Abstract

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 β-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/β-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/β-carotene supplementation ameliorates this risk to a large extent. Am J Epidemiol 2000;152:542–7.

Maternal night blindness is marked by impairment in scotopic vision during pregnancy that commonly recurs during repeated pregnancies and occasionally extends into the postpartum period. This ability for vision to adapt under dim illumination depends on efficient retinal rod cell production of a photosensitive pigment, rhodopsin, that requires vitamin A (cis-retinal). Deficiency of vitamin A results in delayed adaptation to the dark and when, sufficiently severe, leads to night blindness. A history of night blindness is easy to obtain when a local term for the condition exists. Although maternal night blindness is widespread among rural populations of South Asia (14), health risks associated with it have only recently become evident. In Nepal, night-blind pregnant women were more likely to be vitamin A deficient, anemic, wasted, and ill than were controls matched for gestational age and season (5, 6). Supplementing women throughout pregnancy with a recommended dietary allowance of vitamin A reduced the incidence of night blindness by approximately 67 percent (7).

Recently, we reported that weekly low-dose vitamin A or β-carotene supplementation of women of reproductive age in a randomized community trial in the Nepalese population reduced maternal mortality by 40 percent (8). The mechanism underlying improved survival is uncertain, although the importance of adequate vitamin A in maintaining epithelial “barrier” integrity and immune competence (911) suggests that changes in infectious morbidity and mortality may play a role. Puerperal morbidity in American women has been associated with both low dietary vitamin A intake and serum retinol concentrations during pregnancy (12). An early report from England showed that women who were given vitamin A during their third trimester through 7 days postpartum had fewer episodes of pyrexia and puerperal sepsis compared with those who did not receive vitamin A (13). More recently, in Indonesia, vitamin A supplementation of pregnant women reduced the frequency of puerperal fever (one definition of infection) at least 1 day during the postpartum period (14).

The many adverse health and nutritional factors associated with maternal night blindness and its recurrence in pregnancy suggest that this condition identifies women who are chronically vitamin A deficient and possibly at increased risk of poor maternal health and survival. We examined the risk of dying during and after pregnancy among those with and those without night blindness during pregnancy in a subgroup of women participating in a vitamin A/β-carotene supplementation trial in Nepal (8).

MATERIALS AND METHODS

Study design and subjects

Subjects for this study were married women aged 13–45 years who participated in a double-masked, placebo-controlled, cluster-randomized trial that assessed the effects of a single weekly dose of vitamin A (7,000 µg retinol equivalents (RE)) and all trans β-carotene (42 mg or approximately 7,000 µg RE) on maternal, fetal, and infant mortality (8). The study was carried out in Sarlahi, a poor, rural district of Nepal located in the southeastern plains bordering India, in a total of 30 village development communities (VDC), which are small subdistricts, each of which comprises nine wards. Briefly, 270 wards were randomized to three treatment groups. Consenting women within these wards were offered their assigned supplements containing vitamin A, β-carotene, or a placebo every week over a 3½-year period by 426 local female staff. Each week, women were asked whether they were pregnant. No confirmatory test was used to validate their report. Once reported to be pregnant, women were interviewed twice during pregnancy and twice during the 6 months after delivery to obtain weekly histories of diet, health, and work activity. Data on their previous pregnancy history and socioeconomic status were also obtained. Pregnancy outcomes, including livebirths, stillbirths, miscarriages, and maternal deaths, were recorded each week.

In 19 of the 30 study VDC, approximately 300 local female staff who distributed study supplements also elicited weekly night blindness histories from women from the time they declared being pregnant until termination of pregnancy (5). Our analyses include data from only these 19 night blindness surveillance VDC.

Supplementation for women of reproductive age in the study area was started approximately 1 year before pregnant women began to be enrolled on July 18, 1994. Pregnancies declared thereafter, for which an outcome was reported by June 29, 1997, were included in this analysis. This allowed a follow-up of at least 12 weeks after the outcome for all pregnancies before the closure of the trial in late September 1997. Women who reported being pregnant for 6 weeks or more, but who did not die or report a livebirth, stillbirth, or miscarriage, were presumed to have had pregnancies that ended as an undetected fetal loss and were included in the analysis. Women who declared being pregnant for less than 6 weeks without an apparent outcome were considered false positives and were excluded from the analysis.

