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Prenatal Cocaine Exposure and the Development of the Human Eye
Prenatal Cocaine Exposure and the Development of the Human Eye John R. Stafford, Jr., MD,! Tove S. Rosen, MD,1 Marco Zaider, PhD,2 John C. Merriam, MD3 Purpose: The use of cocaine during pregnancy has been associated with congenital abnormalities of the developing eye. The authors report a prospective, controlled study of 40 cocaine-exposed and 40 nonexposed (control) preterm and full-term infants. Methods: Detailed maternal and obstetric histories were obtained by chart review and interview. Infants with a positive urine toxicology screen for cocaine at birth or whose mothers tested positive for cocaine were recruited into the exposed group. Nonexposed infants were recruited at random from newborns admitted to the authors' nurseries. Mothers of these infants received routine prenatal care in the authors' clinics, and nonexposure was documented by maternal history and/or negative urine toxicologies that were available in 30% of these mother-infant pairs. General physical and ocular examinations, including measurement of axial length and intraocular pressure, were performed on all infants. Results: Forty infants were recruited in each group, with gestational ages ranging from 25 to 42 weeks. Twenty-nine of the exposed infants and 26 of the control infants were full-term (gestational age, 37 weeks or older). A total of 160 eyes were examined. No differences were seen in the incidence of congenital anomalies, subconjunctival hemorrhages, retinal hemorrhages, or optic nerve abnormalities between the two groups. No differences in mean axial length (16.9 ± 0.6 mm [exposed group] versus 17.1 ± 0.7 mm [control group]) or intraocular pressure (15.4 ± 3.8 mmHg [exposed group] versus 15.0 ± 3.0 mmHg [control group]) were seen between full-term infants in both groups. Axial length correlated strongly with gestational age, birth weight, head circumference, and body length over the range of gestational ages evaluated in both groups. No effect of cocaine exposure on these correlations was demonstrated. The range of axial length was 12.1 to 18.0 mm in the exposed group and 12.4 to 18.6 mm in the control group. Conclusion: In this study group, no significant effect of prenatal cocaine exposure was seen on the infant eye. In both exposed and non ex posed groups, axial length measurements agreed closely with known statistical norms and correlated closely with other parameters of fetal growth. Ophthalmology 1994;101:301-308
Originally received June 22, 1992. Revision accepted: July 30, 1993. I Division of Neonatology, Department of Pediatrics, Columbia-Presbyterian Medical Center, New York. 2 Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York. 3 Edward S. Harkness Eye Institute, Columbia-Presbyterian Medical Center, New York. Presented in part at the Annual Ophthalmology Clinical and Scientific Meeting of the Massachusetts Eye and Ear Infirmary Alumni Association, Boston, May 1992.
Cocaine abuse during pregnancy and the potential for adverse effects on the fetus and newborn have become a source of increasing concern in the last decade. Cocaine has been shown to be teratogenic in some animal studies. I ,2 However, its effect on human infants is controversial. 3-8 Isolated case reports have suggested that maternal cocaine use can affect the developing eye, and retrospecReprint requests to John C. Merriam, MD, Edward S. Harkness Eye Institute, 635 West l65th Street, New York, NY 10032.
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tive and uncontrolled studies also have noted an adverse effect on the developing visual system. 9- 13 Retinal abnormalities, optic nerve abnormalities, and microphthalmia are some of the many anomalies that have been described in infants exposed to cocaine while in utero. The purpose of this study is to identify a population of cocaine-exposed mothers and newborns and to compare them with a nonexposed population with respect to social characteristics, drug use, medical/obstetric histories, neonatal medical problems, and incidence of congenital anomalies. Cocaine exposure was defined as a positive urine toxicology result in the mother at any time during pregnancy and/or a positive result in the infant at delivery. Nonexposure was ascertained by detailed history during routine prenatal care with verification by urine toxicology only in cases with a history of prior drug abuse or abnormal behavior. To look for gross congenital anomalies, we performed detailed general and ocular examinations on 40 preterm and full-term cocaine-exposed infants and a control group of 40 nonexposed preterm and full-term infants. By analyzing axial length measurements over a range of gestational ages, we looked for subtle drug effects on ocular growth that might be overlooked on physical examination. Axial length measurements have been made previously in full-term newborns,14-'6 but available data in preterm neonates are limited. 16,17
Methods The study was conducted in the newborn nurseries and neonatal intensive care units of the Babies Hospital and the Allen Pavilion of the Columbia-Presbyterian Medical Center, New York, from January 1991 to May 1992. The study was approved by the Institutional Review Board of the Columbia-Presbyterian Medical Center, and informed consent was obtained from all mothers. Exposed subjects were selected from inborn full-term and preterm infants of mothers who tested positive for cocaine and/or its metabolites on urine toxicology screening at term or any time during pregnancy. Control subjects were selected at random from full-term and preterm infants born to mothers in our clinic population and admitted to our newborn nurseries and intensive care units. Negative urine toxicologies were available in 30% of control infants and mothers. Those mothers who had prenatal care at our institution were not tested routinely for drugs of abuse, unless specifically indicated by medical history or behavior characteristics consistent with drug abuse. The hospital charts were reviewed for information concerning age, race, gravity/parity, prenatal care, medical and obstetric complications, and delivery history. A detailed drug history was obtained from all mothers. Infant charts were reviewed for birth and postnatal histories. Detailed general physical examinations were performed on all infants, and the fOllowing data were collected: birth weight, head circumference, body length, estimated gestational age, abnormal physical findings, and presence of congenital anomalies.
