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The Journal of Nutrition Vol. 128 No. 9 September 1998,
pp. 1458-1463
-Carotene Supplementation Reduces but Does Not Eliminate Maternal Night Blindness in Nepal1
Center for Human Nutrition, Department of International Health, School of Hygiene & Public Health, Johns Hopkins University, Baltimore, MD 21205 and * Nepal Intervention Project Sarlahi-NNIPS, The National Society for Eye Health and Blindness Prevention, Nepal Eye Hospital Complex, Tripureswor, Kathmandu, Nepal
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ABSTRACT |
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Abstract
Introduction
Methods
Results
Discussion
References
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We investigated the effect of supplementing women weekly with 7000 µg retinol equivalents as preformed vitamin A or 
-carotene vs. a placebo, on the incidence of night blindness during pregnancy and the postpartum period in the rural plains of Nepal. Over a period of ~3 y, ~29,000 women of child-bearing age, living in 171 wards that were randomized to one of the three supplements, contributed 9932 first pregnancies. A prospective, weekly surveillance identified night blindness in pregnant women, verified further by detailed questioning about nighttime vision. After delivery, women were also interviewed at ~3 and ~6 mo postpartum to elicit a night blindness history over the preceding 3 mo. Vitamin A supplementation reduced the incidence of night blindness during pregnancy from 10.7% among controls to 6.7% (relative risk 0.62, 95% confidence interval: 0.45-0.85). -Carotene supplementation had less of an effect (0.83, 0.63-1.11). Among women who took >95% of their vitamin A supplements during pregnancy, incidence of verified night blindness was reduced by 67%. Incidence (per 100 person-years) of night blindness during the first 3 mo postpartum was 11.3 in the control, 4.3 in the vitamin A and 8.7 in the -carotene groups, yielding corresponding relative risks of 0.38 (0.26-0.55) and 0.77 (0.57-1.04). In the second 3 mo postpartum, both vitamin A and -carotene reduced night blindness by ~50%. Vitamin A intakes approaching a recommended amount for pregnancy markedly reduced but did not eliminate night blindness in Nepali women. Greater intakes of vitamin A than provided and/or other nutrients may be needed to prevent maternal night blindness in rural South Asia.
-carotene ·
Nepal
Maternal night blindness is receiving increased attention by the nutrition community as evidence accumulates to show that it occurs widely in South and South-East Asia. Studies in Nepal have revealed important facets of this largely ignored and underreported illness. Specifically, recent population surveys report that 10-20% of pregnant women and 6% of lactating women experience night blindness (Demographic Health Surveys 1997, Katz et al. 1995 A randomized, double-masked community trial was conducted in Sarlahi District, located in the south-eastern plains of Nepal, from March 1994 to October 1997. Thirty village development communities (VDC)3 with nine wards in each, participated in the trial. Each week, 7000 µg retinol equivalents (RE) of vitamin A, as either retinyl palmitate or Selection criteria.
Only women in their first pregnancies enrolled in the trial who had an outcome by the first week of April 1997 (formal closeout for pregnancy outcomes in the trial) were included in the analysis. Also, women with eligible pregnancies had to have met the following criteria: 1) declared being pregnant for at least 4 wk, 2) been asked about night blindness for Statistical analysis.
General characteristics of the eligible pregnant women across the three treatment groups were compared by ANOVA and chi-square tests, as appropriate, employing a 5% Type I error to define significance. The incidence rate of night blindness during pregnancy was calculated by dividing the number of pregnant women with a positive history ("cases") by the total number of pregnant women for each treatment group. Relative risks (RR) and 95% confidence intervals (CI) were calculated using the ratio of the incidence rate of night blindness in the vitamin A or Pregnant women in the three randomized groups were comparable with regard to demographic, socioeconomic, nutritional and other characteristics (Table 1). Slightly more women in the vitamin A group were poorer than in the other two groups. Most differences were small and were significant because of the large sample size. Fifty to sixty percent of women had eaten any preformed sources of vitamin A or dark green leaves, but only 30-40% had eaten any yellow fruits and vegetables in the previous week. Strenuous work (e.g., working in the fields or carrying firewood) was reported by 15-20% of women. Almost 30% of the women had smoked cigarettes and 8-13% had drunk alcohol in the previous week.
