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Articles

Vitamin A or ß-Carotene Supplementation Reduces Symptoms of Illness in Pregnant and Lactating Nepali Women¹

Parul Christian^*2, Keith P. West, Jr.^*, Subarna K. Khatry, Joanne Katz^*, Steven C. LeClerq^*, Elizabeth Kimbrough-Pradhan^*, Sanu Maiya Dali^** and Sharada Ram Shrestha

^* Johns Hopkins School of Public Health, Baltimore, Maryland; The National Society for Prevention of Blindness, Kathmandu, Nepal and ^** The National Maternity Hospital, Kathmandu, Nepal

²To whom correspondence should be addressed at Room 2041, 615 N. Wolfe St.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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 ß-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 ß-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. ß-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 ß-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.

KEY WORDS: • illness symptoms • pregnancy and lactation • vitamin A • ß-carotene • humans

	INTRODUCTION

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Maternal death reflects the "tip of the iceberg" of the burden of reproductive illness among women. Every year, an estimated 62 million women in developing countries experience pregnancy-related illnesses, labor and delivery complications, postpartum complications and chronic conditions that result from pregnancy (Koblinsky et al. 1992 ). This translates into a rate of 100 acute episodes per maternal death. Research has focused on potential life-threatening conditions such as hypertension, vaginal bleeding and sepsis during pregnancy but less on more common and less severe conditions such as fever, nausea, vomiting and so on (Liskin 1992 ) that nevertheless can debilitate and affect quality of life. One study of 281 women in rural India reported a high prevalence of such maternal complications in the community (Datta et al. 1980 ).

Given the high coincidence of malnutrition and illness among women in developing countries, it is plausible that nutritional status influences the health and well-being of a woman during pregnancy, at the time of delivery when she is faced with obstetric and infectious risks and later during lactation. However, the extent to which maternal nutritional status before and during pregnancy can affect maternal health and pregnancy outcome is not well understood (Koblinsky 1995 ). A review of the effectiveness of nutritional interventions in the prevention of maternal complications found that certain micronutrients, such as calcium, iron and folate, may have some potential benefit, although more research is required (Kulier et al. 1998 ).

In Nepal, a double-masked, cluster-randomized, placebo-controlled trial showed that weekly supplementation of women of reproductive age with normal dietary levels of vitamin A or ß-carotene could reduce pregnancy-related deaths by 40 and 49%, respectively (West et al. 1999 ). A case-control study nested into this trial found that night blind pregnant women, who were vitamin A deficient, were more likely to have symptoms of urinary and reproductive tract infections (UTI/RTI),³ lower and upper gastrointestinal infections and preeclampsia/eclampsia than were control women (Christian et al. 1998 ), suggesting that vitamin A deficiency during pregnancy may predispose women to pregnancy-related complications.

The present analysis examines the effect of weekly vitamin A or ß-carotene supplementation on self-reported pregnancy and postpartum illness symptoms and labor and delivery complications among Nepali women. We hypothesized that supplementation with either nutrient will reduce pregnancy and postpartum complications and complications of labor and delivery, which could potentially help explain the observed impact on pregnancy-related deaths in this population.

	SUBJECTS AND METHODS

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Study design and protocol

The study was carried out in 270 wards of 30 village development communities (9 wards in each) in Sarlahi District, located in the southeastern plains of Nepal. Within each village development committee, 3 wards were randomized for women aged 12–45 y who were married and living with their husbands to receive 7000 µg retinol equivalents of vitamin A as retinyl palmitate, 42 mg of all-trans ß-carotene or placebo. The treatments were delivered in identical gelatin capsules containing peanut oil and 5 mg of dl--tocopherol as an antioxidant. ß-Carotene was included as an intervention to represent the major form in which vitamin A is consumed in populations of South Asia. Eligible women were enumerated at baseline and enrolled for supplementation into the study after they provided consent. Newly married women were enrolled prospectively throughout the study. The 270 wards were subdivided into smaller units (total of 426) called sectors. In each sector, a local female worker was hired and trained to dose the study participants, record menstrual activity and determine pregnancies on a weekly basis. Dosing with supplements was direct and workers were not allowed to leave supplements behind when women were not at home, but instead they made repeated visits to contact and dose the women. Supplement intake data were recorded each week. The median compliance rate among pregnant women was 80% and was comparable between the three treatment groups (West et al. 1999 ). From July 1994, after 20 wk of supplementation, women who reported being pregnant were enrolled into a protocol of assessment and follow-up. Pregnancy enrollment continued for 3 subsequent y. For the present analysis, women who reported being pregnant in July 1994 or later and had an outcome through March 1997 were included. This allowed all women to be followed to 6 mo postpartum by August 1997, when the study ended. A small proportion of women (9%) contributed more than one pregnancy during the study period. Pregnant women were visited at home on four different occasions for an interview as follows: at enrollment, on average at 12 wk of gestation; 12 wk later, on average at 28 wk of gestation; and at 3 and 6 mo postpartum (in the event of live birth). At each visit, 7-d recall data were collected on morbidity, diet, work activity and the use of alcohol and tobacco products. Data regarding previous pregnancy history and socioeconomic status were also collected.

