Cigarette smoking during pregnancy in rural Nepal. Risk factors and effects of beta-carotene and vitamin A supplementation.

OBJECTIVE: We examined risk factors of smoking and the association between smoking and pregnancy-related and 6-month infant mortality in rural Nepal, where 30% women reported smoking during pregnancy. DESIGN: Cross-sectional analysis of risk factors associated with smoking status and health consequences of smoking, using prospective data collected as part of a randomized community trial to examine the effect of maternal vitamin A or beta-carotene supplementation on maternal mortality. SETTING: Rural, southeastern plains of Nepal. SUBJECTS AND METHODS: A total of 17 767 women contributed at least one pregnancy during 3.5 y of the study. Data on cigarette or bidi (rolled tobacco) smoking were collected using a 7-day recall, twice during pregnancy. Associations between smoking status and maternal diet, morbidity profile, household socioeconomic status and serum concentration of retinol, carotenoids and tocopherols were examined. Further, relative risk (RR) and 95% confidence intervals (CI) were calculated to estimate supplement effects on pregnancy-related mortality, stratified by smoking status during pregnancy. RESULTS: Smokers were more likely to be older, illiterate and poor compared to nonsmokers. Fruit and vegetable consumption among smokers and nonsmokers did not vary. However, smokers were more likely to consume meat/fish/eggs and less likely to consume milk than nonsmokers. They were also more likely to report symptoms of vaginal bleeding, edema, severe headache and convulsions during pregnancy relative to nonsmokers. Mortality per 100,000 pregnancies appeared to be higher among smokers than nonsmokers in the placebo group (915 vs 584, RR=1.57, 95% CI: 0.80-3.08). beta-Carotene supplementation reduced pregnancy-related mortality both among smokers (RR=0.31 95% CI: 0.11-0.89) and nonsmokers (RR=0.41, 95% CI: 0.19-0.89). Similar results obtained with vitamin A supplementation were not statistically significant. Infant mortality up to 6 months was approximately 30% higher among smokers compared to nonsmokers in the placebo group both before and after adjusting for confounding factors. Neither supplement given to women reduced infant mortality. CONCLUSIONS: Cigarette smoking during pregnancy is associated with an increased risk of maternal and infant mortality in rural Nepal. beta-Carotene and to some extent vitamin A may reduce the risk of pregnancy-related mortality, but not infant mortality, among both smokers and nonsmokers.

Twinning rates and survival of twins in rural Nepal.

BACKGROUND: Twin pregnancies are common but there are few data on rates of twinning or survival of liveborn twin infants in developing countries. METHODS: The rates of multiple births were calculated in a population-based cohort of married women of childbearing age who were enrolled in a randomized community trial to assess the impact of vitamin A or beta-carotene on maternal and infant health and survival. RESULTS: The rate of twinning was 16.1 per 1000 pregnancies (7.4 if only twin pregnancies resulting in two liveborn infants were used). The rate for triplets and quadruplets was 0.19 and 0.06 per 1000 pregnancies. Twinning rates were higher among women of higher parity, but were not associated with maternal age. Twinning rates among twins where at least one was live born (or increased in utero survival) were 30% (95% CI : -1%, 71%) and 44% (95% CI : 9%, 89%) higher among women receiving vitamin A and beta-carotene supplements than placebo, after adjusting for maternal age, gestational age, and parity. The perinatal mortality rate was 8.54 times higher for twins than singletons, 7.32 higher for neonatal mortality, and 5.84 higher for cumulative 24-week mortality. This difference was reduced but not erased by adjusting for gestational age. No difference in survival of liveborn twin infants was seen by supplement group. A higher mortality rate among male twins was largely explained by gestational age. CONCLUSIONS: Multiple births are relatively common occurrences in rural Nepal, and carry a much higher mortality risk for the infants than for singletons. Vitamin A or beta-carotene supplementation appeared to increase the rate of twinning, or improve the survival of twins in utero, but did not increase twin survival after birth.

Zinc supplementation might potentiate the effect of vitamin A in restoring night vision in pregnant Nepalese women.

BACKGROUND: Zinc deficiency may result in abnormal dark adaptation or night blindness, a symptom primarily of vitamin A deficiency. During a placebo-controlled trial in Nepal, weekly vitamin A supplementation of women reduced but failed to eliminate the incidence of night blindness during pregnancy, suggesting a role for zinc. 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, beta-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, beta-carotene, or placebo receipt, to receive 25 mg Zn or placebo daily for 3 wk. Thus, the 6 groups studied were as follows: beta-carotene + zinc, beta-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 beta-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 micromol/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.

Maternal night blindness increases risk of mortality in the first 6 months of life among infants in Nepal.