The occurrence of night blindness during pregnancy was high in this Nepali population as indicated by an incidence rate of 11 cases per 100 pregnancies for groups without intervention. Because women were often not observed for their entire pregnancy, the observed incidence rates may underestimate actual rates during pregnancy. These data reveal, as previously reported (Katz et al. 1995
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
, Linehan et al. 1996). Rural women consider night blindness to be a severe condition of pregnancy and find it deletorious to their daily work activities (Christian et al. 1998a). Night-blind pregnant women are significantly vitamin A-deficient relative to nonnight-blind controls and also face other nutritional and health risks such as wasting malnutrition, anemia and reproductive morbidity (Christian et al. 1998c). In this paper, we examine the efficacy of a weekly, low dose supplement of vitamin A or -carotene in reducing the incidence of night blindness during pregnancy and the postpartum period in Nepal where such an intervention has demonstrated a reduction in pregnancy-related mortality (West et al. 1997).
MATERIALS AND METHODS
Abstract
Introduction
Methods
Results
Discussion
References
-carotene (42 mg), or a placebo was given to married women 12-45 y of age (n = ~44,000) to assess the effect on fetal loss, and infant and maternal mortality. Randomization to the three treatment arms was done by ward. From September 1994, a weekly surveillance was set up to identify night-blind pregnant women in 19 of 30 VDC (171 wards with ~29,000 women), allowing us to measure the effect of vitamin A or -carotene supplementation on the incidence of maternal night blindness. It was hypothesized that weekly vitamin A or -carotene supplementation before and during pregnancy would reduce the occurrence of night blindness during pregnancy and the postpartum period. With a sample size of 3200 per group, there was adequate power (80%) to detect a decrease of >20% in the incidence of night blindness, without any consideration for design effect.
-carotene in their respective (masked) treatment arms. A few women who were not reportedly night blind at the time of interview, but reported a recent episode that disappeared either with self-treatment or spontaneously, were also considered "verified." Among women delivering a live birth, histories of night blindness for the previous 3 mo were obtained at the 3- and 6-mo postpartum home visits by trained interviewers. At the 3-mo postpartum interview, cases were also asked about the number of days after delivery when they developed the condition.
1 wk and 3) survived the pregnancy. A total of 9932 women over a pregnancy enrollment period of ~3 y were eligible, based on the above criteria, and formed the cohort for the present analysis. Of these, 868 women reported being night blind at least once during their pregnancy.
-carotene group to the placebo group (Kahn and Sempos 1989). The confidence intervals were inflated by ~15% (in their natural logarithm) to adjust for clustering of night blindness using the overdispersion from a binomial regression to estimate the design effect (Katz et al. 1988, McCullagh and Nelder 1989). Incidence rates and RR were also calculated stratified by compliance to the supplement. Design effect-adjusted CI were calculated separately for each stratum of compliance.
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
View this table:
Table 1.
General characteristics of pregnant women
(at mid-pregnancy) by treatment group in the
night blindness study area
-carotene groups (Table 2). This yielded RR (95% CI) of 0.62 (0.45-0.85) and 0.84 (0.63-1.11), or 38 and 16% reductions in night blindness with vitamin A and -carotene supplementation, respectively. Interviewer-verified rates of night blindness were slightly lower but associated with stronger protective effects, with RR (95% CI) of 0.49 (0.33-0.72) in the vitamin A group and 0.73 (0.52-1.03) in the -carotene group. This suggests that misclassification of night blindness from histories elicited by local supplement distributors weakened the estimated efficacy of vitamin A or -carotene by 11-13% in this population. The higher effect of vitamin A vs. -carotene supplementation was not significant for either unverified (RR = 0.74, 95% CI = 0.63-0.88) or verified night blindness (RR = 0.62, 95% CI = 0.62-0.86).
View this table:
Table 2.
Effect of maternal vitamin A and -carotene supplementation on the incidence of night blindness during pregnancy
65% compliance, there was no apparent protection from night blindness with vitamin A supplementation as shown by a RR of ~1.0. A similar analysis of -carotene resulted in a small increase in the protective effect of -carotene among high (96-100%) compliers, but the 95% confidence interval about the RR did not exclude 1.0.
View larger version (14K):
[in a new window]
Fig 1.