    Substudy. Three (10%) of the 30 village development communities (27 wards, 9 per treatment group) were selected to carry out a substudy that involved clinic-based examination of women and their infants to assess the impact of supplementation on maternal and infant serum retinol and carotenoid concentrations and infant growth. All consenting women from the selected substudy area were transported to the project clinic at 12 wk of gestation (at enrollment) and at 3 mo postpartum to undergo a clinical examination, anthropometric assessment and venous blood draw. Infant anthropometric measurements were taken at birth and at 3 mo of age. Clinical examination included measurement of blood pressure with a standard sphygmomanometer and of oral temperature with a digital thermometer. The substudy procedures were conducted in addition to the other home-based interviews that were conducted throughout the study area. Data on blood pressure and temperature measurements were used for the present analysis to test the hypothesis that vitamin A or ß-carotene supplementation can reduce hypertension and fever, respectively, among women during pregnancy and lactation.

    Morbidity assessment. The home-based interviews included a 7-d recall of 21 morbidity symptoms. The question asked for each morbidity symptom was, "Have you had (symptom) in the past 7 d?" And if yes, the interviewer asked, "For how many days in the past 7 d did you have (the symptom)?" Although data on the number of days of illness in the 7-d period were collected, the results were similar when illness symptoms were dichotomized or stratified into categories of illness days, in part because there were too few women with more days of complications to examine a dose-response with supplementation. Furthermore, we did not collect data on the total length of illness episodes but rather on the number of days that the subject was ill during the previous 7-d period. Thus, morbidity data for the present analysis were dichotomized into the presence or absence of a symptom.

Interviews were conducted by 30 experienced and trained interviewers. All morbidity terms on the questionnaires were given in the local language and had been previously field-tested. At the 3-mo postpartum interview, women were also asked to report whether they had experienced a limited number of more severe illness symptoms in the 3 mo before and after birth. At the 6-mo postpartum interview, a history of severe illness symptoms was again elicited for the previous 3 mo.

Statistical analysis

Maternal characteristics recorded at pregnancy enrollment were examined by treatment group to assess whether treatment randomization had resulted in comparable groups.

Based on an a priori hypothesis regarding the impact of maternal vitamin A or ß-carotene supplementation on infectious conditions of the urinary/reproductive, gastrointestinal and lower respiratory tracts, as well as conditions such as preeclampsia, clusters of illness symptoms were grouped together to represent each type of complication. Thus, for example, vaginal discharge, lower abdominal pain and painful urination formed a cluster of illness symptoms representing UTI/RTI.

    Morbidity during pregnancy. Women tended to declare their pregnancy at different gestational ages due to being uncertain of whether they were truly pregnant or because they were previously away from home. As a result, their enrollment (and consequent follow-up) pregnancy interviews were conducted at different times of gestation (although this did not vary by treatment group). To overcome this problem and because gestational age is a strong determinant of morbidity prevalence, we combined data from the two pregnancy interviews and stratified them into three categories of gestational age (<12, 13–28 and >28 wk). Women who were administered both pregnancy interviews contributed data to two different categories of gestational age. If women had been interviewed twice during the same gestational age category for the same pregnancy (e.g., enrollment interview at 13 wk and follow-up interview at 25 wk of gestation), data from only the later interview were used to avoid the problem of intraindividual correlation. This occurred in 2737 women across the three categories of gestational ages.

