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Original Research Communication |
1 From the Division of Human Nutrition, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, and the Society for Prevention of Blindness, Kathmandu, Nepal.
2 This trial was a collaboration between the Center for Human Nutrition, Department of International Health at The Johns Hopkins School of Public Health, and the National Society for Eye Health and Blindness Prevention (Nepal Netra Jyoti Sangh), Kathmandu, Nepal. It was supported by the Nestle Foundation, Lausanne, Switzerland; cooperative agreement DAN HRN-A-00-97-00015-00 between The Johns Hopkins University, Baltimore, and the Office of Health and Nutrition, US Agency for International Development (USAID); and the Task Force Sight and Life Institute. The supplements were donated by CE Jamieson & Co Ltd, Ontario. The retinol binding protein analysis was kindly performed by the Program for Appropriate Technology in Health (PATH), Seattle, under the Technologies for Health (HealthTech) project cooperative agreement with USAID. 3 Address reprint requests to P Christian, The Johns Hopkins School of Hygiene and Public Health, Division of Human Nutrition, Room 2041, 615 North Wolfe Street, Baltimore, MD 21205. E-mail: pchristi{at}jhsph.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: The study examined the efficacy of daily zinc supplementation in restoring night vision of pregnant women who developed night blindness while routinely receiving either vitamin A, ß-carotene, or placebo in a field trial.
Design: Women (n = 202) who reported to be night blind during pregnancy were randomly assigned in a double-blind manner, stratified on vitamin A, ß-carotene, or placebo receipt, to receive 25 mg Zn or placebo daily for 3 wk. Thus, the 6 groups studied were as follows: ß-carotene + zinc, ß-carotene alone, vitamin A + zinc, vitamin A alone (vitamin A + placebo), zinc alone (zinc + placebo), and placebo (2 placebos: one for the vitamin A or ß-carotene study and one for the zinc study). Women underwent a clinic-based assessment that included pupillary threshold testing and phlebotomy before and after supplementation. Supplement use and daily history of night blindness were obtained at home twice every week.
Results: Zinc treatment increased serum zinc concentrations, but alone (zinc alone group), failed to restore night vision or to improve dark adaptation. However, women in the vitamin A + zinc group who had baseline serum zinc concentrations <9.9 µmol/L were 4 times more likely to have their night vision restored (95% CI: 1.1, 17.3) than were women in the placebo group and tended to have a small improvement in pupillary threshold scores (by 0.21 log candela/m2; P = 0.09).
Conclusion: These data suggest that zinc potentiated the effect of vitamin A in restoring night vision among night-blind pregnant women with low initial serum zinc concentrations.
Key Words: Zinc • night blindness • pregnancy • vitamin A • pupillary threshold • dark adaptation • women • Nepal
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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18% (4). In a large field trial, weekly, low-dose vitamin A supplementation (7000 µg retinol equivalents, or RE) reduced the incidence of night blindness during pregnancy by 67% among women who took >95% of the supplements throughout pregnancy, thus reducing, but not eliminating, maternal night blindness (5). ß-Carotene supplementation (42 mg, or 7000 µg RE) resulted in a 27% reduction in the occurrence of night blindness that was not statistically significant. Vitamin A supplementation also improved dark adaptation assessed by pupillary threshold detection in pregnant and lactating women (6). Zinc supplementation was previously shown to improve dark adaptation among cirrhotic patients with abnormal dark adaptation who were not responsive to vitamin A and had low serum zinc concentrations (7). A potential role of zinc deficiency may be hypothesized in the etiology of night blindness during pregnancy in relation to its interaction with vitamin A (8, 9). First, zinc is required in the hepatic synthesis or secretion of retinol binding protein (RBP), the transport protein of vitamin A (8; BJ Burrie, B Sutherland, N Lowe, JC King, unpublished observations, 1999; L Quadro, M Gottesman, V Colantuoni, S Vogel, P Gouras, WS Blaner, unpublished observations, 1999). In zinc deficiency, RBP production can be reduced, resulting in secondary vitamin A deficiency that is reflected by low serum vitamin A concentration (8, 10). Thus, even in the presence of vitamin A adequacy, night blindness could occur when zinc deficiency exists. The other role of zinc may be in the visual cycle. Although zinc deficiency was previously thought to impair zinc-dependent 11-cis retinol dehydrogenase activity, the enzyme required for conversion of all-trans retinal to 11-cis retinal in the retina (11), it is now known that this enzyme is zinc independent (12–14). However, numerous other enzymes important in the visual cycle (15) may likely be zinc dependent.
