the enterocolitis, retinopathy of prematurity (ROP), intraventricular hemor- fetus. Also, cocaine use by women has been linked to an increased rhage (IVH), and bronchopulmonary dysplasia (BPD) between the two risk of spontaneous abortion and of stillbirth associated with groups. Cocaine-exposed infants received surfactant treatment less often abruptio placenta.6,7 (73% vs. 48%, p<0.0035), received fewer mean doses of surfactant (0.4 vs. Due to the vasoconstrictive properties of cocaine, it has been 10.0, p<0.0014), and were intubated less frequently (44% vs. 65%, hypothesized that cocaine-exposed newborns would have an p<0.012). There was no significant difference between groups for increased risk of intraventricular hemmorhage (IVH) and intubation at 24 and 48 hours and for the development of necrotizing enterocolitis (NEC). As for the incidence of IVH bronchopulmonary dysplasia. among cocaine-exposed very low birth weight (VLBW) infants, the data have been conflicting to date.7 Sehgal et al.8 found an increased incidence of NEC without an increased risk of IVH. Department of Pediatrics ( I. L. H., L. N. ), Division of Neonatology, Jacobi Medical Center, Albert Recent studies have also attempted to assess the effect of Einstein College of Medicine, Bronx, NY; and Department of Pediatrics ( T. J. M., M. K., J. J. Y. ), intrauterine cocaine exposure on the development of respiratory Division of Neonatology, Bronx Lebanon Hospital Center, Albert Einstein College of Medicine, Bronx, NY. distress syndrome (RDS) in VLBW infants. However, much controversy still exists in this area. Several studies found that Presented in part at the annual meeting of the Society for Pediatric Research, San Diego, CA, May 7 – 11, 1995. intrauterine cocaine exposure did not alter the incidence of RDS in these VLBW infants.9,10 In contradistinction, one retrospective Address correspondence and reprint requests to Ivan L. Hand, MD, Department of Pediatrics, Jacobi Medical Center, Room 803, 1400 Pelham Parkway, Bronx, NY 10461. case–control study and one prospective study did demonstrate a

Table 1 Perinatal Risk Factors Table 3 Respiratory Complications Cocaine, Nondrug, p Value Cocaine, Nondrug, p Value n=48 n=101 n=48 n=101

Mean birth weight±SD (g) 1190±180 1109±208 0.02 Surfactant requirement 73% 48% 0.0035 Mean gestational age (wk) 29±2.8 29±2.3 0.08 (0 doses) Sex (male) 54% 54% 0.90 Mean surfactant doses 0.4±.70 1.0±1.22 0.0014 Race (black) 79% 57% 0.01 Intubated initially 44% 65% 0.012 Maternal age 29.4±5.1 24.4±6.6 0.00002 Intubated at 24 hr 44% 57% 0.11 No prenatal care 48% 14% 0.00007 Intubated at 48 hr 38% 50% 0.13 Abruptio placenta 17% 6% 0.036 BPD 30% 37% 0.40 Maternal hypertension 8.3% 21% 0.06 Prolonged rupture of 19% 26% 0.35 membranes ( >24 hr) antenatal steroid use, APGAR scores at 1 and 5 minutes, usage of Positive RPR 25% 2% 0.00006 surfactant, intubation and NCPAP (within the first 6 hours and at 24 Antenatal steroids 4% 9% 0.33 and 48 hours after birth), and the development of IVH, NEC, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP, defined as stage 3 or plus disease), patent ductus arteriosus decreased incidence of RDS among premature infants exposed to (PDA), and RPR status. 11,12 cocaine. The medical records of 184 infants were identified of which 160 The aim of this study was to evaluate the effect of intrauterine were available for review and had complete historical and cocaine exposure on the VLBW (750 to 1500 g) infant with respect to toxicological data available. Eleven infants had mothers who used their meeting clinical criteria for surfactant treatment and for drugs other than cocaine or drugs in addition to cocaine and were ventilatory support. excluded from the analysis. The 149 infants who met the study criteria were divided into two groups (cocaine and non–cocaine METHODS group) based on maternal history and/or urine drug screens. Cocaine-exposed infants (n=48) consisted of those with positive A retrospective chart review of all infants with birth weight between urine toxicology for only cocaine or a positive history of only cocaine 750 and 1500 g, gestational age <34 weeks, who were appropriate use. The nonexposed infants (n=101) had a negative urine for gestational age and in-born at Bronx Lebanon Hospital Center toxicology and a negative history. between January 1992 and January 1995, was conducted. Bronx Quantitative urine drug testing was done using gas chromatog- Lebanon is a 725-bed general medical center with 3200 deliveries per raphy and confirmed by mass spectrophotometry. In addition to year and serves an economically disadvantaged population. Due to testing for cocaine and benzoylecgonine (the major urinary the high prevalence of drug use in this population, all infants metabolite of cocaine), opiates, methadone, barbiturates, phency- admitted to the neonatal intensive care unit received urine toxicology clidine, and marijuana were tested. All infants received standard testing. neonatal intensive care. RDS was diagnosed based on clinical signs Data were collected from the charts regarding maternal age and such as grunting, retractions, need for O2, positive airway pressure or race, sex of the infant, birth weight, gestational age, prenatal care mechanical ventilation, and radiologic evidence of RDS within the history, toxicology results, presence of abruptio placenta, hyper- first 6 hours of life. Treatment with exogenous surfactant (Survanta) tension, and prolonged rupture of membranes ( >24 hours), was given to those newborns with a diagnosis of RDS and 13 mechanically ventilated with a fraction of inspired O2>0.4.

