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To determine whether children who do not develop fetal alcohol syndrome (FAS) despite heavy alcohol exposure are at risk for eye abnormalities
We screened 9628 pregnant women and identified 101 women who were drinking ≥ 2 ounces of absolute alcohol per day and 101 non-drinking control women. We followed 43 exposed and 55 control offspring ages 4 to 9 years and performed masked, standardized ophthalomologic exams.
The groups did not differ in their rates of impaired visual acuity, refractory errors, ptosis, epicanthal folds, or short palpebral fissures. Biomicroscopy examinations were normal in all exposed subjects; two (4%) controls and no exposed had cataracts. Seven (16%) exposed subjects versus 8 (15%) controls had arterial tortuosity. No subjects had optic nerve hypoplasia.
Previous research has reported that children with FAS have a high incidence of serious ophthalmologic defects; our data show that the risk is limited to children with FAS, not children exposed to high levels of alcohol prenatally but who do not develop FAS. Eye examinations are unlikely to clarify the diagnosis in children suspected of having alcohol related damage.
Prenatal exposure to high levels of alcohol causes fetal alcohol spectrum disorders (FASD), a range of developmental abnormalities. Fetal alcohol syndrome (FAS), the most severe effect of prenatal alcohol exposure, is characterized by pre and post natal growth restriction, developmental abnormalities, and malformations (most commonly craniofacial)(1). Children who do not meet the criteria for FAS may still have adverse effects of alcohol including physical anomalies, growth problems, developmental delay, and behavioral problems.
A number of studies have reported that ophthalmologic abnormalities are an important finding in FASD(2–18). These disorders may include external eye malformations, intraocular abnormalities, and impaired visual acuity(3, 4, 19). Previous investigations had limitations including studying only children with FAS who were referred for ophthalmologic evaluation because of known or suspected problems, providing little or no information regarding the extent of in utero alcohol exposure, performing limited evaluations of visual function, or examining only a small number of subjects. As a result, little is known regarding the risk of eye malformations among children who are exposed to heavy levels of alcohol in utero but who did not develop FAS.
We conducted a prospective study of children born to women who consumed large amounts of alcohol (at least two ounces of absolute alcohol per day or ≥ 48 grams/day) during pregnancy and children of women who abstained from alcohol during pregnancy. The cohort was drawn from an unselected population of women attending a prenatal care facility in Santiago, Chile. The alcohol exposure was documented during the pregnancy. We performed detailed ophthalmologic examinations in the children to determine whether prenatal exposure to large quantities of alcohol is associated with ocular malformations and visual impairment.
The subjects were part of a prospective cohort study of the effects of prenatal exposure to alcohol on offspring of heavy drinking mothers in Chile – The NICHD-University of Chile Alcohol in Pregnancy Study. The study methods have been reported in detail previously (20). In brief, alcohol exposure was identified prenatally by interviewing 9628 (of 10 917) women receiving prenatal care at a community health clinic serving approximately 60% of a lower middle class population in Santiago, Chile, generally at their first prenatal visit, between August 1995 and July 2000. Those suspected of heavy drinking (n=887) had follow-up home visits to confirm their exposure status. These visits identified 101 women who were drinking at least 2 ounces of absolute alcohol per day (≥ 48 grams) on average. Unexposed subjects (n= 101) were selected prenatally from the same cohort of women. They were confirmed to be non-drinkers by home visits. The groups were individually matched on maternal age, parity, and gestational age at entry. This study was approved by the IRBs at University of Chile and the NICHD. Women signed informed consent forms at time of enrollment into the study.
The infants of these women were then followed prospectively for up to eleven years. Two children (one in each group) were stillborn. Children (n=200) were invited to undergo ophthalmologic examination between December, 2003 and January, 2005.
All patients were examined by one ophthalmologist (MFB) who was masked to the exposure group of the children. The ophthalmologic examination included assessment of visual acuity (best-corrected visual acuity), ocular motility, slit-lamp examination, fundus examination with both direct and indirect ophthalmoscopy, and refraction under cycloplegia. Best-corrected visual acuity (BCVA) was tested with methods deemed suitable by the examiner for age and developmental level of the child (most commonly Snellen chart), and was recorded in the logMAR (logarithm of minimal angle of resolution) scale. The results were then grouped by the ophthalmologist into categories roughly based on severity of acuity deficits: normal (>0.7 – 1), mild deficit (0.5 – 0.7), severe deficit (0.1 – <0.5).
Ophthalmologic findings including short palpebral fissure length, blepharoptosis, epicanthus, hypertelorism, strabismus, anterior segment abnormalities (i.e. cataracts), nystagmus, blepharophimosis, microphthalmia, optic nerve hypoplasia, retinal vessel tortuosity, and other abnormalities of the fundus were recorded. Determination of short palpebral fissure length (2 standard deviations below the mean) was made by comparing measurements to age adjusted percentile standards from a US population published by Hall et al., 1989 (21). The measurements from the inner canthus to the outer canthus were obtained in millimeters with a rigid ruler with the examiner seated directly in front of the subject.
