Original Article
Maternal Vitamin A Supplementation and Lung Function in Offspring
N Engl J Med 2010; 362:1784-1794May 13, 2010
- Abstract
Background
Vitamin A is important in regulating early lung development and alveolar formation. Maternal vitamin A status may be an important determinant of embryonic alveolar formation, and vitamin A deficiency in a mother during pregnancy could have lasting adverse effects on the lung health of her offspring. We tested this hypothesis by examining the long-term effects of supplementation with vitamin A or beta carotene in women before, during, and after pregnancy on the lung function of their offspring, in a population with chronic vitamin A deficiency.
Methods
We examined a cohort of rural Nepali children 9 to 13 years of age whose mothers had participated in a placebo-controlled, double-blind, cluster-randomized trial of vitamin A or beta-carotene supplementation between 1994 and 1997.
Results
Of 1894 children who were alive at the end of the original trial, 1658 (88%) were eligible to participate in the follow-up trial. We performed spirometry in 1371 of the children (83% of those eligible) between October 2006 and March 2008. Children whose mothers had received vitamin A had a forced expiratory volume in 1 second (FEV1) and a forced vital capacity (FVC) that were significantly higher than those of children whose mothers had received placebo (FEV1, 46 ml higher with vitamin A; 95% confidence interval [CI], 6 to 86; FVC, 46 ml higher with vitamin A; 95% CI, 8 to 84), after adjustment for height, age, sex, body-mass index, calendar month, caste, and individual spirometer used. Children whose mothers had received beta carotene had adjusted FEV1 and FVC values that were similar to those of children whose mothers had received placebo (FEV1, 14 ml higher with beta carotene; 95% CI, −24 to 54; FVC, 17 ml higher with beta carotene, 95% CI, −21 to 55).
Conclusions
In a chronically undernourished population, maternal repletion with vitamin A at recommended dietary levels before, during, and after pregnancy improved lung function in offspring. This public health benefit was apparent in the preadolescent years.
Media in This Article
Figure 1
Recruitment and Enrollment of Study Participants.Figure 2
FEV1 in Children Whose Mothers Received Beta Carotene, Vitamin A, or Placebo before, during, and after Pregnancy.Article Activity
- Article
Vitamin A deficiency affects 190 million preschool-aged children and 19 million pregnant women worldwide.1 It is the underlying cause of 650,000 early childhood deaths2 and has become recognized as an important problem among women of reproductive age in many developing countries. Chronic vitamin A deficiency may increase the risks of complications and death during pregnancy and in the postpartum period3-9 and, on the basis of evidence from studies in animals, may also adversely affect the embryonic and postnatal development of the offspring.10-14
The importance of vitamin A in regulating growth through cell proliferation and differentiation was recognized early in the 20th century.10-12 Results from animal research have since shown that vitamin A plays a key role in mediating fetal growth, morphogenesis, and maturation of multiple organ systems, including the respiratory system.14-20 Depletion of vitamin A from the diet of female rats before and during pregnancy is associated with agenesis or hypoplasia of the lungs in offspring, conditions that can be prevented with vitamin A supplementation in early, but not late, pregnancy.14 Furthermore, vitamin A depletion in pregnant rats has been associated with dose-dependent decreases in DNA content in the lung tissue of their offspring.17,18
Since alveolarization begins in utero at about the 36th week of gestation,21 maternal vitamin A deficiency during pregnancy may have lasting effects on the lung maturation of progeny. Although results from studies in animals have shown that vitamin A is an important determinant of early lung development and size, data are lacking on the long-term consequences of vitamin A deficiency on lung health in human populations. We studied the effect of antenatal vitamin A supplementation on the lung function of preadolescent children in a chronically undernourished population in rural Nepal. The study cohort consisted of children, 9 to 13 years of age, whose mothers had participated in a randomized, placebo-controlled trial of vitamin A or beta-carotene supplementation before, during, and after pregnancy.
Methods
Study Setting
We conducted the original vitamin A trial and this follow-up study in the Sarlahi District of southern Nepal, in the densely populated, low-lying southern plains (Terai). The weather is usually warm and humid in this region, with temperatures exceeding 40°C in the hot, dry season (April through June), followed by a season of monsoon rains (July through October), and thereafter by a cooler, dry season (November through March). The Terai is an area of chronic undernutrition and vitamin A deficiency.22,23 Rice is the staple of the diet. It is supplemented with small amounts of seasonal fruits, vegetables, lentil soup, and occasionally meat, fish, and eggs.