During the course of the study, 11,476 pregnancies were recruited in the night blindness surveillance area. For women who contributed two or three pregnancies to the study (n = 1,033, 9.9 percent), only the last pregnancy and subsequent follow-up period were included in this analysis. Women who reported night blindness for at least 1 week during pregnancy were considered night-blind cases. Survival status was recorded from the time women declared being pregnant (median, 4 months gestation) until the end of the study. The median follow-up time from declaration of pregnancy until the end of the study was 90 weeks (interquartile range, 64–121 weeks), a period that included a follow-up of approximately 70 weeks after a full-term parturition.

A verbal autopsy interview was conducted with the family members of deceased women, usually within 1 month of death, to obtain a history of events and illnesses preceding death. Interviewers and family members were masked to the treatment assignment at the time of the interview. These data were reviewed independently by two physicians (one of whom was a gynecologist) who were also masked to treatment allocation and were unaware of hypotheses related to maternal night blindness. Each reviewer assigned a “proximate” cause of death. A decision about a consensus proximate cause was reached after further discussion between reviewers. Puerperal sepsis as a cause of death in women who died within 6 weeks postpartum was classified as “obstetric.” Death attributed to sepsis after 6 weeks postpartum was classified as “infection related.”

Statistical analysis

As the overall impact of vitamin A and β-carotene on maternal survival was similar (8), these two arms of the trial were pooled in this analysis. Kaplan-Meier survival analysis (15) was used to estimate and compare differences in survival probability of women in four different groups: 1) women with night blindness in the placebo group, 2) women without night blindness in the placebo group, 3) women with night blindness in the combined vitamin A/β-carotene supplement group, and 4) women without night blindness in the combined vitamin A/β-carotene supplement group. Mortality rates were expressed per 100,000 pregnancies. Relative risks and 95 percent confidence intervals were calculated by using the rates in the night-blind women in the placebo group as the reference. Multiple logistic regression analysis was used to examine the association between night blindness and maternal mortality after adjustment for potential confounders such as maternal age, caste, land holdings, and nutritional status assessed by mid-upper arm circumference. Consensus “cause-specific” mortality rates were compared between night-blind and nonnight-blind women by relative risk and 95 percent confidence interval estimation.

Ethical approval

Ethical approval for the study was obtained by the Nepal Health Research Council, Kathmandu, Nepal, and the Joint Committee on Clinical Investigation and the Committee on Human Research at the Johns Hopkins School of Medicine and School of Hygiene and Public Health, respectively, in Baltimore, Maryland. Informed oral consent was obtained from the women before starting supplementation and at each interview. Women were free to withdraw from participation at any time during the course of the study. Supplementation status was not known until the code was broken at the completion of the maternal mortality trial (8).

RESULTS

Table 1 summarizes the number of pregnant women recruited by treatment allocation during the study period. The total number of pregnancies and pregnant women evaluated in this study was 10,422. The incidence of night blindness during pregnancy was highest in the placebo group (10.6 percent), and lower in the β-carotene (8.2 percent) and vitamin A (6.6 percent) groups. Eighty-nine (854 per 100,000 pregnancies) women died during the course of the study. The proportion of women who died in the vitamin A and β-carotene groups was 40 percent lower than that in the placebo group, similar to the parent study (8). A small proportion of women in each group (6–7 percent) was lost to follow-up, and their vital status remained unknown at the end of the study period.

TABLE 1.