Table 2 Neonatal Complications Cocaine, Nondrug, p Value Table 4 Multiple Logistic Regression Analysis of Risk Factors Affecting n=48 n=101 Surfactant Use Median APGAR 5 (1–9) 5 (1–9) 1.0 Dependent variable Independent variable p Value (1 min) (range) Median APGAR (5 min) 7 (4–10) 7 (2–10) 1.0 Surfactant use Drug 0.0188 IVH (Grade 0) 85% 81% 0.44 Gestational age 0.0001 IVH (Grades 3 and 4) 8.4% 9% 0.90 Race 0.3137 NEC 8% 2% 0.06 Hypertension 0.7974 ROP 25% 21% 0.62 Sex 0.0860 PDA 22% 26% 0.512 Prolonged rupture of membranes 0.0127

Journal of Perinatology 2001; 21:372 – 375 373 Hand et al. Effects of In Utero Cocaine Exposure on VLBW Infants

Pretreatment was administered if the infant continued to require a DISCUSSION fraction of inspired O2>0.4 after 6 hours. This study demonstrated a significantly decreased usage of surfactant Data were analyzed using -squared analysis, Student’s t-test, treatment in VLBW infants exposed prenatally to cocaine. The effect and multiple logistic regression analysis. A p value of <0.05 was of cocaine exposure on surfactant treatment remained significant considered significant. Database V for Windows was used for data even when maternal factors or conditions known to accelerate lung entry. EpiInfo Version 6 was used for -squared analysis and maturity such as prolonged rupture of membranes, maternal Student’s t-test and SPSS 8 was used for multiple logistic regression hypertension, and antenatal steroid use were also taken into analysis. The study had a power of 0.8 to detect a 50% reduction in account.14,15 the primary outcome variable of surfactant usage. Numerous possible mechanisms may explain the effects of cocaine on the apparent requirement for surfactant. Cocaine is a known potent vasoconstrictive agent and causes decreased uterine RESULTS blood flow in the pregnant ewe through increased resistance in the Of the 149 subjects included in our study, 48 were exposed to only uterine vascular bed.4 Similarly, another study on the effects of cocaine and 101 were non–cocaine-exposed. Infants in the cocaine cocaine found a dose-dependent increase in maternal blood pressure group had an older maternal age, greater percentage of blacks, and a decrease in uterine blood flow with accompanying fetal greater birth weight, less prenatal care, more abruptio placenta, and hypoxemia, hypertension, and tachycardia.5 Thus cocaine appears to more positive syphilis serology. The groups did not differ with respect affect the fetus in two fashions: by an indirect effect through to sex, gestational age, maternal hypertension, antenatal steroid use, decreased uterine blood flow with placental insufficiency, and a direct and prolonged rupture of membranes (Table 1). adrenergic effect on the fetus. We speculate that decreased uterine As for neonatal complications, the two groups did not differ with blood flow and subsequent hypoxemia is analogous to stress placed respect to APGAR scores at 1 and 5 minutes or the incidence of IVH, on the fetus during hypertensive disease of pregnancy. In 1980, Yoon NEC, ROP, and PDA (Table 2). et al.16 demonstrated a decreased incidence of RDS in infants born to With respect to respiratory complications, the cocaine-exposed hypertensive mothers due to accelerated fetal lung maturity. Gluck group had a significantly lower incidence of surfactant and Kulovich14 also found an association between maternal treatment (73% vs. 48%, p=0.0035) as well as a lower mean hypertension and accelerated fetal lung maturity as assessed by number of surfactant doses (0.4 vs. 1.0, p=0.0014) and amniotic fluid phospholipid analysis. incidence of initial intubation (44% vs. 65%, p=0.012). In addition to the vasoconstrictive properties of cocaine, the drug However, incidence of intubation at 24 and 48 hours and the is also known to block the reuptake of catecholamines at nerve incidence of BPD was not significantly different between the two terminals and therefore increase circulating levels of catechol- groups (Table 3). amines in pregnant women.5 We speculate that cocaine use near the Data were also analyzed by multiple logistic regression analysis to time of delivery may serve to increase surfactant secretion and determine the significance of multiple perinatal risk factors on resorption of lung fluid due to increased catecholamine levels.17,18,19 respiratory outcome. Of these risk factors, cocaine exposure This may explain the transient improvements noted in the ( p=0.0188), gestational age ( p=0.0001), and prolonged rupture respiratory status of cocaine-exposed newborns and their decreased of membranes ( p=0.0127) had significant independent effects on need for surfactant. surfactant use (Table 4). Although incidence of initial intubation Preliminary animal data have been conflicting so far with respect was lower in the cocaine-exposed group based on -squared to the effects of cocaine on fetal lung maturation. Sosenko in 199119 analysis, when multiple logistic regression analysis was performed demonstrated an increased surfactant maturation in fetal rats using the initial intubation as the dependent variable, only following cocaine administration to pregnant rats. The exact gestational age ( p=0.0000) and sex ( p=0.0023) had a significant mechanism by which cocaine may do this remains unclear. Another effect (Table 5). study using alveolar type II cells from adult female rabbits suggested that the direct effect of cocaine is to impair surfactant phospholipid Table 5 Multiple Logistic Regression Analysis of Risk Factors Affecting synthesis and subsequently reduce its secretion.20 Further work clearly Intubation needs to be done to elucidate the molecular effect of cocaine on surfactant production. Dependent variable Independent variable p Value Our study also demonstrated a significantly lower need for initial Intubation Drug 0.0555 intubation among the cocaine-exposed babies. This may also be Gestational age 0.0000 explained by the drug causing a stress on the fetus and by its Race 0.8432 increasing the resorption of lung fluid due to increased catechol- Hypertension 0.3688 amine levels as previously hypothesized. However, this effect was no Sex 0.0023 longer present at 24 and 48 hours of life nor did it impact the Prolonged rupture of membranes 0.2611 development of bronchopulmonary dysplasia. Although there was a