Incidence of night blindness in pregnant women by level of compliance to vitamin A and placebo supplements during pregnancy. Relative risks of night blindness in the vitamin A group compared with the placebo group for each compliance stratum are given above the bars; *95% confidence interval (corrected for design effect) excludes 1.0.
-carotene, verification did not appear to improve its efficacy; the RR estimated among those with 96-100% was 0.72, almost identical to the RR estimate of 0.73 observed on average.
View this table:
Table 3.
Incidence of verified cases of night blindness in pregnant women by compliance to vitamin A and placebo supplements during pregnancy
-carotene groups (26 wk) (Table 4). Episodes also lasted longer in the placebo (5.0 wk) than vitamin A (3.7 wk) and -carotene groups (4.4 wk).
View this table:
Table 4.
Onset and duration of night blindness during pregnancy in women according to treatment group
-carotene groups, yielding corresponding RR (95% CI) of 0.38 (0.26-0.55) and 0.77 (0.57-1.04) (Table 5). The risk of night blindness was the highest in the first 30 d after delivery (Fig. 2). It was halved in mo 2 and dropped further in mo 3 postpartum. Vitamin A supplementation significantly reduced the risk of night blindness during all three time periods. The early 1-mo specific risk of night blindness in the -carotene group was lower than that of the placebo group, but this difference was not significant. The incidence rate (per 100 person-years) in the second 3-mo postpartum was lower, i.e., 7.1 in the placebo group, 3.6 in the vitamin A group and 3.2 in the -carotene group. Both vitamin A and -carotene supplementation reduced night blindness in the second 3 mo by ~50%.
View this table:
Table 5.
Effect of vitamin A and -carotene supplementation on night blindness during the postpartum period
View larger version (15K):
[in a new window]
Fig 2.
Incidence of night blindness by number of days postpartum in women receiving placebo, vitamin A and -carotene supplements. Relative risks of night blindness in the vitamin A and -carotene groups compared with the placebo group for each stratum of postpartum days are given above the bars; *95% confidence interval (corrected for design effect) excludes 1.0.
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
), that maternal night blindness is a problem of public health significance in the rural plains of Nepal. Serum retinol concentrations available for 117 verified night-blind women and their 117 matched controls in groups without intervention were strongly associated with night blindness (Christian et al. 1998c), providing evidence of the validity of maternal night blindness histories in a subsample of women.
, Sommer and West 1996). We used a weekly dosage that provided slightly more than 1 recommended dietary allowance (RDA) (for periods of pregnancy and lactation) of vitamin A (7000 µg RE). This dosage may not have been adequate to prevent night blindness during pregnancy even for 33% of interviewer-verified cases among the highest compliers. The current WHO recommendation for treating women of reproductive age with night blindness or Bitot's spots is 1501-3003 µg RE of vitamin A/d or 7507 µg RE/wk for at least 4 wk (WHO 1997), although to our knowledge, there have been no trials demonstrating the efficacy of these regimens in doing so. The latter weekly recommendation is similar to the prophylactic dosage used in this study. Although our findings do not relate to treatment, they suggest a need to re-evaluate the treatment recommendation and possibly revise it upward to maximize efficacy and to prevent relapse among vitamin A-responsive cases.
). The late onset of night blindness in pregnancy suggests that fetal demands on maternal vitamin A stores late in gestation may exacerbate a chronic, low vitamin A status in women. Findings of a previous case-control study in this population showed a dramatic difference in the serum retinol level of women with and without night blindness during pregnancy (0.72 vs. 1.03 µmol/L). Fifty-two percent of cases vs. 21% of controls had a serum retinol concentration <0.7 µmol/L (Christian et al. 1998c). High levels of infection may also contribute to an increased demand for vitamin A and a consequent lowering of vitamin A status during pregnancy. In Nepal, night blind women were at a 14-fold higher risk of diarrhea in the past week (Christian et al. 1998b). An acute phase protein response in pregnant women with diarrhea was associated with a 0.54 µmol/L decrease in the serum retinol level, suggesting that infection-induced hyporetinolemia may further predispose women to night blindness during pregnancy, especially in those already vitamin A deplete (Christian et al. 1998b).