Numbers and percentages of pregnancies, cases of night blindness, deaths, and losses to follow-up by treatment group, Nepal, 1994–1997

 Placebo
 
β-carotene
 
Vitamin A
 
Total
 
 No. No. No. No. 
Total pregnancies* 3,413 100 3,294 100 3,715 100 10,422 100 
 1 3,071 89.9 2,948 89.5 3,370 90.7 9,389 90.1 
 2 333 9.8 342 10.4 337 9.1 1,012 9.7 
 3 0.3 0.1 0.2 21 0.2 
Night blind cases 361 10.6 271 8.2 245 6.6 877 8.4 
Deaths 42 1.2 24 0.7 23 0.6 89 0.9 
Lost to follow-up§ 195 5.7 225 6.8 241 6.5 661 6.3 
 Placebo
 
β-carotene
 
Vitamin A
 
Total
 
 No. No. No. No. 
Total pregnancies* 3,413 100 3,294 100 3,715 100 10,422 100 
 1 3,071 89.9 2,948 89.5 3,370 90.7 9,389 90.1 
 2 333 9.8 342 10.4 337 9.1 1,012 9.7 
 3 0.3 0.1 0.2 21 0.2 
Night blind cases 361 10.6 271 8.2 245 6.6 877 8.4 
Deaths 42 1.2 24 0.7 23 0.6 89 0.9 
Lost to follow-up§ 195 5.7 225 6.8 241 6.5 661 6.3 
*

Women contributed varying numbers of pregnancies over the course of the study.

Women who reported night blindness during pregnancy. For those who contributed more than one pregnancy, night blindness history of the last pregnancy was used.

Survival status measured after declaration of pregnancy until the end of the study. For women who contributed more than one pregnancy, survival status was measured after the declaration of the last pregnancy.

§

Women whose survival status was unknown at the end of the study.

There was a statistically significant difference (p < 0.001) in the survival of women who belonged to the four different subgroups (figure 1). Placebo recipients who developed night blindness experienced a nearly fourfold higher mortality (3,601/100,000 pregnancies) than did placebo recipients who did not develop night blindness (950/100,000 pregnancies). Night blindness was also associated with an elevated risk of dying in the vitamin A/β-carotene group (1,163/100,000 pregnancies), but was much lower than among night-blind placebo recipients. Nonnight-blind women who received vita-min A/β-carotene had the lowest rate of death (631/100,000 pregnancies). Differences in survival across the latter three groups were not statistically significant, however.

FIGURE 1.

Survival of women by night blindness status during pregnancy and treatment allocation, Nepal, July 1994 to September 1997. p < 0.001 based on Kaplan-Meier survival analysis. XN, night blind; PL, placebo; VA/BC, vitamin A/β-carotene.

FIGURE 1.

Survival of women by night blindness status during pregnancy and treatment allocation, Nepal, July 1994 to September 1997. p < 0.001 based on Kaplan-Meier survival analysis. XN, night blind; PL, placebo; VA/BC, vitamin A/β-carotene.

With the night-blind women in the placebo group as a reference (relative risk (RR) = 1.0), the RR of dying among nonnight-blind placebo women was 0.26 (95 percent confidence interval (CI): 0.13, 0.55) and 0.32 (95 percent CI: 0.10, 0.91) and 0.18 (95 percent CI: 0.09, 0.36) among women with and those without night blindness, respectively, in the vitamin A/β-carotene group. Control for potentially confounding factors, such as maternal age, caste, mid-upper arm circumference, and land ownership, by logistic regression analysis did not change the results (data not shown).

At every time period from pregnancy through approximately 2 years postpartum, the mortality rate among women who had been night blind during pregnancy was consistently higher than that among nonnight-blind women in the placebo group (figure 2).

FIGURE 2.

Period-specific mortality rate (per 100,000 pregnancies) among women by night blindness status during pregnancy in the placebo group, Nepal, July 1994 to September 1997.

FIGURE 2.

Period-specific mortality rate (per 100,000 pregnancies) among women by night blindness status during pregnancy in the placebo group, Nepal, July 1994 to September 1997.