During pregnancy, maternal plasma zinc concentrations start to decrease as early as 6 wk of gestation and continue to decline until delivery (16). In Nepal, maternal plasma zinc concentrations were found to be low compared with those of healthy US women, presumably because of the high content of fiber and phytate in the Nepalese diet and because of increased exposure to infections (17). The present study was conducted to examine the efficacy of daily zinc (25 mg) supplementation for 3 wk in restoring night vision among night-blind pregnant women who were receiving vitamin A, ß-carotene, or placebo as part of a maternal supplementation trial (18). The specific aim of the study was to determine the extent of zinc-responsive night blindness during pregnancy in rural Nepal.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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7000 µg RE) all-trans ß-carotene, or a placebo that did not contain either nutrient. As part of the larger trial, women of reproductive age were visited once every week by locally hired women, who delivered the study supplements, ascertained pregnancy, and, in two-thirds of the study area, elicited a history of night blindness during pregnancy. Women who reported night blindness during pregnancy were randomly assigned to receive 25 mg elemental Zn in the form of zinc gluconate or placebo, once daily, for 3 wk. This dosage of zinc, about twice the recommended dietary allowance for pregnant women, is considered safe and was used in previous studies of zinc supplementation during pregnancy (19, 20). Women were enrolled in the study from April 1997 to January 1998. The sample size required at an expected 5–40% spontaneous (or self-treated) cure rate among placebo recipients and a detectable difference of 30–60% (percentage of those cured in the treatment group - percentage of those cured in the placebo group), with a one-sided type I error of 5% and type II error of 20%, was 20 per group within each of the 3 treatment arms (vitamin A, ß-carotene, and placebo) of the larger trial. Thus, the total number of night-blind women required for the study reported here was 120. Because night blindness occurred less frequently in the vitamin A group than in the other 2 groups, enrollment continued until the sample size requirements were met in the vitamin A group. The study received ethical approval from the Nepal Health Research Council in Nepal and from the Committee on Human Research of Johns Hopkins University, Baltimore.
Assessment of night blindness
A total of 235 women reported night blindness during the 3rd year of the larger trial. Positive histories of night blindness were probed by a more detailed interview about the symptoms of poor vision during the day, at dusk, and at night. Women with inadequate vision during the daytime who reported being night blind (33 of 235, or 14%) received an ophthalmic examination, pupillary testing, and phlebotomy. Women with impaired daytime vision were older (25.4 compared with 23.7 y; NS), had better pupillary thresholds (-0.99 compared with -0.84 log candela/m2; NS), had higher serum retinol concentrations (1.03 compared with 0.87 µmol/L; P < 0.05), and were more frequently myopic (24% compared with 10%; P < 0.05) than those who did not report these problems. Women with impaired daytime vision were considered false-positive cases and were excluded from the study. Women who described poor or inadequate vision in the evening or night, but had adequate daytime vision, were considered eligible cases.
Baseline assessment
After obtaining consent, night-blind women were brought to the project clinic for a baseline assessment that included drawing blood for hemoglobin estimation and later for serum zinc, retinol, and other analyses. Women with anemia (hemoglobin <110 g/L) received a month's supply of iron-folate supplements containing 60 mg Fe and 400 µg folate. Pupillary thresholds were assessed in a dark room by using a prototype scotopic (dim light vision) sensitivity instrument (6). Anthropometric measurements included height, weight, midupper arm circumference, and triceps and subscapular skinfold thicknesses (21). A 7-d morbidity history and food-frequency recall were done, and data on socioeconomic status were collected. An eye examination, performed by an experienced senior ophthalmic assistant, included measurement of visual acuity and intraocular pressure, as well as examination of the anterior segment and the fundus by indirect ophthalmoscopy.
Study assignment
Of the 202 eligible women, 74, 48, and 80 women in the ß-carotene, vitamin A, and placebo groups of the larger trial reported becoming night blind. After the baseline examination, women were individually randomly assigned in blocks of 8 to receive either zinc or placebo, within each of the 3 supplement groups of the larger trial [ie, ß-carotene + zinc, ß-carotene alone, vitamin A + zinc, vitamin A alone (vitamin A + placebo), zinc alone (zinc + placebo), and placebo (2 placebos: one for the vitamin A or ß-carotene study and the other for the zinc study)]. The zinc and placebo tablets were identical in shape, size, and color. Twenty-eight tablets were given to the women in a small bottle with instructions to take one tablet every night before going to bed 2 h after eating dinner. The first tablet was observed being consumed at the clinic.