Night blindness occurs commonly among women during pregnancy in rural NEPAL: We examined the relationship between maternal night blindness and the risk of mortality occurring among infants in the first 6 mo of life. Stratified analysis by maternal night blindness status during pregnancy was done for 10,000 women participating in a randomized, placebo-controlled trial of vitamin A and beta-carotene supplementation. Mortality of infants of non-night blind women in all three supplementation groups was similar, and when combined, was 63/1000 live births. Relative to this, mortality was higher by 63% [95% confidence interval (CI): 9-138%) and 50% (95% CI: -3 to 133%) among infants of night blind women receiving placebo and beta-carotene, respectively, but only by 14% (95% CI: -33 to 93%) among those receiving vitamin A. Thus, 6-mo mortality was higher among infants of women who had night blindness during pregnancy. Maternal receipt of vitamin A reduced this risk.

Vitamin A or beta-carotene supplementation reduces symptoms of illness in pregnant and lactating Nepali women.

The contribution of nutritional interventions to the reduction in maternal morbidity rates in developing countries is not well known. We assessed the impact of weekly vitamin A and beta-carotene supplementation on the prevalence of pregnancy and postpartum illness symptoms among 15,832 Nepali women in a placebo-controlled, double-masked, cluster-randomized trial. There was no impact of either supplement on morbidity rates reported up to 28 wk of gestation, inclusive. However, in late pregnancy (>28 wk), symptoms of nausea, faintness and night blindness were reduced with vitamin A, but not beta-carotene, supplementation. Vitamin A supplementation shortened the length of labor by 1.5 h 50 min among nulliparous and multiparous women, respectively. Both interventions reduced the postpartum prevalence of at least four loose stools and night blindness. beta-Carotene supplementation also reduced symptoms of high fever postpartum. The mean number of days of any reported illness symptoms was 3-4 per wk throughout pregnancy. Among women receiving vitamin A, the total number of days of illness symptoms accrued over the last 12 wk of pregnancy was lower by 5 d compared with the placebo recipients. We found the burden of pregnancy-related illness symptoms to be high in this rural area of Nepal where antenatal care is poor and most deliveries occur at home. Maternal vitamin A or beta-carotene supplementation resulted in a reduction in the prevalence of selected illness symptoms during late pregnancy, at the time of birth and during 6 mo postpartum, suggesting that a diet adequate in vitamin A may be important for improving women's reproductive health.

Hookworms, malaria and vitamin A deficiency contribute to anemia and iron deficiency among pregnant women in the plains of Nepal.

Anemia and iron deficiency during pregnancy are prevalent in developing countries, but their causes are not always known. We assessed the prevalence and severity of anemia and iron deficiency and their association with helminths, malaria and vitamin A deficiency in a community-based sample of 336 pregnant women in the plains of Nepal. Hemoglobin, erythrocyte protoporphyrin (EP) and serum ferritin were assessed in venous blood samples. Overall, 72.6% of women were anemic (hemoglobin < 110 g/L), 19.9% had moderate to severe anemia (hemoglobin < 90 g/L) and 80.6% had iron deficiency (EP > 70 micromol/mol heme or serum ferritin < 10 microg/L). Eighty-eight percent of cases of anemia were associated with iron deficiency. More than half of the women (54.2%) had a low serum retinol concentration (<1.05 micromol/L), 74.2% were infected with hookworms and 19.8% had Plasmodium vivax malaria parasitemia. Hemoglobin, EP and serum ferritin concentrations were significantly worse and the prevalence of anemia, elevated EP and low serum ferritin was increased with increasing intensity of hookworm infection. Hookworm infection intensity was the strongest predictor of iron status, especially of depleted iron stores. Low serum retinol was most strongly associated with mild anemia, whereas P. vivax malaria and hookworm infection intensity were stronger predictors of moderate to severe anemia. These findings reinforce the need for programs to consider reducing the prevalence of hookworm, malaria infection and vitamin A deficiency where indicated, in addition to providing iron supplements to effectively control anemia.

Night blindness during pregnancy and subsequent mortality among women in Nepal: effects of vitamin A and beta-carotene supplementation.

Night blindness due to vitamin A deficiency is common during pregnancy among women in Nepal. The authors assessed the risk of maternal death during and after a pregnancy with night blindness among women participating in a cluster-randomized, placebo-controlled vitamin A and beta-carotene supplementation trial in Nepal from July 1994 to September 1997. Subjects were 877 women with night blindness and 9,545 women without night blindness during pregnancy. Women were followed from the time they declared that they were pregnant through the end of the study, representing a median follow-up of 90 weeks (interquartile range: 64-121 weeks). Mortality of night-blind women in the placebo group was 3,601 per 100,000 pregnancies. In comparison, the relative risk of dying among nonnight-blind women in the placebo group was 0.26 (95% confidence interval (CI): 0.13, 0.55), and the relative risk among women with or without night blindness in the vitamin A/beta-carotene group was 0.32 (95% CI: 0.10, 0.91) and 0.18 (95% CI: 0.09, 0.36), respectively. Night-blind women were five times (95% CI: 2.20, 10.58) more likely to die from infections than were women who were not night blind. These findings show that night blindness during pregnancy is a risk factor of both short- and long-term mortality among women. Vitamin A/beta-carotene supplementation ameliorates this risk to a large extent.