374 Journal of Perinatology 2001; 21:372 – 375 Effects of In Utero Cocaine Exposure on VLBW Infants Hand et al.

significant reduction in surfactant use between the two groups, dosage of cocaine and other substances on the developing fetus failure to find a difference in rates of intubation at 24 and 48 hours throughout pregnancy. as well as the incidence of BPD and other morbidities may be related to the relatively small sample size of this study and the lack of power to prove these effects. This may also be related to factors such as the References timing of drug use and the amount of the drug that was used 1. Chasnoff IJ, Burns WJ, Schnoll SH, et al. Cocaine use in pregnancy. N Engl J throughout the pregnancy. These factors could not be assessed Med 1985;313:666–9. 2. Zuckerman DA, Zuckerman BS, Amaro H, et al. Cocaine use during accurately. Whether the critical factor is chronic stress on the fetus pregnancy: prevalence and correlates. Pediatrics 1988;82:888–95. with maturation of the surfactant system or the more transient effect 3. MacGregor SN, Keith LG, Chasnoff IJ, et al. Cocaine use during pregnancy: of high catecholamine levels perinatally causing surfactant secretion adverse perinatal outcome. Am J Obstet Gynecol 1987;157:686–90. and lung fluid resorption remains unclear. Similarly, the greater the 4. Moore TR, Sorg J, Miller L, et al. Hemodynamic effects of intravenous cocaine amount of drug that is used near delivery will create an even greater on the pregnant ewe and fetus. Am J Obstet Gynecol 1986;155:883–8. stress on the fetus and may actually serve to mature the lungs more 5. Woods JR, Plessinger MA, Clark KE. Effect of cocaine on uterine blood flow quickly. and fetal oxygenation. JAMA 1987;257:957–61. When the data were analyzed by multiple regression analysis to 6. Acker D, Sachs BP, Tracey KJ, et al. Abruptio placenta associated with cocaine determine the effect of independent variables on the need for use. Am J Obstet Gynecol 1983;146:220. intubation, only gestational age and sex had a significant impact. 7. Dusick AM, Covert RF, Schreiber MD, et al. Risk of intracranial hemorrhage This indicates that many factors, in addition to drug use, determine and other adverse outcomes after cocaine exposure in a cohort of 323 very the respiratory status of a VLBW infant and confound the clinical low birthweight infants. J Pediatr 1993;122:438–45. 8. Sehgal S, Ewing C, Waring P, et al. Morbidity of low-birthweight infants with picture. Future studies that separate these various factors and that intrauterine cocaine exposure. J Natl Med Assoc 1993;85:20–4. examine concomitant alcohol and tobacco use, in addition to 9. Beeram MR, Abedin M, Young M, et al. Effect of intrauterine cocaine assessing the timing, duration, and quantity of cocaine used may exposure on respiratory distress syndrome in very low birthweight infants. J help understand the effect of cocaine on the respiratory status of Natl Med Assoc 1994;86:370–2. VLBW infants. 