The prevalence of individual and clusters of related morbidity symptoms was calculated in the placebo group. The odds ratio (OR) of experiencing a morbidity symptom in the vitamin A and ß-carotene treatment arms was calculated by logistic regression analysis, with the placebo group as the reference category, and adjustment for gestation of pregnancy within each gestational age category.

As a summary measure, the mean number of days of any reported illness symptom per week was calculated for women within treatment groups by gestational age of pregnancy, aggregated within the three gestational age intervals. In the event of multiple symptoms experienced by women in the same week, the maximum number of days with symptoms was used to calculate the means. The mean days of illness per week within each interval was compared between placebo and the treatment groups using a t test.

    Morbidity in the postpartum period. The two interviews conducted at 3 and 6 mo postpartum were combined because there no differences were found in either the prevalence rates or treatment effects on morbidity. Because women contributed two interviews during the postpartum period, the OR of experiencing individual or clusters of related morbidity symptoms were calculated using a Generalized Estimating Equations logistic regression model to adjust for the intraindividual correlation (Liang and Zeger 1986 ), with placebo as the reference category. The number of weeks postpartum when the interview took place was included as a covariate in the analysis.

The OR of severe illness symptoms during 3-mo intervals before and after the delivery and the OR for the presence of fever and hypertension at enrollment were calculated in the vitamin A and ß-carotene groups compared with the placebo group. The ² and t tests were used to examine differences in the prevalence of labor and delivery complications between treatment groups.

Although 95% confidence intervals around the OR were calculated, only P-values arising from logistic regression analyses are presented. Because both treatments (vitamin A and ß-carotene) were compared against the same placebo group, we used the Bonferroni adjustment for multiple comparisons to adjust the critical of 0.05 (Box et al. 1978 ). Based on this adjustment, a P-value of 0.025 was considered statistically significant. However, comparisons achieving P-values of <0.05 have also been noted.

Ethical approval

Ethical approval for the study was obtained from the Nepal Health Research Council of the Ministry of Health in Kathmandu, Nepal, the Johns Hopkins Joint Committee on Clinical Investigation in Baltimore and the Teratology Society in Bethesda, MD.

	RESULTS

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A total of 43,559 women of reproductive age, who were married and living with their husbands, participated in the study over its duration (Table 1 ). Of these, 1136 (2.6%) either refused to participate or outmigrated after enrollment. In all, 15,832 (36.3%) reported being pregnant at least once from July 1994 and had an outcome by March 1997. These women contributed data on 17,373 pregnancies to the trial; 15,868 experienced a live birth. Women were interviewed during pregnancy and the postpartum periods (Table 1) . A total of 1191 and 1050 clinical assessments (blood pressure and body temperature) were carried out at 12 wk of pregnancy and at 3 mo postpartum, respectively. Loss to follow-up did not vary by treatment group.

Based on a 3-mo recall of selected severe illnesses, both vitamin A and ß-carotene supplementation reduced the prevalence of loose stools and night blindness in the postpartum period (Table 4 ), consistent with 7-d recall histories during this same period (Table 3) . Reported high fever was significantly (P < 0.025) lowered in the first 3 mo of postpartum with ß-carotene supplementation.

The mean number of days of illness with any symptoms ranged from 3 to 4 per wk depending on the gestational duration of pregnancy (Table 7 ). Although supplementation with vitamin A or ß-carotene had no impact on the number of days of reported symptoms in the early part of pregnancy, vitamin A supplementation reduced the mean frequency of illness days after gestational wk 28. The total number of days of illness symptoms accrued during the last 12 wk of pregnancy was 5 d less in the vitamin A group than in the placebo group (35 versus 40 d). The specific illness symptoms that showed a reduction in the mean number of days per week included nausea (by 1.25 d), vomiting (0.5 d), productive cough (1.5 d), faintness (3 d) and night blindness (1.5 d) (all P < 0.025).