Original Vitamin A Trial
The original study, which was conducted between April 1994 and September 1997, was a double-blind, placebo-controlled, cluster-randomized trial involving married women of childbearing age. The study was designed to determine the effects of weekly supplementation with a low dose of vitamin A or beta carotene on the rates of maternal death related to pregnancy.7 We invited all eligible women from 30 village development communities (VDCs) to participate in the trial. Each VDC is composed of 9 wards (for a total of 270 wards). The unit of block randomization was the ward, and each ward within a VDC was randomly assigned to one of the three study groups. A total of 44,646 women were enrolled and received weekly supplementation with 7000-μg retinol-equivalents of vitamin A, 7000-μg retinol-equivalents of beta carotene, or placebo. Both supplements, as well as the placebo, were given in the form of gelatinous capsules taken orally. A total of 75% of the pregnant women received at least half the allowable dose (i.e., ≥50% of a dietary allowance in the case of those receiving vitamin A or beta carotene).7 We prospectively identified all pregnant women and followed the mothers and their infants for an assessment of vital status and health outcomes. Supplementation with vitamin A or beta carotene resulted in a reduction in the rates of maternal death related to pregnancy, from 704 per 100,000 pregnancies in the placebo group to 395 per 100,000 pregnancies in the combined vitamin A–beta-carotene groups (a 44% relative reduction with the supplements).7 Neither supplement had an effect on infant mortality.24 We enrolled a subgroup of pregnant women and their live-born infants from three VDCs (27 of the 270 wards) in a substudy with a more detailed protocol that involved interviews about illnesses, diet, and other exposures; collection of blood samples at mid-pregnancy and at 3 months post partum; clinical examinations; and anthropometric measurements. Serum retinol levels, assessed in the women post partum and in their infants at 3 months of age, were higher in the vitamin A group than in the placebo group and were moderately higher in the beta-carotene group than in the placebo group.7,24 A total of 2055 children were born alive to mothers in the subsample who completed the pregnancy-to-postpartum dosing protocols. Of these children, 1894 (92%) were alive at the end of the trial (September 30, 1997).
Enrollment in the Follow-up Study
In 2006, we revisited the households of children whose mothers had participated in the original subsample study. Fieldworkers were unaware of the group assignments of the mothers in the original study. We used a household list derived from the original trial to generate an updated list of children who were eligible to participate in the follow-up study. Households in which the children were absent at the time of the visit were visited up to three times to maximize enrollment. The follow-up study was approved by the institutional review board at the Johns Hopkins University in Baltimore and at the Institute of Medicine, Tribhuvan University, in Kathmandu. We obtained oral or written informed consent from the mothers and assent from the children.
Spirometric Assessments
The objective of the follow-up trial was to determine whether there were differences in the forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) among children according to the group assignment of their mothers in the original trial. We used 20 SpiroPro (JAEGER) spirometers during the study period. SpiroPro is a lightweight, battery-operated, portable pneumotachometer with factory-precalibrated pneumotachometer tubes. We used only one pneumotachometer tube per participant.
During a 6-month period before the start of the study, we trained 11 technicians and 3 supervisors in the performance of spirometry. We numbered all our spirometers and asked technicians to use a different spirometer each day. Technicians visited the study children at their homes to perform spirometry. Each child underwent spirometry while in a sitting position and wearing a nose clip, until three acceptable and reproducible maneuvers, of a maximum of eight, had been performed.25 Technicians reviewed with a supervisor all the flow-volume curves that were obtained each day. Flow-volume curves were transmitted weekly to Johns Hopkins University for additional review. Approximately every 3 months, we performed direct supervision and in-person review of all flow-volume curves with each technician.
Statistical Analysis
The values for FEV1 and FVC were adjusted for height, age, sex, body-mass index, calendar month, and caste. Because biases can occur among different spirometers, we also adjusted for the specific spirometer that was used for the measurement. All analyses were performed according to the intention-to-treat principle. Because clustering by ward or VDC may have affected the estimation of standard errors, we used a linear mixed-effects model26 with two levels of random effects — VDC and ward within VDC — to account for the multilevel design of the trial. In subgroup analyses, we examined whether socioeconomic indicators or early exposures confounded the effects of the mother's original study-group assignment on lung function.
In a subgroup of mothers in whom serum retinol levels or serum beta-carotene levels were measured post partum, we examined the relationship between the postpartum levels of these micronutrients in the mothers and the lung function of their preadolescent children. We compared proportions across study groups and according to enrollment status, using standard methods.27
P values of less than 0.05 were considered to indicate statistical significance. We used the R statistical package (www.r-project.org) for analyses.