302
Ophthalmologic examination included assessment of lid position, gross ocular motility, subconjunctival hemorrhage, and pupillary response to light. Eyes were anesthetized with 0.5% proparacaine hydrochloride and dilated with 1.0% tropicamide and 2.5% phenylephrine hydrochloride. The eyes were then examined with penlight and a small pupil indirect ophthalmoscope (MIRA, Waltham, MA). Intraocular pressure was measured with a Tonopen 2 (Bio-Rad, Glendale, CA). Axial length was measured with an ophthalmic ultrasound (A-lOOO, Sonomed, Lake Success, NY) with a special lO-mHz solid probe. Multiple measurements of each eye were obtained. Mean values for axial length and intraocular pressure were determined for each eye. Eighty eyes were examined in each group of 40 infants. Differences between groups were analyzed using chisquare analysis and Student's t test. Differences in measurements of axial length, intraocular pressure, and corneal diameter were assessed using Student's t test. A comparison between axial length in the exposed group and in the control group was performed with the Wilcoxon signed-rank test. The correlations of axial length with gestational age, birth weight, head circumference, and body length were analyzed using linear and multiple regression analysis. The effect of cocaine, smoking, race, sex, and the use of other drugs also was analyzed using analysis of covariance. Follow-up examinations were performed on four premature infants, and consecutive axial length measurements of the eyes of these infants were analyzed using regression analysis. Infants with abnormalities on initial evaluation were required to return for outpatient follow-up.
Results Forty cocaine-using mothers and their infants and 37 control mothers and their 40 infants (3 sets of twins) were enrolled in the study. Eighty eyes were evaluated in each group, for a total of 160 eye examinations. Maternal characteristics are summarized in Table I. The cocaine-using mothers tended to be older, to have had more pregnancies and live births, and to have had no prenatal care. There was a greater percentage of African-American women in the exposed group, whereas the control group included a greater percentage of Hispanic women. Table 1 summarizes cocaine habits and the use of tobacco and other drugs. The cocaine-using mothers were more likely to have used other drugs, including tobacco. Obstetric data are summarized in Table 2. The only significant difference was the higher incidence of maternal syphilis in the exposed group. The only known cases of human immunodeficiency virus, herpes simplex virus, and active tuberculosis were found exclusively in the exposed group, but the differences were not statistically significant. No differences between groups were seen in maternal hypertension or vaginal bleeding (a sign of abruptio placentae). Delivery data (Table 2) show a higher incidence of "precipitous" deliveries as well as meconium-stained amniotic fluid (an
Stafford et al
Prenatal Cocaine Exposure
Table 1. Maternal Data Exposed
Age (yrs)* Gravida* Para* Abortions
Race Black* Hispanic White Prenatal care* Cocaine used Crack Cocaine Freebase Combination (crack and cocaine) Other drugs Marijuana Alcohol Heroin Methadone Combinationst Barbiturate Tobacco* None* SD = standard • p < 0.01.
t
Control
(n = 40)
(n = 37)
Mean ± SD
Mean ± SD
30 ± 5 6±3 3± 2 2±2
25 ± 5 3±2
No. (%)
No. (%)
28 (70) 11 (28) 1 (2) 12 (30)
11 (30) 24 (65) 2 (5) 34 (91)
1± 1 1± 1
14 (35) 20 (50) 1 (2) 5 (13) 4 (10) 12 (30) 1 (3) 1 (3) 8 (20) 1 (3) 31 (78) 13 (32)
caine intoxication). More of the exposed infants had congenital anomalies, but this difference was not statistically significant (Tables 3 and 4). The presence of congenital anomalies was not related to the type of cocaine used during gestation or to the frequency of cocaine use (3 times per week or greater by history) during the first trimester. Eye findings are presented in Table 5. There were no differences in the incidence of retinal and subconjunctival hemorrhages. No abnormalities of the cornea, pupil, lens, or vitreous were found in either group. Three infants in the exposed group had suspected optic nerve hypoplasia at birth. On repeat examination at 6 to 9 months after delivery, however, all three infants were found to have normal optic nerves. Eye measurements are summarized in Table 5. We detected no significant differences in axial length, intraocular pressure, or horizontal corneal diameter between groups. Full-term male infants in the control group had longer axial lengths than full-term female controls (Table 6). This sex-related difference in axial length was not seen in the exposed infants. No racial differences in birth weight, head circumference, body length, or axial length
1 (3)
8 (20)
Table 2. Obstetric and Delivery Data
0(-) 1 (3) 1 (3) 0(-)
Exposed No.
11 (30) 26 (70)
deviation.
p < 0.05.
index of increased fetal distress) and the need for resuscitation at delivery in the exposed group. No significant differences in mean birth weight (2762 ± 662 g [exposed group] versus 2698 ± 859 g [control group]), gestational age (37.6 ± 3.1 weeks [exposed group] versus 36.8 ± 4.2 weeks [control group]) or head circumference (32.6 ± 2.2 cm [exposed group] versus 32.1 ± 3.1 cm [control group]) were found between the two groups. Birth weight ranged from 740 to 4080 g in the exposed group and from 835 to 3900 g in the control group. Gestational age ranged from 25 to 41 weeks in the exposed infants and from 26 to 42 weeks in the control infants. Twenty-nine exposed infants and 26 control infants were full-term (gestational age, 37 weeks or older), and no differences were seen between these two subgroups. Infant medical information is shown in Table 3. No differences were seen in the incidence of respiratory distress syndrome, sepsis, or intraventricular hemorrhage of the brain. As expected from the maternal data, more of the exposed infants were treated for suspected but asymptomatic congenital syphilis. More of the exposed infants showed signs and symptoms of jitteriness and irritability (potential signs of co-
(%)
Control No.
(%)
Obstetric Data Infections Syphilis* KnownHIV+ Known HSV+ Active Tb Known problems Preeclampsia Hypertension Preterm labor Vaginal bleed
(n = 40)
(n =
15 5 4 3
38 13 10 8
0 0 0 0
20 35 5
3 9 15 3
0 8
14
2
37)
8 24
40
8
Delivery Data Mode of delivery Normal vaginal C-section Breech Prolonged rupture of membranes Extramural delivery "Precipitous" vaginalt Meconium-stained amniotic fluidt Resuscitationt HIV
(n = 40)
(n = 40)
32 6 1 5 3 7
33 6 0 9 0 0 5 12
14 24
80 15 3 13 8 18 35 69
83 15 24
13 30
= human immunodeficiency virus; HSV = herpes simplex virus.
* P < 0.01.
t
P < 0.05.