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

The burden of illness during and after pregnancy, as reported by women, was high in this rural Nepali population. Women were likely to experience one or more illness symptoms on average 3–4 d/wk throughout pregnancy. Assuming a normal gestational duration of 40 wk (or 280 d) for a pregnancy, this calculates to 120–160 d of illness with one or more of the 21 symptoms. Vitamin A supplementation reduced this burden by 5 d in late pregnancy (>28 wk), a time when illness prevalence increased. The symptoms for which duration of illness was reduced due to vitamin A supplementation were the same ones for which prevalence was reduced. Although the 7-d recall elucidated the number of days of illness within the previous 7-d period, it did not capture the length of episode of illness. However, because women provided 7-d histories of morbidity symptoms during different gestational periods, we were able to construct the overall burden of morbidity across the pregnancy, assuming that the 7-d history provided a "snapshot" of morbidity during that gestational period.

Except for an increase in vaginal discharge, neither vitamin A nor ß-carotene supplementation affected illness in early pregnancy. However, symptoms of nausea, faintness and night blindness were lessened in late pregnancy due to supplement receipt. The incidence of acute lower respiratory tract infection and vaginal bleeding was lower by 30–50% in the third trimester due to supplementation, but the sample size for this low prevalence condition was too small for the difference to achieve statistical significance (P > 0.025). Lowering of some morbidity symptoms in later pregnancy due to supplementation may be related in part to the higher prevalence of vitamin A deficiency observed during later pregnancy as reflected by a higher occurrence of night blindness and lower circulating serum retinol concentration (Christian et al. 1998 ). Both vitamin A and ß-carotene reduced symptoms of lower gastrointestinal infections such as loose stools in the postpartum period on the basis of either 7-d or 3-mo recall data. ß-Carotene supplementation also reduced the prevalence of high fever in the 3 mo after birth. In the substudy, the prevalence of a body temperature of >37.8°C was lowered by 70% with ß-carotene (P < 0.05) and by 57% with vitamin A (P > 0.05) supplementation, although neither reduction was significant (P > 0.025). Daily vitamin A supplementation during pregnancy has been previously shown to reduce fever (one indicator of infection) during the postpartum period in Indonesian (Hakimi et al. 1999 ) and English (Green et al. 1931 ) women.

Supplementation with vitamin A significantly shortened the reported length of labor among both primiparous and multiparous women. Such a finding has not been previously reported but may reflect improved health and feeling of well-being due to supplementation (lower nausea, faintness) among women going into labor. Prolonged or obstructed labor is a major cause of maternal complications (AbouZhar 1998 , Family Health Division 1998 , World Health Organization 1988 ). In settings in which the availability of emergency obstetric care is limited, the potential for vitamin A supplementation to reduce the length of labor, especially among primiparous women, suggests that an adequate vitamin A intake during pregnancy may be an important factor for achieving a normal delivery, although explanatory mechanisms for such a link remain unknown.

Diastolic blood pressure usually decreases by 10 mm Hg by the midpoint of pregnancy (Cunningham and Lindheimer 1992 ). This was evident from our data that showed the prevalence of high diastolic blood pressure was low (<1%) at <20 wk of gestation but then increased to 6%. Although high diastolic blood pressure was significantly increased due to vitamin A supplementation among women with <20 wk of gestation, the clinical significance of this is not clear. The Committee on Terminology of the American Colleges of Obstetricians and Gynecologists defines preeclampsia as hypertension (diastolic 90 mm Hg, systolic 140 mm Hg) induced by pregnancy after 20 wk of gestation concurrent with proteinuria (not assessed in the present study) or edema or both (Hughes 1972 ). It seems unlikely that the higher prevalence of high diastolic blood pressure among women at <20 wk of gestation is of clinical importance. It is plausible to infer that vitamin A supplementation may have prevented low diastolic blood pressure, which is common in early pregnancy, rather than increase the prevalence of high blood pressure. This interpretation is congruent, given the protective OR for both diastolic and systolic blood pressure as well as preeclampsia among women at 20 wk of gestation who received vitamin A.

Vaginal discharge was found to be significantly higher among women in the vitamin A group in the first trimester of pregnancy. Previously, the relative risk for cough was found to be higher among vitamin A–supplemented West Javanese infants (Dibley et al. 1996 ), possibly reflecting recovery in the clearance of pathogens from the respiratory airway that might follow a reversal of keratinizing metaplasia of the respiratory tract to mucus-producing epithelium (Sommer and West 1996 ). In our study population, improved tissue vitamin A nutriture may have also increased reproductive and urinary tract mucus secretion, resulting in greater vaginal discharge.