10. Hadeed AJ, Siegel SR. Maternal cocaine use during pregnancy: effect on the The infants in our cocaine-exposed group also had mothers newborn infant. Pediatrics 1989;84:205–10. with a significantly increased age, less prenatal care, more reactive 11. Zuckerman B, Mayanrd EC, Cabral H. A preliminary report of prenatal VDRL, more abruptio placenta, and were predominantly black. cocaine exposure and respiratory distress syndrome in premature infants. These features have all been previously observed in cocaine-exposed AJDC 1991;145:696–8. infants.2 One unusual characteristic about the cocaine-exposed 12. Maynard EC, Dreyer SA, Oh W. Prenatal cocaine exposure and hyaline babies in our study was that they had a significantly greater birth membrane disease. Pediatr Res 1989;25:223A. weight than the nonexposed babies. This is in contrast to previous 13. Liechty EA, Donovan E, Purohit D, et al. Reduction of neonatal mortality after multiple doses of bovine surfactant in low birth weight neonates with studies that have reported lower mean birth weights among cocaine respiratory distress syndrome. Pediatrics 1991;88:19–28. 8 babies. This outcome needs to be further clarified by future studies 14. Gluck L, Kulovich MV. Lecithin/sphingomyelin ratios in amniotic fluid in that focus on the timing and amount of drug used. Cocaine-using normal and abnormal pregnancy. Am J Obstet Gynecol 1973;115:539. mothers in our group could have used predominantly the drug 15. Yoon JJ, Harper RG. Observations on the relationship between duration of close to the time of delivery, which would not have a great impact rupture of the membranes and the development of respiratory distress on birth weight, whereas drug use throughout pregnancy would syndrome. Pediatrics 1973;52:161–8. most likely have a more significant effect. This behavior could be 16. Yoon JJ, Kohl S, Harper RG. The relationship between maternal hypertensive explained by the desire of some mothers to promote delivery disease of pregnancy and the incidence of idiopathic respiratory distress through cocaine use. syndrome. Pediatrics 1980;65:735–9. In summary, our study found a significantly decreased need for 17. Enhorning G, Chamberlain D, Contreras C, et al. Isoxsuprine-induced surfactant treatment and initial intubation in the cocaine-exposed release of pulmonary surfactant in the rabbit fetus. Am J Obstet Gynecol infants. There remains a need for further molecular studies on the 1977;129:197. 18. Walters DW, Olver RE. The role of catecholamines in lung liquid absorption developing surfactant system, as well as the developing lung and its at birth. Pediatr Res 1978;12:239. adaptation to extrauterine life. One of the limitations of our study is 19. Sosenko TRS. Cocaine administration to pregnant rats produces increased the lack of information on drug use early on in pregnancy, other surfactant maturation without affecting antioxidant enzyme development. than was obtained by history. The use of urine toxicology testing of Pediatr Res 1991;29:330A. our infants only can detect drug use for a period of days before 20. Guy J, Dhanireddy R. Effect of cocaine on surfactant synthesis and secretion delivery. Studies need to be done on the relative effects of timing and by alveolar type II cells. Pediatr Res 1991;29:60A.

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