Proximate causes of death obtained by verbal autopsy and consensus discussion were grouped into infection-related, obstetric, injury-related, and miscellaneous causes (table 2). Overall, night-blind women were significantly more likely to have died of infection-related causes than were nonnight-blind women (RR = 4.99, 95 percent CI: 2.20, 10.58), although mortality due to “obstetric” causes was similar in the two groups. There were seven injury-related deaths in the nonnight-blind group and none among night-blind women. Deaths due to miscellaneous causes, which included those that could not be assigned a cause and those due to chronic illnesses, were more frequent among night-blind than among nonnight-blind subjects, although this difference was not statistically significant.

TABLE 2.

Proximate causes of female death by night blindness status and treatment allocation, Nepal, 1994–1997*

 Infection
 
Obstetric
 
Injury-related§
 
Miscellaneous
 
 No. Mortality rate RR# 95% CI# No. Mortality rate RR 95% CI No. Mortality rate RR 95% CI No. Mortality rate RR 95% CI 
Placebo                 
 Not night blind (n = 3,052) 10 327.6 1.0  229.4 1.0  163.8 1.0  196.6 1.0  
 Night blind (n = 361) 1,939.6 5.92 1.91, 7.22 554.0 2.42 0.24, 12.69    554.0 2.82 0.28, 15.7 
Vitamin A/β-carotene                 
 Not night blind (n= 6,493) 14 215.6 1.0  20 308.0 1.0  30.8 1.0  77.0 1.0  
 Night blind (n = 516) 775.2 3.59 0.86, 11.45 193.8 0.63 0.02, 3.93    193.8 2.52 0.05, 22.5 
Total                 
 Not night blind (n = 9,545) 24 251.4 1.0  27 282.9 1.0  73.3 1.0  11 115.2 1.0  
 Night blind (n = 877) 11 1,254.3 4.99 2.20, 10.58 342.1 1.21 0.23, 3.93    342.1 2.96 0.53, 11.24 
 Infection
 
Obstetric
 
Injury-related§
 
Miscellaneous
 
 No. Mortality rate RR# 95% CI# No. Mortality rate RR 95% CI No. Mortality rate RR 95% CI No. Mortality rate RR 95% CI 
Placebo                 
 Not night blind (n = 3,052) 10 327.6 1.0  229.4 1.0  163.8 1.0  196.6 1.0  
 Night blind (n = 361) 1,939.6 5.92 1.91, 7.22 554.0 2.42 0.24, 12.69    554.0 2.82 0.28, 15.7 
Vitamin A/β-carotene                 
 Not night blind (n= 6,493) 14 215.6 1.0  20 308.0 1.0  30.8 1.0  77.0 1.0  
 Night blind (n = 516) 775.2 3.59 0.86, 11.45 193.8 0.63 0.02, 3.93    193.8 2.52 0.05, 22.5 
Total                 
 Not night blind (n = 9,545) 24 251.4 1.0  27 282.9 1.0  73.3 1.0  11 115.2 1.0  
 Night blind (n = 877) 11 1,254.3 4.99 2.20, 10.58 342.1 1.21 0.23, 3.93    342.1 2.96 0.53, 11.24 
*

No information was available for two deaths in the night blind group and one death in the not-night blind group. Mortality rate expressed per 100,000 pregnant women.

Includes gastroenteritis (n =5), sepsis (n = 3), tuberculosis (n = 11), other respiratory infections (n = 6), hepatitis (n = 3), leishmaniasis (n = 5), meningitis (n = 1), and typhoid (n = 1).

Includes antepartum and postpartum hemorrhage (n = 7), puerperal sepsis (n = 7), retained placenta (n = 4), obstetric shock (n = 5), and eclampsia (n = 7).

§

Includes drowning, hanging, suicide, burns, and snake bites (n = 7).

Includes uncertain causes of death (n = 8), chronic illnesses, such as asthma (n = 3), breast cancer (n = 1), leukemia (n = 1), and perforated ulcer (n = 1).

#

RR, relative risk; CI, confidence interval.