Follow-up at home
After their visit to the clinic for the baseline assessment, women were visited twice weekly by project staff, who monitored tablet consumption and recorded a history of night blindness for each of the 3–4 preceding days. On the day of the visit, the interviewer counted the remaining tablets in the bottle and asked the women if they had consumed a tablet on each day since the last visit. Thus, daily tablet consumption and night blindness history data were obtained for the 3-wk period of the women's participation in the study. For women who delivered in the 3-wk period of the study, night blindness history and tablet consumption data were obtained up to the day before delivery.
Follow-up at clinic
A follow-up visit was scheduled at the end of 3 wk. Consenting women were transported to the clinic on the 22nd day of their participation in the study. In the event that subjects were unable to come on the 22nd day, they were scheduled 7 d later on the 29th day. Those women who had delivered were not brought to the clinic for the second visit. Women underwent the same procedures (except anthropometry) as at the baseline clinic visit.
Pupillary threshold
The pupillary threshold test has been validated among Asian children (22, 23) and women in this population (6) as an index of vitamin A deficiency. Although this test is responsive to vitamin A supplementation, there is no cutoff established at present for classifying individuals as abnormal or normal. Briefly, at baseline and at follow-up clinic visits, women were dark-adapted for 10 min after their eyes were bleached with a camera flashgun in a dark room. This procedure was followed by measuring the pupillary response to a high-intensity light stimulus (-4.16 to 0.44 log candela/m2) by placing the machine over the subject's left eye, while the right eye was observed with a 2.5x loop under red illumination from a side-mounted light on the machine. The light intensity was increased in short intervals until a pupillary response (quick contraction of the pupil on presenting the stimulus) of the contralateral eye was clearly observed on 2 successive trials. A high pupillary threshold reflects a pupillary response achieved at a greater light intensity and, therefore, is indicative of poorer dark adaptability. All tests were performed by 3 well-trained and standardized examiners. As described previously (6), interobserver and intraobserver reliability tests were carried out, and examiners were certified only after their scores were within 1 unit of the trainer's scores for 10 successive subjects.
Laboratory analysis
Hemoglobin was estimated with the use of a hemoglobinometer (HemoCue Inc, Mission Viejo, CA). All blood samples were collected in evacuated tubes containing no additives (trace-metal-free Vacutainers; Becton Dickinson, Franklin Lakes, NJ). Blood was allowed to sit at room temperature for 30 min before being centrifuged at 1530 x g for 20 min at room temperature to separate the serum. Serum was divided and placed in trace-metal-free cryotubes and was stored and transported under liquid nitrogen to Johns Hopkins University, after which it was stored at -70°C until analyzed. Serum was analyzed for total zinc by use of atomic absorption spectrophotometry (model 3100; Perkin-Elmer, Norwalk, CT). Retinol and carotenoids were analyzed by using Craft's (24) reversed-phase HPLC method (System Gold, Beckman Instruments, Fullerton, CA). Both assays were standardized by using standard reference materials (SRMs) of known retinol (1.033 ± 0.045 and 3.11 ± 0.31 µmol/L, SRM968b) and zinc (0.89 ± 0.06 µg/g, SRM1598) concentrations. Serum RBP was analyzed with the use of a rapid enzyme immunoassay developed by the Program for Appropriate Technology in Health (PATH), Seattle, with a monoclonal anti-RBP antibody conjugated to horseradish peroxidase (HRP).
Statistical analysis
We used 2 outcome measures for evaluating the effect of zinc supplementation on night blindness during pregnancy. One measure was the restoration of night vision on the basis of daily histories of night blindness obtained from women, twice weekly, over the 3-wk period of supplementation. The second measure was the change in pupillary response, expressed in log candela/m2, from baseline to follow-up with the use of pupillary threshold scores measured at the clinic. Treatment effects were examined in a subgroup of women who had low serum zinc concentrations (<9.9 µmol/L) at baseline. Previously, zinc therapy given to zinc-deficient (but not all) cirrhotic patients was shown to result in improved dark adaptation (7).