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Table
3. Infant Data
Medical Information
Exposed (n = 40)
Control (n = 40)
Mean ± SO
Mean ± SO
7± 2 9± 1 18 ± 16
8± 1 9± 1 14 ± 24
No. (%)
No. (%)
19 (48) 21 (S2) 14 (3S) 10 (2S) 6 (IS) 6 (IS) 16 (40) S (13) 1 (3) 1 (3) 2 (S)
19 (48) 21 (S2) 14 (3S) 1 (3) 2 (S) 8 (20) 0(-) 9 (23) 0(-) 0(-) 2 (S)
I-min apgar S-min apgar Hospital stay (days)
Sex
M
F NICU admission Jitteriness/irritability· Congenital anomalies Suspected/proven sepsis Syphilis treatmentt Respiratory distress syndrome Asphyxia Meconium aspiration Intraventricular hemorrhage SO = standard deviation; NICU • P < 0.05.
Table
were noted. Neither the type of cocaine used nor heavy maternal cocaine use during the first trimester had any detectable effect on axial length. Regression analysis showed that axial length correlated strongly with gestational age, birth weight, head circumference, and body length in both groups. These relationships appeared linear over this range of gestational ages (25-42 weeks) as seen in Figure 1. Multiple regression analysis and analysis of covariance showed no effect of cocaine on these measures of growth. Race,
4.
Congenital Anomalies
Exposed Infants
Control Infants (n = 2)
Cleft lip/palate (case 8) Partial syndactyly (case 8) Flat philtrum (cases 14, 2S) Swollen facies (case IS) Clinodactyly (case 73) Congenital heart block (case 27)
Pre-auricular "pit" (case 38) Clinodactyly (case 63)
(n = 6)
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Ocular Findings and Measurements
Ocular Findings· (all eyes) Subconjunctival hemorrhages Retinal and macular hemorrhages Ocular Measurements All infants Axial length (mm) Intraocular pressure (mmHg) Corneal diameter (mm) Full-term infants
Exposed (n = 80)
Control (n = 80)
No. (%) S (6)
No. (%) 8 (10)
14 (18)
12 (IS)
Range
Range
12.1-18.0 3.0-23.5 7.0-10.5
12.4-18.6 6.5-27.0 7.0-11.0
(n
Axial length (mm) Intraocular pressure (mmHg) Corneal diameter (mm)
= 58)t
(n
= 52)t
Mean ± SO
Mean ± SO
16.9 ± 0.6 lS.4 ± 3.8 9.4 ± 0.5
17.1 ± 0.7 1S.0 ± 3.0 9.7 ± 0.5
so = standard deviation. • All infants in both groups were normal with respect to corneal clarity, gross motility, pupillary response, and clarity of the lens and vitreous. t Full-term eyes only.
= neonatal intensive care unit.
t P < 0.01.
Table
5.
smoking, and polydrug use also had no effect on these interactions. As can be seen, axial length correlated strongly with gestational age, birth weight, head circumference and body length. Linear equations for these relationships also are presented. Because no statistically significant differences were noted in axial length between the two groups, we combined the data from both groups for further analysis (n = 160 eyes). Axial length was found to increase from a minimum of 12.1 mm at 25 weeks gestational age to a maximum of 18.6 mm at term. Figure 2 shows strong linear correlations with gestational age, birth weight, head circumference, and body length. Sex-related differences were not apparent over all gestational ages. However, when analyzing the full-term infants from both control and exposed groups (n = 55), male infants were found again to have longer axial lengths (Table 6). Table
6. Sex-related Differences in Axial Length
Full-term controls· Full-term exposed All full-term infants·
so =
standard deviation.
• P < 0.05.
Male Infants
Female Infants
Mean ± SO
Mean ± SO
17.3±0.8 16.9 ± 0.7 17.2 ± 0.7
16.7 ± 0.6 16.8 ± 0.5 16.8 ± 0.5
Stafford et al . Prenatal Cocaine Exposure 19
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where x(t) is the added difference at gestational age t in weeks. The denominator is the best fit of Figure 2A, and X(40) was taken as the standard value at the 40week gestational age. We find that differences, X(40), smaller than 0.25 mm in mean axial length could not be detected. Therefore, the statistical sensitivity of this analysis is 0.25 mm. According to the manufacturer's estimation, the known uncertainty in axial length measurement by A-scan is 0.1 mm with eyes capable of fixation. Because the newborn infant is incapable of fixation, the experimental error in axial length in our study population must be greater than 0.1 mm. Thus, a larger sample size would not have increased the sensitivity of the analysis. We also have analyzed limited data on the postnatal growth of the premature eye. Serial measurements of axial length were obtained from four of our preterm subjects (2 control and 2 exposed) and are plotted against postconceptual age (gestational age + postnatal age [in weeks]) in Figure 3. As can be seen, the slope and y-intercept of
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Ophthalmology
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Volume 101, Number 2, February 1994
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Discussion Several case reports and retrospective studies have alluded to a potentially harmful effect of maternal cocaine use on the developing eye. 9- 13 Ferriero and co-workers (abstract; Ann NeuroI1989;26:458) reported three cocaine-expos€d infants with retinal abnormalities and microphthalmia. Merriam et al9 described the rehabilitation of a child exposed to crack cocaine who was born with severe bilateral microblepharon, lid colobomas, congenital corneal opacities, complex craniofacial anomalies, and unilateral syndactyly. Teske and TreselO described a full-term, cocaineexposed infant with retinopathy of prematurity-like fundus and persistent hyperplastic primary vitreous. Good et alii described 13 cocaine-exposed infants with optic nerve abnormalities (optic nerve hypoplasia and optic atrophy), delayed visual maturation, and profound eyelid edema. Dominguez and co-workers l2 described ten infants with developmental delay and congenital cerebral anomalies (midline cerebral malformations, hydranencephaly, and perinatal "strokes"), nine of whom had coexisting ophthalmologic abnormalities, including strabismus, nystagmus, and hypoplastic optic discs. Isenberg et al 13 prospectively reported tortuous and/or dilated iris vessels in 13 cocaine-intoxicated infants.