, Smith 1980) and is believed to be widespread (Caulfield et al. 1998), may contribute to night blindness of pregnancy. In the retina, retinol is converted to retinal, the form required to synthesize the photosensitive pigment rhodopsin, through a reaction requiring a zinc-dependent retinol dehydrogenase (Huber and Gershoff 1975). Zinc deficiency could inhibit this reaction and result in abnormal dark adaptation or night blindness. Zinc is also required for retinol-binding protein synthesis; thus, its deficiency could impair vitamin A transport (Duncan and Hurley 1978, Mejia 1986). In pregnancy, maternal plasma zinc starts to decrease as early as 6 wk of gestation and continues to decline until delivery (Tamura and Goldberg 1996). Fetal demands on zinc appear to accelerate, especially in the third trimester of pregnancy (Reifen and Zlotkin 1993), which could in part underlie both an increased risk of night blindness at this stage of gestation as well as its partial nonresponsiveness to vitamin A, as seen in this study. Riboflavin deficiency has also been associated with night blindness in adults (Venkataswamy 1967). These studies suggest that multiple nutrient supplementation or a more varied diet may be required to prevent maternal night blindness.
-carotene supplementation, given at presumed retinol equivalency, was not as efficacious as vitamin A in either reducing night blindness or improving circulating retinol levels during pregnancy (West et al. 1997). This may have been because -carotene did not efficiently convert to vitamin A in this undernourished population. Factors such as intestinal helminths, protein-energy malnutrition and deficiencies of zinc, iron and vitamin A could influence the conversion of -carotene to retinol (Erdman et al. 1993). -Carotene may also be redirected for other immunoregulatory (Prabhala et al. 1991) and antioxidant functions (Allard et al. 1994) that are independent of its role as provitamin A.
-carotene appeared to be higher during the postpartum period. Although the requirements of vitamin A are greater in lactation than in pregnancy (NRC 1989), the risk of night blindness in breastfeeding populations has been reported to be higher during pregnancy (Katz et al. 1995, Malyavin et al. 1996). Factors such as plasma volume expansion of pregnancy (Kelner et al. 1969, McGanity et al. 1954), which can lower maternal plasma retinol over the course of the pregnancy, and favored partitioning of vitamin A toward fetal tissues in women with marginal or low serum retinol levels (Butte and Calloway 1982, Gebre-Medhin and Vahlquist 1984, Shirali et al. 1989) may make women more vulnerable to vitamin A deficiency during late pregnancy than lactation. Pregnancy may also be a unique state during which other etiologies such as zinc deficiency could influence dark adaptation. Local cultural practices promoting better diets in the postpartum period relative to the pregnancy period could also explain a lower incidence of night blindness during lactation.
) may be high in the first month. In the second 3 mo of lactation, the incidence of night blindness was lower, and vitamin A and -carotene supplements had a similar relative effect on its occurrence. Several countries, including Nepal, have recently adopted a policy to dose women with 60,060 µg RE of vitamin A within the first 6 wk of delivery to improve the health and status of infants. Although this policy remains to be implemented nationally in Nepal, it may have a potential benefit on preventing the maternal night blindness that occurs in the first few months after birth.
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FOOTNOTES |
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Manuscript received 18 February 1998. Initial reviews completed 22 March 1998. Revision accepted 26 May 1998.
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ACKNOWLEDGMENTS |
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This study was done in 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, supported under Cooperative Agreement DAN 0045-A-00-5094-00 between the Johns Hopkins University, Baltimore, MD and the office of Health and Nutrition, U.S. Agency for International Development (USAID), assisted by Task Force Sight and Life, Basel, Switzerland and the Sushil Kedia Foundation, Hariaun, Sarlahi, Nepal. We thank members of the Nepal Nutrition Intervention Project-Sarlahi in Nepal (beyond the authors) for their assistance in the conduct of this study, especially R. Adhikari, S. M. Dali, R. P. Pokhrel and R. J. Stoltzfus; D. N. Mandal, T. R. Shakiya, G. Subedi, U. Shankar, A. Bhetwal and D. B. Khadka.
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Abstract
Introduction
Methods
Results
Discussion
References
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K. P West Jr, J. Katz, S. K Khatry, S. C LeClerq, E. K Pradhan, S. R Shrestha, P. B Connor, S. M Dali, P. Christian, R. P Pokhrel, et al. Double blind, cluster randomised trial of low dose supplementation with vitamin A or beta carotene on mortality related to pregnancy in Nepal BMJ, February 27, 1999; 318(7183): 570 - 575. [Abstract] [Full Text]
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