Baseline comparability between the zinc and placebo treatment groups was assessed by using a t test for continuous variables and a chi-square test for categorical variables. Comparisons of changes in serum zinc, retinol, and RBP concentrations and pupillary scores between treatment groups within each group of the larger trial were also done by using t tests. Indicator variables were created for the regression analyses as follows: placebo, zinc alone, ß-carotene alone, vitamin A alone, zinc + ß-carotene, and zinc + vitamin A. Odds ratios (ORs) and 95% CIs were computed to estimate the odds of vision being restored in each category of the indicator variable relative to the placebo group, adjusting for baseline gestational age, pupillary score, and hemoglobin concentration. Only covariates that were statistically significantly associated with the outcome variable were retained in the model. To examine treatment effects on restoration of night vision, we used participation for 
2 wk in the study to allow for a minimum period of time to achieve a beneficial effect of the supplement. Change in pupillary scores was examined first by using t tests and then in a multiple regression analysis by using the indicator variables as the independent variables adjusted for baseline pupillary thresholds among women with low serum zinc at baseline. Data were analyzed with SAS software version 6 (SAS Institute Inc, Cary, NC).
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RESULTS |
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. The highest number of night-blind women was, as expected, found in the placebo group of the larger trial (n = 80), followed by the ß-carotene (n = 74) and vitamin A (n = 48) groups. Night-blind women in the vitamin A and ß-carotene groups were treatment failures, developing night blindness despite receipt of these nutrients before and during pregnancy on a weekly basis. The proportion of women who were followed for a 3-wk assessment ranged between 67% and 80% in the 3 treatment groups in the larger trial. Of the 102 women assigned to receive zinc in the present study, 69% came for the follow-up visit at the clinic, 19% had a live birth before the end of 3 wk of follow-up, 7% refused to continue participating, and 6% went to their mother's home for delivery. In the placebo group, 81% came for the follow-up assessment, 13% of women delivered a baby, and 2% each had a stillbirth, refused to participate, or went to their mother's home for delivery.
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, the baseline characteristics of the subjects were not significantly different between the 2 treatment groups (ie, those receiving zinc and those receiving placebo). Mean age (23–24 y) and gestational age of pregnancy (27 wk) at the time of the onset of night blindness were not different by treatment group. Nutritional status, as reflected by anthropometry, by hemoglobin, and by serum zinc, retinol, and RBP concentrations, and pupillary scores also did not differ between the 2 groups. At baseline, neither socioeconomic status measured by literacy rate nor the proportion of women who had consumed any animal sources of vitamin A in the past week differed between the 2 groups. The proportion of women who received iron–folate supplements to treat anemia (hemoglobin <110 g/L) at baseline also did not differ between the 2 groups.
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The change in serum zinc concentration by treatment allocation (ie, zinc or placebo) among women who underwent both baseline and follow-up assessments is shown in Table 2. There was a significant increase in the mean serum zinc concentrations of women who received zinc. In contrast, zinc concentrations declined slightly in placebo recipients (NS). The increase in serum zinc concentration was larger among women in the ß-carotene and vitamin A groups of the larger trial than in those in the placebo group of the larger trial. The increase in serum zinc in the vitamin A group, although large, was not statistically significant because of the small sample size. Also, the serum zinc concentration increased more with zinc supplementation in women with serum zinc concentrations <9.9 µmol/L at baseline in the vitamin A and ß-carotene groups. No significant effect of zinc supplementation was observed on serum retinol or RBP concentrations (data not shown).
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). There tended to be a small increase in the odds of being cured (OR = 1.7; 95% CI: 0.6, 4.9; NS) among women who received both zinc and vitamin A relative to those who received placebo only. When the analysis was repeated among women with a serum zinc concentration <9.9 µmol/L at baseline who were in the study for 2 wk, the relative odds of night vision being restored was 4-fold higher (95% CI: 1.1, 17.2) among those receiving both zinc and vitamin A than in placebo recipients (Table 3). No such improvement was observed in women taking zinc alone or zinc + ß-carotene.
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). These findings were examined in a multiple linear regression analysis among women with serum zinc <9.9 µmol/L at baseline with the outcome variable being the change in pupillary threshold scores from baseline to follow-up (Table 5). There was an indication of improvement in the pupillary thresholds (by 0.21 log candela/m2; P = 0.09) among women who received zinc + vitamin A relative to those who received placebo only, an improvement that was not observed with either zinc alone or zinc + ß-carotene.
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DISCUSSION |
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Two reasons seem most apparent for not finding a zinc treatment effect. Either the amount of zinc used as treatment (25 mg) was too low or the length of supplementation (3 wk) was too short. The amount of zinc used was almost twice the recommended dietary intake for pregnancy and was used in previous studies of zinc supplementation in pregnancy (19, 20). However, although serum zinc responded significantly to treatment, a high proportion of women continued to have low serum zinc at follow-up (78% at baseline compared with 61% at follow-up in the zinc group). But again, serum or plasma zinc is not a good indicator of zinc status and responds to supplementation only under conditions of extreme deficiency (25). Although 3 wk may be considered too short to allow for adequate turnover of zinc to increase tissue availability, Morrison et al (7) showed that zinc therapy (45 mg) lasting from 1 to 4 wk among zinc-deficient cirrhotic patients resulted in improving their abnormal dark adaptation.