Categorical demographic variables were compared using Chi Squared tests, while continuous variables were compared using Student’s t-test. SAS version 9.1 (SAS, Cary, North Carolina) was used for these analyses. Ocular malformations and abnormalities were analyzed using p-values and CI of the difference of proportions from the unconditional exact method for two binomial samples of StatXact (StatXact-4, Cytel Software Corporation, Cambridge, Massachusetts).
There were 43 children of heavy alcohol-drinking mothers and 55 children of the non-drinking mothers who underwent ophthalmologic examination. The average alcohol exposure among women in the exposed group was 9.7 (range 5.3–19.1) standard drinks per day prior to knowledge of pregnancy. Even though there was some decrease during pregnancy, in most women this decrease was modest, with an average of 5.8 standard drinks per day throughout the remainder of pregnancy. Only 7 (16%) women stopped drinking, 4 (9%) early in the second trimester and 3 (7%) during the third trimester. Unexposed controls were significantly younger (average age 5.6 years) than the exposed subjects (average age 6.3 years) (p = 0.005), because exposed subjects were matched to controls which took some time (Table I). While statistically significant, the difference in mean age between the groups was only 0.75 years. Mothers of the exposed children had significantly fewer years of school completed (10.2 years versus 11.5 years, p = 0.024) and were significantly more likely to have single marital status when compared with controls (p = 0.007). There were no significant differences between the groups in maternal age, parity, infant sex, gestational age at delivery, or birth weight.
There was no significant difference in the rates of retinal vessel tortuosity or abnormalities of the optic nerve (Table II). Seven exposed subjects versus 8 controls had mild increased arteriolar tortuosity (p = 0.88). One control had a tilted optic nerve and one control had small paramacular pigmented lesions in the left eye. Optic nerve hypoplasia, one of the serious abnormalities frequently reported in studies of children with FAS, was not found in any of our subjects.
There were no statistically significant differences between the two groups. The external ocular examination found that short palpebral fissures were present in 14% of exposed[h2] children versus 18% of control children (p = 0.66), epicanthus in 21% of exposed versus 11% of controls (p = 0.33), and one child in each group had ptosis. One exposed child demonstrated a positive Kappa angle, and one had a lateral ectropion. One control child was noted to have convergence insufficiency. Two control children were noted to have cataracts. No other abnormalities (Axenfeld-Rieger anomaly, Peters anomaly, microcornea, shallow anterior chamber, congenital glaucoma, persistent hyaloids or corneal opacities) were noted in the anterior segment in our population.
BCVA ranged from 0.1 to 1.0 (Table III). Visual acuity was examined successfully in 38 children the exposed group and 45 children in the control group. Five children in the exposed group and 10 children in the control group were not able to cooperate with the visual acuity examination. Two children in the exposed group had abnormal BCVA bilaterally, one mild (BCVA between 0.5 and 0.7) and one severe (BCVA < 0.5). Two children in the control group had abnormal acuity, one with mild acuity deficit (BCVA between 0.5 and 0.7) in left eye only, the other with severe deficit (BCVA < 0.5) bilaterally. Refraction determined under cycloplegia ranged from −1.25 to +5.75 (spherical equivalent). Mean refraction in the right eye was 0.92 ± 1.74 in the exposed group compared with 1.05 ± 0.61 in the control group (p = 0.64). In the left eye, mean refraction was 1.17 ± 1.79 in the exposed group versus 1.07 ± 0.67 in the control group (p = 0.73). Refraction data were incomplete on 4 control children. Myopia was found in one exposed child but not found in any controls. Astigmatism was present in one exposed child and one control child. Hyperopia, defined as ≥ 2.0 diopters, was present in 8 exposed children and 4 control children (p = 0.29). Hyperopia can be a normal developmental finding up to age 7 years (22). Three of the 8 in the exposed group and 1 of the 4 in the control group with hyperopia were greater than or equal to seven years of age at the time of the examination. Only one exposed child with hyperopia was > 7 years of age at the time of exam. There were no statistically significant differences in visual acuity or refraction between the exposed group and the controls.
We determined the prevalence of visual and ocular abnormalities in an unselected cohort of Chilean children exposed to large quantities of alcohol in utero compared with matched controls. Major ocular anomalies and vision problems were no more common in our heavily exposed children than in unexposed controls. It is reassuring that the majority of exposed children had no more visual problems than control children, given the high prevalence of ocular abnormalities previously reported among children diagnosed with FAS(2, 4, 5, 8, 9, 13–16, 18, 19, 23–27).
Although many studies have reported a high rate of major eye malformations in children with FAS, little is known about children who are exposed to high levels of alcohol but do not develop FAS, despite the fact that most heavily exposed children do not develop FAS. There are only two previous studies of the visual system in alcohol-exposed children that included those children who did not have FAS. The first report of ocular abnormalities in alcohol-exposed children who did not have FAS includes only 10 children who did not meet criteria of FAS and of those children; 4 had eye abnormalities (maculopathy, tortuosity, esotropia, and nystagmus)(28). These children, however, are siblings of those with FAS and may have been referred for evaluation because of eye problems.