306
In this prospective study, we examined 80 eyes of 40 cocaine-exposed infants and 80 eyes of 40 nonexposed infants, ranging in gestational age from 25 to 42 weeks. We noted a significant difference in the incidence of maternal syphilis between groups, probably a reflection of the social and environmental conditions associated with cocaine abuse in the inner city. In addition, an increase in " precipitous" deliveries and deliveries of "stressed" infants was noted in the exposed group. However, no increase in vaginal bleeding (abruptio placenta) was seen among the cocaine-using mothers, afinding noted in previous reports.19 No significant difference in the incidence of congenital anomalies was seen between the two groups of infants. A history of heavy use of cocaine by mothers during the first trimester of pregnancy did not lead to a significant increase in congenital anomalies or eye abnormalities in their infants. Serum levels of cocaine are higher with crack use than with other forms of cocaine. 20,21 However, we saw no difference in the eye measurements of infants exposed to crack. No significant ocular anomalies were noted in either group. No evidence of retinopathy of prematurity was seen in any of our full-term newborns. In addition, axial length measurements were similar between groups, and the relation of axial length to gestational age, birth weight, head circumference, and body length was not affected in this population by cocaine. Mean values for axial lengths of 17 to 18 mm have been reported in enucleated newborn eyes, and ultrason-
Stafford et al . Prenatal Cocaine Exposure 19 18
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peA (WKS) Figure 3. A plot of axial length against postconceptual age (estimated gestational age + postnatal age) for four preterm subjects (2 exposed and 2 control infants).
ographic measurements in the 16- to 17-mm range have been reported in living newborns. 14- 17 The mean values obtained in our full-term, control group (17.1 ± 0.7 mm) as well as our full-term exposed group (16.9 ± 0.6 mm) compare closely with these earlier results. 14-17 One report indicated that full-term newborn males have slightly but significantly longer eyes than full-term girls, and the differences persisted with postnatal growth. 14 Our full-term, control newborns showed this sex-related difference also, but no sex-related differences in axial lengths were seen in our premature control infants. Although postnatal growth of axial length has been described,14 little is known of the dimensions of the premature eye and how they correlate with preterm growth. 16,17 With survival of premature infants increasing, knowledge of these normal preterm dimensions may be important because some studies have shown an influence of prematurity and low birth weight on ocular development later in life, specifically an arrest of corneal growth and a predisposition to the development of myopia. 22- 24 Our control data (n = 80 eyes) are consistent with those of previous authors and show growth of axial length to be rapid and linear over the gestational ages examined. 16, 17 Axial length increased from a minimum of 12.4 mm at 26 weeks gestation to a mean of 17.1 mm at full-term, an increase of almost 5 mm in 14 weeks (Table 5b). In contrast, the "rapid" phase of postnatal growth, as described by Larsen,14 leads to an increase of approximately 3.7 mm in the first 18 months of life. Growth of axial length also was linearly related to growth of head circumference in both groups. As head circumference is an index of brain size, our data point to a high degree of correlation between the size of the de-
veloping brain and the size of the developing eye. Cocaine exposure apparently did not adversely affect this relationship. Axial length also correlated well with birth weight and body length. Embryonic development of the human eye begins at approximately 3 weeks of gestation. 25 By 12 weeks after fertilization, the globe, retina, lens, and cornea are clearly identifiable. Development of the eyelids progresses from approximately weeks 8 to 12 when fusion occurs. Separation of the lids begins by the fifth month and is completed by the sixth to seventh month. The first trimester of gestation generally is considered the critical period for organogenesis. Unfortunately, precise quantification of drug exposure during this critical period is a problem encountered in all studies investigating the teratogenicity of cocaine. Our study has two limitations. First, we could identify cocaine use only at or near term, and historic data are almost certainly incomplete or inaccurate. Teratogenicity of a drug is dependent on several variables, such as the route and frequency of drug use, the postconceptual age of fetal exposure, pharmacokinetics of the drug, and placental transfer of the drug. 20,2 1 Because cocaine-using mothers are less likely to seek prenatal care, it is very difficult to determine these aspects of drug use. Second, "nonexposure" in the control group was verified by negative urine toxicology in only 30% of patients and may be subject to the same historic inaccuracies as the exposed group. Despite these limitations, data from our exposed, control, and combined groups agree very closely with previously reported statistical norms. 16,17 In this study population, cocaine use during pregnancy did not lead to an increase in ophthalmologic abnormalities or congenital ocular anomalies. Cocaine use did not affect axial length of the eye over the gestational ages evaluated or the correlation of axial length with other important measurements of fetal growth. This study, however, does not rule out the possibility that cocaine, or cocaine used with other drugs, could be teratogenic if taken in an excessive "dose" at a critical time in gestation.
References 1. Mahalik MP, Gautieri RF, Mann DE Jr. Teratogenic potential of cocaine hydrochloride in CF-l mice. J Pharm Sci 1980;69:703-6. 2. Webster WAS, Brown-Woodman PD. Cocaine as a cause of congenital malformations of vascular origin: experimental evidence in the rat. Teratology 1990;41:689-97. 3. Chasnoff IJ, Burns WJ, Schnoll SH, Burns KA. Cocaine use in pregnancy. N Engl J Med 1985;313:666-9. 4. Bingol N, Fuchs M, Diaz V, et al. Teratogenicity of cocaine in humans. J Pediatr 1987;110:93-6. 5. Hadeed AJ, Siegel SR. Maternal cocaine use during pregnancy: effect on the newborn infant. Pediatrics 1989;84: 205-10. 6. Madden JD, Payne TF, Miller S. Maternal cocaine abuse and effect on the newborn. Pediatrics 1986;77:209-11. 7. Lutiger B, Graham K, Einarson TR, Koren G. Relationship between gestational cocaine use and pregnancy outcome: a meta-analysis. Teratology 1991 ;44:405-14.