Maternal low-dose vitamin A or beta-carotene supplementation has no effect on fetal loss and early infant mortality: a randomized cluster trial in Nepal.

BACKGROUND: The effect of vitamin A supplementation on the survival of infants aged <6 mo is unclear. Because most infant deaths occur in the first few month of life, maternal supplementation may improve infant survival. OBJECTIVES: The objective was to assess the effect of maternal vitamin A or beta-carotene supplementation on fetal loss and survival of infants <6 mo of age. DESIGN: Married women of reproductive age in 270 wards of Sarlahi district, Nepal, were eligible to participate. Wards were randomly assigned to have women receive weekly doses of 7000 microg retinol equivalents as retinyl palmitate (vitamin A), 42 mg all-trans-beta-carotene, or placebo. Pregnancies were followed until miscarriage, stillbirth, maternal death, or live birth of one or more infants, who were followed through 24 wk of age. RESULTS: A total of 43559 women were enrolled; 15832 contributed 17373 pregnancies and 15987 live born infants to the trial. The rate of fetal loss was 92.0/1000 pregnancies in the placebo group, comparable with rates in the vitamin A and beta-carotene groups, which had relative risks of 1.06 (95% CI: 0.91, 1.25) and 1.03 (95% CI: 0.87, 1.19), respectively. The 24-wk mortality rate was 70.8/1000 live births in the placebo group, comparable with rates in the vitamin A and beta-carotene groups, which had relative risks of 1.05 (95% CI: 0.87, 1.25) and 1.03 (95% CI: 0.86, 1.22), respectively. CONCLUSIONS: Small weekly doses of vitamin A or beta-carotene given to women before conception, during pregnancy, and through 24 wk postpartum did not improve fetal or early infant survival in Nepal.

Double blind, cluster randomised trial of low dose supplementation with vitamin A or beta carotene on mortality related to pregnancy in Nepal. The NNIPS-2 Study Group.

OBJECTIVE: To assess the impact on mortality related to pregnancy of supplementing women of reproductive age each week with a recommended dietary allowance of vitamin A, either preformed or as beta carotene. DESIGN: Double blind, cluster randomised, placebo controlled field trial. SETTING: Rural southeast central plains of Nepal (Sarlahi district). SUBJECTS: 44 646 married women, of whom 20 119 became pregnant 22 189 times. INTERVENTION: 270 wards randomised to 3 groups of 90 each for women to receive weekly a single oral supplement of placebo, vitamin A (7000 micrograms retinol equivalents) or beta carotene (42 mg, or 7000 micrograms retinol equivalents) for over 31/2 years. MAIN OUTCOME MEASURES: All cause mortality in women during pregnancy up to 12 weeks post partum (pregnancy related mortality) and mortality during pregnancy to 6 weeks postpartum, excluding deaths apparently related to injury (maternal mortality). RESULTS: Mortality related to pregnancy in the placebo, vitamin A, and beta carotene groups was 704, 426, and 361 deaths per 100 000 pregnancies, yielding relative risks (95% confidence intervals) of 0. 60 (0.37 to 0.97) and 0.51 (0.30 to 0.86). This represented reductions of 40% (P<0.04) and 49% (P<0.01) among those who received vitamin A and beta carotene. Combined, vitamin A or beta carotene lowered mortality by 44% (0.56 (0.37 to 0.84), P<0.005) and reduced the maternal mortality ratio from 645 to 385 deaths per 100 000 live births, or by 40% (P<0.02). Differences in cause of death could not be reliably distinguished between supplemented and placebo groups. CONCLUSION: Supplementation of women with either vitamin A or beta carotene at recommended dietary amounts during childbearing years can lower mortality related to pregnancy in rural, undernourished populations of south Asia.

Vitamin A or beta-carotene supplementation reduces but does not eliminate maternal night blindness in Nepal.

We investigated the effect of supplementing women weekly with 7000 microg retinol equivalents as preformed vitamin A or beta-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 approximately 3 y, approximately 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 approximately 3 and approximately 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). beta-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 beta-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 beta-carotene reduced night blindness by approximately 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.

Effects of vitamin A on growth of vitamin A-deficient children: field studies in Nepal.