In the second study assessing alcohol exposed children, Carter et al prospectively studied effects of prenatal alcohol exposure on visual acuity in 131 South African infants at 6.5 months of age. This study, however, only assessed vision using Teller Acuity Cards and did not examine the ocular structures. This group demonstrated that prenatal alcohol exposure was linked with diminished visual acuity in infancy (27.3% versus 9.3% of the controls, P < 0.005)(3). This study was limited by lack of complete eye examination; therefore, they were unable to determine the cause (refractive errors, retinal changes, or central nervous system abnormalities) of lower visual acuity scores in infants exposed prenatally to alcohol. The authors also made the important point that acuity deficits seen at 6.5 months may reflect only a maturational deficit or delay in visual system development. They emphasized that their findings required re-evaluation by complete visual assessment later in childhood.
Most of what is known regarding ocular findings in children with complete FAS was described by Stromland et al. Her work has focused primarily on comprehensive examinations performed on children who were diagnosed with FAS(13–16, 18, 19, 27, 29). She reported that the majority of children with FAS have ocular findings including optic disc hypoplasia (48%) or retinal vessel tortuosity (49%)(13). These rates could be elevated by the fact that children may have been referred for visual problems. Moreover, the examiners were not masked to diagnosis.
Other data suggest that rates of ocular malformations are not as high as reported from Sweden. A recent study from Portugal of 32 children with FAS and 25 controls reported retinal vessel tortuosity in 30% and optic nerve hypoplasia in 25% of children with FAS, lower rates than demonstrated previously in Sweden(11). This group also noted that their patients had better visual acuity (82.7% with normal acuity vs. 35% in the Swedish study), and that the malformations were notably less severe than those seen in Sweden(13). The authors suggest that referral/selection bias, patterns of drinking, and genetic factors may play a significant role in these differences in rates and severity of abnormalities.
Our data suggest that the high rate of anomalies found by Stromland and others could be due, at least in part, to the way subjects were selected and that Carter’s results may have been due to maturational delay. A possible explanation for the low incidence of ocular abnormalities in our study is that exposure was based on maternal use of alcohol prenatally, not FAS. It is likely that only those subjects with FAS have high rates of ocular abnormalities. The mothers of the exposed population were young (mean age 23.02 years) and the majority of our women were primiparous (63%) potentially attenuating the damaging effects of alcohol, as increasing maternal age and parity are directly correlated with severity of defects caused by prenatal alcohol exposure in both animal and human studies (30–33). It is also possible that some of the mothers decreased their consumption of alcohol as a result of being enrolled in this study, and that defects involving growth and development of ocular structures (such as growth of the optic nerve and retinal vessels) may have been averted by this decrease in alcohol consumption. Most mothers in our cohort, however, did not significantly reduce their drinking after study enrollment. Genetic or nutritional differences between the populations studied might also affect the risk of damage to the developing visual system secondary to exposure to alcohol(34–36).
This prospective study examined the ocular structures and visual function comprehensively in unselected children exposed to alcohol and unexposed controls. Eye examinations were performed on all exposed subjects, not just those who had phenotypic changes related to alcohol damage. The ophthalmologist was masked to the exposure status of the children. Our study had some limitations as well. It was designed to examine the effects of heavy exposure to alcohol prenatally; our small number of children does not enable us to comment on the frequency of eye malformations among children with FAS. The reference population used for palpebral fissures was not standardized for the Chilean population and there are no published data regarding ethnic differences in palpebral fissure lengths in the Chilean population. Therefore, we can not rule out that ethnic differences are the reason for the high rates of short palpebral fissure. The relatively high prevalence of short palpebral fissure lengths and epicanthal folds in both the exposed and the control groups may represent a normal variant in this population. Although the precise reason for the high rate of these findings remains unclear, we postulate that the young age of the subjects in combination with the ethnic differences in the Chilean population is the most likely reason for the increase in these findings. Palpebral fissures are known to vary in size according to ethnicity and age(37, 38). Because of the young age and developmental status of subjects, lack of cooperation could have produced some measurement error. We were also limited by our inability to get many of the subjects to return for eye examinations due to difficulties contacting them.
The high frequency of reported ocular and visual findings among children with FAS has led some to advocate ophthalmologic exams as a diagnostic tool for FASD. Our data indicate that ophthalmologic examinations are not likely to help diagnose FASD, but they may be important in the assessment/evaluation of a child who has FAS.
In summary, this study demonstrates that the teratogenic effect of alcohol on the developing visual system is likely to be limited to children who have FAS, rather than those exposed to high levels of alcohol prenatally who do not develop FAS. These results have several potentially important clinical implications. First, eye examinations are unlikely to help clarify the diagnosis in children suspected of having alcohol related damage. Second, children who do not have classic FAS are not at high risk for eye abnormalities.
Financial support was provided by The Intramural Research Program of NICHD and by Protocol/Project Number OHSR-96-04 from National Institute of Child Health and Human Development (NICHD) National Institutes of Health, Bethesda, Maryland
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The authors declare no conflicts of interest[h1].