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8. Mayes LC, Granger RH, Bornstein MH, Zuckerman B. The problem of prenatal cocaine exposure. A rush to judgment. JAM A 1992;267:406-8. 9. Merriam JC, Stalnecker MC, Merriam GR Jr. Reconstruction of the lids ofa child with microblepharon and multiple congenital anomalies. Trans Am Ophthalmol Soc 1988;86: 55-93. 10. Teske MP, Trese MT. Retinopathy of prematurity-like fundus and persistent hyperplastic primary vitreous associated with maternal cocaine use. Am J Ophthalmol 1987;103: 719-20. 11. Good WV, Ferriero DM, Golabi M, Kobori JA. Abnormalities of the visual system in infants exposed to cocaine. Ophthalmology 1992;99:341-6. 12. Dominguez R, Aguirre Vila-Coro A, Slopis JM, Bohan TP. Brain and ocular abnormalities in infants with in utero exposure to cocaine and other street drugs. Am J Dis Child 1991; 145:688-95. 13. Isenberg SJ, Spierer A, Inkelis SH. Ocular signs of cocaine intoxication in neonates. Am J Ophthalmol 1987; 103:21114. 14. Larsen JS. The sagittal growth of the eye. IV. Ultrasonic measurement of the axial length of the eye from birth to puberty. Acta Ophthalmol 1971;49:873-86. 15. B10mdahl S. Ultrasonic measurements of the eye in the newborn infant. Acta Ophthalmol 1979;57: 1048-56. 16. Grignolo A, Rivara A. Biometry of the human eye from the sixth month of pregnancy to the tenth year of life. In: Vanysek J, ed. Diagnostica Ultrasonica in Ophthalmologica. Brno: Universita J. E. Purkyne,
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17. 18. 19. 20. 21.
22. 23.
24. 25.
1968;251-7. (Acta Facultatis Universitatis Brunensis; 35). Tucker SM, Enzenauer RW, Levin AV, et al. Corneal diameter, axial length, and intraocular pressure in premature infants. Ophthalmology 1992;99: 1296-1300. Beyer WH, ed. Handbook of Tables for Probability and Statistics. Boca Raton, Rorida: CRC Press, 1981;399. Acker D, Sachs BP, Tracey KJ, Wise WE. Abruptio placentae associated with cocaine use. Am J Obstet Gynecol 1983; 146:220-1. Farrar HC, Kearns GL. Cocaine: clinical pharmacology and toxicology. J Pediatr 1989; 115:665-75. Rosen TS. Infants of addicted mothers. In: Fanaroff AA, Martin RJ, eds. Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant, 5th ed. Vol. I. St. Louis: Mosby Year Book, 1992; chap. 34. Redelius He. Ophthalmic changes from age of 10 to 18 years. A longitudinal study of sequels to low birth weight. I. Refraction. Acta Ophthalmol 1980;58:889-98. Redelius He. Ophthalmic changes from age of 10 to 18 years. A longitudinal study of sequels to low birth weight. III. Ultrasound oculometry and keratometry of anterior eye segment. Acta Ophthalmol 1982;60:393-401. Quinn GE, Dobson V, Repka MX, et al. Development of myopia in infants with birth weights less than 1251 grams. Ophthalmology 1992;99:329-40. Torczynski E. Normal development of the eye and orbit before birth: the development of the eye. In: Isenberg SJ, ed. The Eye in Infancy. Chicago: Year Book Medical, 1989;9-30.
Originally received June 22, 1992. Revision accepted: July 30, 1993. I Division of Neonatology, Department of Pediatrics, Columbia-Presbyterian Medical Center, New York. 2 Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York. 3 Edward S. Harkness Eye Institute, Columbia-Presbyterian Medical Center, New York. Presented in part at the Annual Ophthalmology Clinical and Scientific Meeting of the Massachusetts Eye and Ear Infirmary Alumni Association, Boston, May 1992.
Cocaine abuse during pregnancy and the potential for adverse effects on the fetus and newborn have become a source of increasing concern in the last decade. Cocaine has been shown to be teratogenic in some animal studies. I ,2 However, its effect on human infants is controversial. 3-8 Isolated case reports have suggested that maternal cocaine use can affect the developing eye, and retrospecReprint requests to John C. Merriam, MD, Edward S. Harkness Eye Institute, 635 West l65th Street, New York, NY 10032.
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tive and uncontrolled studies also have noted an adverse effect on the developing visual system. 9- 13 Retinal abnormalities, optic nerve abnormalities, and microphthalmia are some of the many anomalies that have been described in infants exposed to cocaine while in utero. The purpose of this study is to identify a population of cocaine-exposed mothers and newborns and to compare them with a nonexposed population with respect to social characteristics, drug use, medical/obstetric histories, neonatal medical problems, and incidence of congenital anomalies. Cocaine exposure was defined as a positive urine toxicology result in the mother at any time during pregnancy and/or a positive result in the infant at delivery. Nonexposure was ascertained by detailed history during routine prenatal care with verification by urine toxicology only in cases with a history of prior drug abuse or abnormal behavior. To look for gross congenital anomalies, we performed detailed general and ocular examinations on 40 preterm and full-term cocaine-exposed infants and a control group of 40 nonexposed preterm and full-term infants. By analyzing axial length measurements over a range of gestational ages, we looked for subtle drug effects on ocular growth that might be overlooked on physical examination. Axial length measurements have been made previously in full-term newborns,14-'6 but available data in preterm neonates are limited. 16,17
Methods The study was conducted in the newborn nurseries and neonatal intensive care units of the Babies Hospital and the Allen Pavilion of the Columbia-Presbyterian Medical Center, New York, from January 1991 to May 1992. The study was approved by the Institutional Review Board of the Columbia-Presbyterian Medical Center, and informed consent was obtained from all mothers. Exposed subjects were selected from inborn full-term and preterm infants of mothers who tested positive for cocaine and/or its metabolites on urine toxicology screening at term or any time during pregnancy. Control subjects were selected at random from full-term and preterm infants born to mothers in our clinic population and admitted to our newborn nurseries and intensive care units. Negative urine toxicologies were available in 30% of control infants and mothers. Those mothers who had prenatal care at our institution were not tested routinely for drugs of abuse, unless specifically indicated by medical history or behavior characteristics consistent with drug abuse. The hospital charts were reviewed for information concerning age, race, gravity/parity, prenatal care, medical and obstetric complications, and delivery history. A detailed drug history was obtained from all mothers. Infant charts were reviewed for birth and postnatal histories. Detailed general physical examinations were performed on all infants, and the fOllowing data were collected: birth weight, head circumference, body length, estimated gestational age, abnormal physical findings, and presence of congenital anomalies.