In a subgroup of women who had low serum zinc concentrations at baseline (<9.9 µmol/L), the cure rate of night blindness among those women supplemented with zinc + vitamin A was 4 times higher than that in women receiving placebo only. Similarly, the improvement in pupillary scores was higher (P = 0.09) in women receiving zinc + vitamin A. Because the effects were restricted to women with low baseline serum zinc concentrations and because the rate of loss to follow-up was high, there was limited power to show a statistically significant improvement in dark adaptation in response to zinc supplementation along with vitamin A. However, both indicators of scotopic vision are independent of one another, serving to reinforce our confidence that zinc potentiated the effect of vitamin A in restoring adequate night vision in this subgroup of women with low serum zinc at the outset.
The present study provides, for the first time, dark-adaptation scores among night-blind, pregnant women. Their mean pupillary scores were -0.83 to -0.86 log candela/m2, much worse than the scores of non-night-blind, Nepali, pregnant women receiving placebo (-1.11 log candela/m2) or vitamin A (-1.24 log candela/m2) or of healthy women tested in the United States (-1.35 log candela/m2) (6).
We assumed that it would require 2–3 wk of daily zinc therapy to improve night vision and dark adaptation. However, in women who had an outcome before the completion of 3 wk, the effect of zinc supplementation could not be assessed. The high numbers of births that occurred midway through the study resulted in a reduced sample size of women who had been supplemented for the full 3-wk duration and who had undergone both baseline and follow-up assessments. Those losses to follow-up were unavoidable because night blindness tends to occur late in pregnancy and sometimes close to its termination (1).
Women lost to follow-up had higher gestational age at the time of reporting night blindness and, therefore, were more likely to have an early outcome (Table 6). They had lower serum retinol concentrations and worse pupillary scores and, thus, were probably more likely to respond had they continued to participate. Unfortunately, because women who are more advanced in pregnancy are at a higher risk of night blindness, of lower serum retinol concentrations (1), and of abnormal pupillary scores (6), they are also most likely to have a delivery before the treatment effects of nutrients such as zinc can be tested. Further, because night blindness disappears spontaneously soon after birth (2, 3), the ability to assess restoration of night vision because of zinc or other nutrient supplementation is lost after the baby is born. This inherent problem might continue to be faced in future studies that examine the treatment for night blindness during pregnancy.
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A second mechanism that was previously proposed for the effect of zinc deficiency on night blindness relates to the isomeric conversion of retinal in the retina through an oxidation-reduction reaction that requires 11-cis retinol dehydrogenase, which was thought to be zinc dependent (11). However, this enzyme, classified as a member of short-chained alcohol dehydrogenases (33), is zinc independent (13, 14). Further, a metalloenzyme inhibitor (1 mmol 1,10-phenanthroline/L) of recombinant human 9-cis retinol dehydrogenase (same as 11-cis retinol dehydrogenase) does not inhibit the oxidation of 9-cis retinol (34). It is plausible, however, that, of the numerous other enzymes involved in the visual cycle (15), one or more may be zinc dependent.
The incidence of night blindness in this study population is 12%, one-third of which is unresponsive to vitamin A (5). Of the remaining 4% of night-blind women unresponsive to vitamin A and who had low serum zinc concentrations (75%), the cure rate with zinc supplementation was 77% (OR = 4.3). Thus, 2.3% of the 12% of night-blind women may possibly reflect the burden of night blindness because of combined vitamin A and zinc deficiencies. The remaining 1.7% incidence of night blindness may be attributed to other nutritional and nonnutritional causes. Thus, in this South Asian population, 67% of maternal night blindness can be attributed to vitamin A deficiency alone (5) that can be eliminated with 1000 RE vitamin A/d, whereas 19% of this condition may be due to combined zinc and vitamin A deficiencies, treatable with 25 mg Zn/d along with the equivalent of a recommended daily allowance of vitamin A. The remaining 14% of maternal night blindness may be attributed to other unknown causes.
In conclusion, zinc deficiency appears to be a necessary condition for zinc therapy to have an effect on night blindness. Among zinc-deficient subjects, however, zinc on its own may not resolve night blindness or poor dark adaptation but acts only to potentiate vitamin A in preventing night blindness.
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ACKNOWLEDGMENTS |
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REFERENCES |
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