DISCUSSION

We previously reported a 44 percent reduction in mortality related to pregnancy due to weekly supplementation of women of reproductive age with vitamin A or β-carotene in amounts that approximated recommended dietary levels (8). In a night blindness surveillance area, we explored the risk of death among women who developed night blindness during pregnancy compared with those who did not, across supplement groups. Our results show that night-blind women were at a significantly higher risk of dying for up to approximately 2 years after pregnancy declaration, which entailed an average of 1.3 years of postpartum follow-up, compared with women who did not have night blindness during pregnancy. Continuous, weekly supplementation for women with normal dietary amounts of vitamin A/β-carotene markedly reduced this risk.

The highest risk of mortality was observed among women with night blindness assigned to the placebo group. The risk of death was much lower among night-blind women assigned to receive vitamin A/β-carotene, which approximated those who were never night blind and received either a placebo or vitamin A/β-carotene, who experienced the lowest apparent risk of all. Both not having night blindness and being supplemented with vitamin A/β-carotene were associated with a lower risk of dying. Having night blindness, however, was associated with an apparent excess risk of dying that was not counteracted fully by supplementation. Night blindness during pregnancy is associated with multiple adverse factors, including protein-energy malnutrition, anemia, and infectious and reproductive morbidity (5). These factors may act alone or in concert with vitamin A deficiency to increase the risk of mortality.

This analysis raises the question of why women assigned to the vitamin A/β-carotene group have a lower risk of mortality but still experience night blindness during pregnancy. In the same trial, we have shown that vitamin A supplementation reduced the incidence of night blindness during pregnancy by 67 percent among women who received 95–100 percent of all their eligible weekly vitamin A supplements throughout pregnancy (7). It is possible that the dosage of vitamin A used (7,000 µg RE per week) and the level of compliance achieved in this study, while adequate for reducing mortality in women (8), were inadequate for eliminating night blindness during pregnancy. Furthermore, although β-carotene supplementation had a strong mortality impact (8), it was less effective in reducing the incidence of night blindness during pregnancy (7) or improving serum retinol concentrations in pregnant women (8). Early experimental studies showed that giving small amounts of vitamin A to deficient rats could prevent death without repleting tissues or alleviating other signs of vitamin A deficiency (16). Among Nepalese children who experienced a 30 percent lower mortality due to receipt of large doses of vitamin A every 4 months, incidence of night blindness was reduced by only 69 percent (17).

Infections as proximate causes of death were significantly more frequent among women with night blindness compared with those who had not been night blind during pregnancy (mortality rate, 1,368 vs. 314 per 100,000), suggesting that chronic moderate-to-severe vitamin A deficiency was strongly associated with infection-related mortality in women. Deaths attributed to sepsis, gastroenteritis, tuberculosis, and other respiratory illnesses were more likely to occur among women who had night blindness during pregnancy. Night blindness during pregnancy appears to be a valid indicator of acute risk of death, not only during and immediately after pregnancy, but also for a period of time extending to 1 year and beyond the end of pregnancy.

The burden of maternal mortality is still very high in the developing world (18), and while malnutrition is widely attributed as an underlying cause, very little is understood regarding its contribution and mechanisms. A recent study has shown, for the first time, the relevance of improved vitamin A or β-carotene intakes in preventing maternal mortality in a setting where vitamin A deficiency is endemic and access to antenatal and obstetric care is poor (8). In this study, we show that an easily measurable indicator of vitamin A deficiency manifest among pregnant women is associated with an excessive long-term risk of maternal death, especially from infection. This risk, which one might think is caused by multiple deficiencies and other adverse conditions associated with night blindness, was largely reversed by vitamin A/β-carotene supplementation that approximated normal dietary levels.

Reprint requests to Dr. Parul Christian, Johns Hopkins School of Hygiene and Public Health, Division of Human Nutrition, Room 2041, 615 N. Wolfe Street, Baltimore, MD 21205.

This study 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 Blindness Prevention (Nepal Netra Jyoti Sangh), Kathmandu, Nepal, supported under Cooperative Agreement HRN-A-00-97-00015-00 between the Johns Hopkins University, Baltimore, MD, and the Office of Health and Nutrition, US Agency for International Development, assisted by Task Force Sight and Life, Roche, Basel, Switzerland, and the Sushil Kedia Foundation, Hariaun, Sarlahi, Nepal.

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