302
Ophthalmologic examination included assessment of lid position, gross ocular motility, subconjunctival hemorrhage, and pupillary response to light. Eyes were anesthetized with 0.5% proparacaine hydrochloride and dilated with 1.0% tropicamide and 2.5% phenylephrine hydrochloride. The eyes were then examined with penlight and a small pupil indirect ophthalmoscope (MIRA, Waltham, MA). Intraocular pressure was measured with a Tonopen 2 (Bio-Rad, Glendale, CA). Axial length was measured with an ophthalmic ultrasound (A-lOOO, Sonomed, Lake Success, NY) with a special lO-mHz solid probe. Multiple measurements of each eye were obtained. Mean values for axial length and intraocular pressure were determined for each eye. Eighty eyes were examined in each group of 40 infants. Differences between groups were analyzed using chisquare analysis and Student's t test. Differences in measurements of axial length, intraocular pressure, and corneal diameter were assessed using Student's t test. A comparison between axial length in the exposed group and in the control group was performed with the Wilcoxon signed-rank test. The correlations of axial length with gestational age, birth weight, head circumference, and body length were analyzed using linear and multiple regression analysis. The effect of cocaine, smoking, race, sex, and the use of other drugs also was analyzed using analysis of covariance. Follow-up examinations were performed on four premature infants, and consecutive axial length measurements of the eyes of these infants were analyzed using regression analysis. Infants with abnormalities on initial evaluation were required to return for outpatient follow-up.
Results Forty cocaine-using mothers and their infants and 37 control mothers and their 40 infants (3 sets of twins) were enrolled in the study. Eighty eyes were evaluated in each group, for a total of 160 eye examinations. Maternal characteristics are summarized in Table I. The cocaine-using mothers tended to be older, to have had more pregnancies and live births, and to have had no prenatal care. There was a greater percentage of African-American women in the exposed group, whereas the control group included a greater percentage of Hispanic women. Table 1 summarizes cocaine habits and the use of tobacco and other drugs. The cocaine-using mothers were more likely to have used other drugs, including tobacco. Obstetric data are summarized in Table 2. The only significant difference was the higher incidence of maternal syphilis in the exposed group. The only known cases of human immunodeficiency virus, herpes simplex virus, and active tuberculosis were found exclusively in the exposed group, but the differences were not statistically significant. No differences between groups were seen in maternal hypertension or vaginal bleeding (a sign of abruptio placentae). Delivery data (Table 2) show a higher incidence of "precipitous" deliveries as well as meconium-stained amniotic fluid (an
Stafford et al
Prenatal Cocaine Exposure
Table 1. Maternal Data Exposed
Age (yrs)* Gravida* Para* Abortions
Race Black* Hispanic White Prenatal care* Cocaine used Crack Cocaine Freebase Combination (crack and cocaine) Other drugs Marijuana Alcohol Heroin Methadone Combinationst Barbiturate Tobacco* None* SD = standard • p < 0.01.
t
Control
(n = 40)
(n = 37)
Mean ± SD
Mean ± SD
30 ± 5 6±3 3± 2 2±2
25 ± 5 3±2
No. (%)
No. (%)
28 (70) 11 (28) 1 (2) 12 (30)
11 (30) 24 (65) 2 (5) 34 (91)
1± 1 1± 1
14 (35) 20 (50) 1 (2) 5 (13) 4 (10) 12 (30) 1 (3) 1 (3) 8 (20) 1 (3) 31 (78) 13 (32)
caine intoxication). More of the exposed infants had congenital anomalies, but this difference was not statistically significant (Tables 3 and 4). The presence of congenital anomalies was not related to the type of cocaine used during gestation or to the frequency of cocaine use (3 times per week or greater by history) during the first trimester. Eye findings are presented in Table 5. There were no differences in the incidence of retinal and subconjunctival hemorrhages. No abnormalities of the cornea, pupil, lens, or vitreous were found in either group. Three infants in the exposed group had suspected optic nerve hypoplasia at birth. On repeat examination at 6 to 9 months after delivery, however, all three infants were found to have normal optic nerves. Eye measurements are summarized in Table 5. We detected no significant differences in axial length, intraocular pressure, or horizontal corneal diameter between groups. Full-term male infants in the control group had longer axial lengths than full-term female controls (Table 6). This sex-related difference in axial length was not seen in the exposed infants. No racial differences in birth weight, head circumference, body length, or axial length
1 (3)
8 (20)
Table 2. Obstetric and Delivery Data
0(-) 1 (3) 1 (3) 0(-)
Exposed No.
11 (30) 26 (70)
deviation.
p < 0.05.
index of increased fetal distress) and the need for resuscitation at delivery in the exposed group. No significant differences in mean birth weight (2762 ± 662 g [exposed group] versus 2698 ± 859 g [control group]), gestational age (37.6 ± 3.1 weeks [exposed group] versus 36.8 ± 4.2 weeks [control group]) or head circumference (32.6 ± 2.2 cm [exposed group] versus 32.1 ± 3.1 cm [control group]) were found between the two groups. Birth weight ranged from 740 to 4080 g in the exposed group and from 835 to 3900 g in the control group. Gestational age ranged from 25 to 41 weeks in the exposed infants and from 26 to 42 weeks in the control infants. Twenty-nine exposed infants and 26 control infants were full-term (gestational age, 37 weeks or older), and no differences were seen between these two subgroups. Infant medical information is shown in Table 3. No differences were seen in the incidence of respiratory distress syndrome, sepsis, or intraventricular hemorrhage of the brain. As expected from the maternal data, more of the exposed infants were treated for suspected but asymptomatic congenital syphilis. More of the exposed infants showed signs and symptoms of jitteriness and irritability (potential signs of co-
(%)
Control No.
(%)
Obstetric Data Infections Syphilis* KnownHIV+ Known HSV+ Active Tb Known problems Preeclampsia Hypertension Preterm labor Vaginal bleed
(n = 40)
(n =
15 5 4 3
38 13 10 8
0 0 0 0
20 35 5
3 9 15 3
0 8
14
2
37)
8 24
40
8
Delivery Data Mode of delivery Normal vaginal C-section Breech Prolonged rupture of membranes Extramural delivery "Precipitous" vaginalt Meconium-stained amniotic fluidt Resuscitationt HIV
(n = 40)
(n = 40)
32 6 1 5 3 7
33 6 0 9 0 0 5 12
14 24
80 15 3 13 8 18 35 69
83 15 24
13 30
= human immunodeficiency virus; HSV = herpes simplex virus.