Symptoms such as faintness and shortness of breath were found in a high proportion of women, suggesting that anemia was a significant problem in this population. This is not surprising because the prevalence of anemia measured with hemoglobin concentrations of <110 g/L was found to be 73% in this Nepali population of pregnant women (Dreyfuss, 2000 ). Vitamin A supplementation significantly reduced the symptoms of faintness, possibly reflective of a reduction in anemia observed with vitamin A supplementation in the trial (Stoltzfus et al. 1997 ).

There are few estimates of population-based, pregnancy-related morbidity rates from different regions of the developing world. The best description of community-based morbidity patterns comes from a rural survey of 281 women in Rajasthan that reported 60 episodes of sickness, of which 16.5 were pregnancy related, for each maternal death (Datta et al. 1980 ). A retrospective Chinese survey found that 37% of women experienced some illnesses during pregnancy, whereas 21% had a difficult labor (Li et al. 1982 ), in a population in which all women received antenatal care and had institutional deliveries (Liskin 1992 ). In a four-country World Health Organization (1988) study, the clinical diagnosis of hypertensive disorders varied widely from 1% in Vietnam and Thailand to 5% in Burma and 31% in China. The prevalence of eclampsia, on the other hand, ranged from 0.1% in China to 0.9% in Thailand. The present study provides community-based prevalence estimates of 21 reproductive and other illness symptoms experienced by women during different stages of pregnancy, at birth and during the first 6 mo postpartum in an environment in which antenatal care is absent.

Maternal morbidity assessment is difficult under community-based conditions. There may be poor agreement between self-reported experiences of childbirth by women and clinical diagnoses of obstetric problems, although this varies with type of complication (Ronsmans et al. 1997 ). Although attempts have been made to provide research guidelines and appropriate definitions for the assessment of maternal complications (World Health Organization 1989 ), little progress seems to have been made in generating reliable population estimates of the maternal morbidity burden in the past decade. Problems of biased recall, especially related to retrospective assessment, and women’s cultural perceptions of illnesses may complicate the interpretation of morbidity data (World Health Organization 1989 ). Although hospital-based assessments of complications may be more accurate clinically, such prevalence estimates fail to represent the morbidity burden in the community and focus on less prevalent, serious illnesses. Our community-based study showed that the prevalence of complications was high during pregnancy. Our assessment, however, was unable to provide an accurate measure of the severity of complications. In addition, it failed to provide a convincing link between supplementation effects on morbidity prevalence and the impact on pregnancy-related mortality reported previously (West et al. 1999 ). Except for a possible effect on the length of labor, the symptoms that were lowered due to supplementation were neither severe nor reflective of "life-threatening" conditions that could lead to maternal death. Future validation studies are required to link reported symptomatologies to clinical disease. Also, improved community-based assessment of preeclampsia, prolonged labor and obstructed delivery, hemorrhage and other conditions known to cause maternal death is required.

Access to essential obstetric care is an important solution to reduce maternal morbidity and mortality rates (Weil and Fernandez 1999 ). However, our findings indicate that a nutrition intervention such as vitamin A supplementation may lower the community burden of complications among pregnant and lactating women in poor malnourished settings, as it does pregnancy-related death (West et al. 1999 ). Although it may be premature to recommend universal vitamin A supplementation during the antenatal care of pregnant women, an initial strategy may be to target women who develop night blindness during pregnancy for vitamin A treatment and dietary counseling, because these women are at a high risk of vitamin A deficiency, complications (Christian et al. 1998 ) and death (Christian et al. 2000 ).

	ACKNOWLEDGMENTS

	FOOTNOTES

 
¹ This trial was a collaboration between the Center for Human Nutrition and Sight and Life Institute, 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, and was supported under Cooperative Agreement HRN-A-00-97-00015-00 between the Johns Hopkins University, Baltimore, MD, and the Office of Health and Nutrition, U.S. Agency for International Development (USAID), Washington, D.C., with additional support from the Sushil Kedia Seva Mandir, Hariaun, Sarlahi, Nepal and the Bill & Melinda Gates Foundation, Seattle, WA.

³ Abbreviations used: OR, odd ratios; UTI/RTI, urinary/reproductive tract infections.

Manuscript received May 19, 2000. Initial review completed June 30, 2000. Revision accepted August 8, 2000.

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