Inconsistencies have been observed in the impact of vitamin A (VA) supplementation on early child growth. To help clarify this issue, a cohort of 3377 rural Nepalese, nonxerophthalmic children 12-60 mo of age were randomized by ward to receive vitamin A [60,000 microg retinol equivalents (RE)] or placebo-control (300 RE) supplementation once every 4 mo and followed for 16 mo. VA had no impact on annual weight gain or linear growth. However, arm circumference (AC) and muscle area (MA) growth improved in VA recipients, by 0.13 cm and 25 mm2, respectively, over controls. Growth of children with xerophthalmia, who were treated with >/= 120, 000 RE at base line, was also compared to that of nonxerophthalmic children, stratified by initial wasting status, and adjusted for sex, baseline age and measurement status. Among initially nonwasted children (AC >/= 13.5 cm), VA-treated xerophthalmic children (n = 86) gained 0.7 cm more in linear growth than nonxerophthalmic children. Among initially wasted children (AC < 13.5 cm), VA-treated children (n = 34) gained additional weight (672 g), height (approximately 1 cm), muscle (76 mm2) and fat (79 mm2) areas, and subscapular skinfold (1.3 mm) compared to changes observed in nonxerophthalmic children. Relative increments in soft tissue growth occurred within 4 mo of VA treatment, while the effect on linear growth was gradual. Moderate-to-severe VA deficiency, marked by xerophthalmia, is likely to impair normal physical growth, but milder stages of deficiency may not have this effect in rural South Asia.

Mortality of infants < 6 mo of age supplemented with vitamin A: a randomized, double-masked trial in Nepal.

The effect of supplementing 11,918 infants < 1 mo and 1-5 mo of age with vitamin A (15,000 and 30,000 micrograms retinol equivalents or 50,000 and 100,000 IU, respectively) or a placebo on subsequent 4-mo mortality was assessed in a randomized, double-masked community trial in the rural plains of Nepal. There were 130 deaths (51.6/1000 child-y) in the control group and 150 deaths (57.1/1000 child-y) in the vitamin A group, yielding a relative risk of 1.11 (95% CI: 0.86, 1.42), which is indicative of no overall effect on early infant mortality. There was a tendency for the relative risk of mortality among vitamin A recipients to rise with improved nutritional status. These results suggest that distribution of a large oral dose of vitamin A to infants < 5-6 mo of age may not benefit short-term survival. This is in contrast with the results of trials in which older infants and children in this same population were supplemented.

Tolerance of young infants to a single, large dose of vitamin A: a randomized community trial in Nepal.

A randomized, double-masked trial was carried out in rural Nepal to investigate the incidence and severity of acute side-effects among neonates ( < 1 month of age) and infants aged 1-6 months who received a large, oral dose of vitamin A (15,000 retinol equivalents (RE) (50,000 IU) and 30,000 RE (100,000 IU), respectively) or placebo (75 RE (250 IU) and 150 RE (500 IU), respectively) in oil. Infants (vitamin A group, n = 1461; controls, n = 1379) were assessed for vomiting, loose stools, fever, and irritability during the 24 hours before and after dosing. Fontanelles were palpated 24 hours after dosing. Neonates exhibited no excess risk of adverse side-effects after receiving 15,000 RE. Compared with controls the older infants who ingested 30,000 RE had a 1.6% excess rate of vomiting (95% confidence interval (CI): 0.2-3.0%) and a 0.5% excess rate (95% CI: -0.1 to 1.1%) in the occurrence of bulging fontanelles. There were no other significant differences in the older infants. The controlled, periodic distribution of a single 15,000 RE dose of vitamin A therefore confers no apparent acute risk to young infants; a 30,000 RE dose is associated with a minimum risk of transient, acute side-effects.

Efficacy of vitamin A in reducing preschool child mortality in Nepal.

Community trials of the efficacy of vitamin A supplementation in reducing preschool childhood mortality have produced conflicting results. To resolve the question, a randomised, double-masked, placebo-controlled community trial of 28,630 children aged 6-72 months was carried out in rural Nepal, an area representative of the Gangetic flood plain of South Asia. Randomisation was carried out by administrative ward; the vitamin-A-supplemented children received 60,000 retinol equivalents every 4 months and placebo-treated children received identical capsules containing 300 retinol equivalents. After 12 months, the relative risk of death in the vitamin-A-supplemented compared with the control group was 0.70 (95% confidence interval 0.56-0.88), equivalent to a 30% reduction in mortality. The trial, which had been planned to last 2 years, was discontinued. The reduction in mortality was present in both sexes (relative risk for boys 0.77; for girls 0.65), at all ages (range of relative risks 0.83-0.50), and throughout the year (0.76-0.67). The reduction in mortality risk was not affected by acute nutritional status, as measured by arm circumference. Thus, periodic vitamin A delivery in the community can greatly reduce child mortality in developing countries.