* P < 0.01.
t
P < 0.05.
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Volume 101, Number 2, February 1994
Table
3. Infant Data
Medical Information
Exposed (n = 40)
Control (n = 40)
Mean ± SO
Mean ± SO
7± 2 9± 1 18 ± 16
8± 1 9± 1 14 ± 24
No. (%)
No. (%)
19 (48) 21 (S2) 14 (3S) 10 (2S) 6 (IS) 6 (IS) 16 (40) S (13) 1 (3) 1 (3) 2 (S)
19 (48) 21 (S2) 14 (3S) 1 (3) 2 (S) 8 (20) 0(-) 9 (23) 0(-) 0(-) 2 (S)
I-min apgar S-min apgar Hospital stay (days)
Sex
M
F NICU admission Jitteriness/irritability· Congenital anomalies Suspected/proven sepsis Syphilis treatmentt Respiratory distress syndrome Asphyxia Meconium aspiration Intraventricular hemorrhage SO = standard deviation; NICU • P < 0.05.
Table
were noted. Neither the type of cocaine used nor heavy maternal cocaine use during the first trimester had any detectable effect on axial length. Regression analysis showed that axial length correlated strongly with gestational age, birth weight, head circumference, and body length in both groups. These relationships appeared linear over this range of gestational ages (25-42 weeks) as seen in Figure 1. Multiple regression analysis and analysis of covariance showed no effect of cocaine on these measures of growth. Race,
4.
Congenital Anomalies
Exposed Infants
Control Infants (n = 2)
Cleft lip/palate (case 8) Partial syndactyly (case 8) Flat philtrum (cases 14, 2S) Swollen facies (case IS) Clinodactyly (case 73) Congenital heart block (case 27)
Pre-auricular "pit" (case 38) Clinodactyly (case 63)
(n = 6)
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Ocular Findings and Measurements
Ocular Findings· (all eyes) Subconjunctival hemorrhages Retinal and macular hemorrhages Ocular Measurements All infants Axial length (mm) Intraocular pressure (mmHg) Corneal diameter (mm) Full-term infants
Exposed (n = 80)
Control (n = 80)
No. (%) S (6)
No. (%) 8 (10)
14 (18)
12 (IS)
Range
Range
12.1-18.0 3.0-23.5 7.0-10.5
12.4-18.6 6.5-27.0 7.0-11.0
(n
Axial length (mm) Intraocular pressure (mmHg) Corneal diameter (mm)
= 58)t
(n
= 52)t
Mean ± SO
Mean ± SO
16.9 ± 0.6 lS.4 ± 3.8 9.4 ± 0.5
17.1 ± 0.7 1S.0 ± 3.0 9.7 ± 0.5
so = standard deviation. • All infants in both groups were normal with respect to corneal clarity, gross motility, pupillary response, and clarity of the lens and vitreous. t Full-term eyes only.
= neonatal intensive care unit.
t P < 0.01.
Table
5.
smoking, and polydrug use also had no effect on these interactions. As can be seen, axial length correlated strongly with gestational age, birth weight, head circumference and body length. Linear equations for these relationships also are presented. Because no statistically significant differences were noted in axial length between the two groups, we combined the data from both groups for further analysis (n = 160 eyes). Axial length was found to increase from a minimum of 12.1 mm at 25 weeks gestational age to a maximum of 18.6 mm at term. Figure 2 shows strong linear correlations with gestational age, birth weight, head circumference, and body length. Sex-related differences were not apparent over all gestational ages. However, when analyzing the full-term infants from both control and exposed groups (n = 55), male infants were found again to have longer axial lengths (Table 6). Table
6. Sex-related Differences in Axial Length
Full-term controls· Full-term exposed All full-term infants·
so =
standard deviation.
• P < 0.05.
Male Infants
Female Infants
Mean ± SO
Mean ± SO
17.3±0.8 16.9 ± 0.7 17.2 ± 0.7
16.7 ± 0.6 16.8 ± 0.5 16.8 ± 0.5
Stafford et al . Prenatal Cocaine Exposure 19
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effect. In doing this, we have scaled the difference according to the gestational age of each matched pair as follows: x(40) 0.28 X 40 + 5.84
x(t) 0.28 X t + 5.84
where x(t) is the added difference at gestational age t in weeks. The denominator is the best fit of Figure 2A, and X(40) was taken as the standard value at the 40week gestational age. We find that differences, X(40), smaller than 0.25 mm in mean axial length could not be detected. Therefore, the statistical sensitivity of this analysis is 0.25 mm. According to the manufacturer's estimation, the known uncertainty in axial length measurement by A-scan is 0.1 mm with eyes capable of fixation. Because the newborn infant is incapable of fixation, the experimental error in axial length in our study population must be greater than 0.1 mm. Thus, a larger sample size would not have increased the sensitivity of the analysis. We also have analyzed limited data on the postnatal growth of the premature eye. Serial measurements of axial length were obtained from four of our preterm subjects (2 control and 2 exposed) and are plotted against postconceptual age (gestational age + postnatal age [in weeks]) in Figure 3. As can be seen, the slope and y-intercept of
305
Ophthalmology
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Volume 101, Number 2, February 1994
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this regression line compare favorably with those of Figure 2A.
Discussion Several case reports and retrospective studies have alluded to a potentially harmful effect of maternal cocaine use on the developing eye. 9- 13 Ferriero and co-workers (abstract; Ann NeuroI1989;26:458) reported three cocaine-expos€d infants with retinal abnormalities and microphthalmia. Merriam et al9 described the rehabilitation of a child exposed to crack cocaine who was born with severe bilateral microblepharon, lid colobomas, congenital corneal opacities, complex craniofacial anomalies, and unilateral syndactyly. Teske and TreselO described a full-term, cocaineexposed infant with retinopathy of prematurity-like fundus and persistent hyperplastic primary vitreous. Good et alii described 13 cocaine-exposed infants with optic nerve abnormalities (optic nerve hypoplasia and optic atrophy), delayed visual maturation, and profound eyelid edema. Dominguez and co-workers l2 described ten infants with developmental delay and congenital cerebral anomalies (midline cerebral malformations, hydranencephaly, and perinatal "strokes"), nine of whom had coexisting ophthalmologic abnormalities, including strabismus, nystagmus, and hypoplastic optic discs. Isenberg et al 13 prospectively reported tortuous and/or dilated iris vessels in 13 cocaine-intoxicated infants.
306
In this prospective study, we examined 80 eyes of 40 cocaine-exposed infants and 80 eyes of 40 nonexposed infants, ranging in gestational age from 25 to 42 weeks. We noted a significant difference in the incidence of maternal syphilis between groups, probably a reflection of the social and environmental conditions associated with cocaine abuse in the inner city. In addition, an increase in " precipitous" deliveries and deliveries of "stressed" infants was noted in the exposed group. However, no increase in vaginal bleeding (abruptio placenta) was seen among the cocaine-using mothers, afinding noted in previous reports.19 No significant difference in the incidence of congenital anomalies was seen between the two groups of infants. A history of heavy use of cocaine by mothers during the first trimester of pregnancy did not lead to a significant increase in congenital anomalies or eye abnormalities in their infants. Serum levels of cocaine are higher with crack use than with other forms of cocaine. 20,21 However, we saw no difference in the eye measurements of infants exposed to crack. No significant ocular anomalies were noted in either group. No evidence of retinopathy of prematurity was seen in any of our full-term newborns. In addition, axial length measurements were similar between groups, and the relation of axial length to gestational age, birth weight, head circumference, and body length was not affected in this population by cocaine. Mean values for axial lengths of 17 to 18 mm have been reported in enucleated newborn eyes, and ultrason-
Stafford et al . Prenatal Cocaine Exposure 19 18
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peA (WKS) Figure 3. A plot of axial length against postconceptual age (estimated gestational age + postnatal age) for four preterm subjects (2 exposed and 2 control infants).
ographic measurements in the 16- to 17-mm range have been reported in living newborns. 14- 17 The mean values obtained in our full-term, control group (17.1 ± 0.7 mm) as well as our full-term exposed group (16.9 ± 0.6 mm) compare closely with these earlier results. 14-17 One report indicated that full-term newborn males have slightly but significantly longer eyes than full-term girls, and the differences persisted with postnatal growth. 14 Our full-term, control newborns showed this sex-related difference also, but no sex-related differences in axial lengths were seen in our premature control infants. Although postnatal growth of axial length has been described,14 little is known of the dimensions of the premature eye and how they correlate with preterm growth. 16,17 With survival of premature infants increasing, knowledge of these normal preterm dimensions may be important because some studies have shown an influence of prematurity and low birth weight on ocular development later in life, specifically an arrest of corneal growth and a predisposition to the development of myopia. 22- 24 Our control data (n = 80 eyes) are consistent with those of previous authors and show growth of axial length to be rapid and linear over the gestational ages examined. 16, 17 Axial length increased from a minimum of 12.4 mm at 26 weeks gestation to a mean of 17.1 mm at full-term, an increase of almost 5 mm in 14 weeks (Table 5b). In contrast, the "rapid" phase of postnatal growth, as described by Larsen,14 leads to an increase of approximately 3.7 mm in the first 18 months of life. Growth of axial length also was linearly related to growth of head circumference in both groups. As head circumference is an index of brain size, our data point to a high degree of correlation between the size of the de-
veloping brain and the size of the developing eye. Cocaine exposure apparently did not adversely affect this relationship. Axial length also correlated well with birth weight and body length. Embryonic development of the human eye begins at approximately 3 weeks of gestation. 25 By 12 weeks after fertilization, the globe, retina, lens, and cornea are clearly identifiable. Development of the eyelids progresses from approximately weeks 8 to 12 when fusion occurs. Separation of the lids begins by the fifth month and is completed by the sixth to seventh month. The first trimester of gestation generally is considered the critical period for organogenesis. Unfortunately, precise quantification of drug exposure during this critical period is a problem encountered in all studies investigating the teratogenicity of cocaine. Our study has two limitations. First, we could identify cocaine use only at or near term, and historic data are almost certainly incomplete or inaccurate. Teratogenicity of a drug is dependent on several variables, such as the route and frequency of drug use, the postconceptual age of fetal exposure, pharmacokinetics of the drug, and placental transfer of the drug. 20,2 1 Because cocaine-using mothers are less likely to seek prenatal care, it is very difficult to determine these aspects of drug use. Second, "nonexposure" in the control group was verified by negative urine toxicology in only 30% of patients and may be subject to the same historic inaccuracies as the exposed group. Despite these limitations, data from our exposed, control, and combined groups agree very closely with previously reported statistical norms. 16,17 In this study population, cocaine use during pregnancy did not lead to an increase in ophthalmologic abnormalities or congenital ocular anomalies. Cocaine use did not affect axial length of the eye over the gestational ages evaluated or the correlation of axial length with other important measurements of fetal growth. This study, however, does not rule out the possibility that cocaine, or cocaine used with other drugs, could be teratogenic if taken in an excessive "dose" at a critical time in gestation.
References 1. Mahalik MP, Gautieri RF, Mann DE Jr. Teratogenic potential of cocaine hydrochloride in CF-l mice. J Pharm Sci 1980;69:703-6. 2. Webster WAS, Brown-Woodman PD. Cocaine as a cause of congenital malformations of vascular origin: experimental evidence in the rat. Teratology 1990;41:689-97. 3. Chasnoff IJ, Burns WJ, Schnoll SH, Burns KA. Cocaine use in pregnancy. N Engl J Med 1985;313:666-9. 4. Bingol N, Fuchs M, Diaz V, et al. Teratogenicity of cocaine in humans. J Pediatr 1987;110:93-6. 5. Hadeed AJ, Siegel SR. Maternal cocaine use during pregnancy: effect on the newborn infant. Pediatrics 1989;84: 205-10. 6. Madden JD, Payne TF, Miller S. Maternal cocaine abuse and effect on the newborn. Pediatrics 1986;77:209-11. 7. Lutiger B, Graham K, Einarson TR, Koren G. Relationship between gestational cocaine use and pregnancy outcome: a meta-analysis. Teratology 1991 ;44:405-14.
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Ophthalmology
Volume 101, Number 2, February 1994
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