Results
Characteristics of the Study Population
The status of the 2055 live-born children from the original subsample is summarized in Figure 1Figure 1
Recruitment and Enrollment of Study Participants.. Of the 1894 children who were alive at the end of the original trial, 118 (6%) were no longer living in the study area at the time of the follow-up study, and 110 (6%) had died. No information was available for eight children (<1%). A total of 1658 children were eligible to participate, and 1371 (83% of those eligible) underwent spirometry between October 2006 and March 2008. We did not find significant differences between study groups in the mean proportions of children who died before September 30, 1997 (P=0.09), children who died after September 30, 1997 (P=0.62), children who moved out of the study area (P=0.78), children who could not be contacted during the study period (P=0.99), or children who declined to participate or whose mothers did not want them to participate in the study (P=0.78). As compared with the 684 children from the original birth cohort who were not included in the follow-up study, children who were contacted and who underwent spirometry were less likely to be members of a low caste (P=0.003), less likely to live in a thatch or bamboo house (P<0.001), more likely to live in a household that owned land or livestock (P<0.001 for both comparisons), and more likely to have a father who was a farmer (P=0.04).In 1322 (96%) of the 1371 children who underwent spirometry, the quality of the spirometry data met American Thoracic Society standards. We did not find significant differences between the study groups in demographic characteristics, anthropometric measurements, socioeconomic indicators, or early exposures (Table 1Table 1
Demographic, Anthropometric, and Socioeconomic Characteristics and Early Exposures among Children in Whom Adequate Spirometric Measurements Were Obtained, According to the Group Assignment of the Mothers.). We also did not find significant between-group differences in the age-adjusted mean height of the children (P=0.51) or in the proportion of children with a history of pneumonia during infancy (P=0.96).Predictors of Lung Function
In an exploratory analysis, FEV1 and FVC were normally distributed. Height, sex, body-mass index, calendar month, caste, and spirometer were significant predictors of FEV1 or FVC. We did not find significant differences in FEV1 or FVC according to the technician who performed the test or the pneumotachometer calibration code, nor did we find significant differences in FEV1 or FVC values over the course of the study.
Effects of Maternal Supplementation on the Lung Function of Offspring
The mean FEV1 and FVC in our study population were 1.54 liters and 1.74 liters, respectively. Children whose mothers had received vitamin A supplementation had higher values of FEV1 than children whose mothers had received placebo (Figure 2Figure 2
FEV1 in Children Whose Mothers Received Beta Carotene, Vitamin A, or Placebo before, during, and after Pregnancy.). The FEV1 of children whose mothers had received vitamin A was, on average, 46 ml higher (95% confidence interval [CI], 6 to 86) than that of children whose mothers had received placebo, after adjustment for age, height, sex, body-mass index, caste, calendar month, and spirometer (P=0.03). The adjusted FEV1 of children whose mothers had received beta carotene was, on average, 14 ml higher (95% CI, −24 to 54) than that of children whose mothers had received placebo (P=0.47).A similar comparison for FVC shows that children whose mothers had received vitamin A had higher values than children whose mothers had received placebo (Figure 3Figure 3
FVC in Children Whose Mothers Received Beta Carotene, Vitamin A, or Placebo before, during, and after Pregnancy.). After adjustment for the same factors as those adjusted for in the FEV1 analysis, the FVC of children whose mothers had received vitamin A was 46 ml higher (95% CI, 8 to 84) than that of children whose mothers had received placebo (P=0.02). The adjusted FVC of children whose mothers had received beta carotene was 17 ml higher (95% CI, −21 to 55) than that of children whose mothers had received placebo (P=0.36). The effects of the mother's study-group assignment on the lung function of the child was not confounded by the mother's socioeconomic status, the presence or absence of a history of pneumonia during the child's infancy, or the presence or absence of a 7-day history of tobacco use by the mother during her pregnancy (see the table in the Supplementary Appendix, available with the full text of this article at NEJM.org). We did not find significant between-group differences in the ratio of FEV1 to FVC (P=0.44), suggesting that lung size and airway caliber were influenced proportionally by maternal vitamin A supplementation.Postpartum Serum Retinol Levels and Lung Function of Offspring
We measured postpartum serum retinol levels in 678 mothers. Supplementation with vitamin A or beta carotene was associated with significantly higher serum retinol levels post partum (Figure 4AFigure 4
Association between Maternal Postpartum Levels of Serum Retinol and Lung Function in Offspring.). Without consideration of the mothers' original group assignments, we found that the FEV1 and FVC levels of the study children were linearly related to the postpartum serum retinol levels of their mothers, after adjustment for height, body-mass index, age, sex, caste, calendar month, and spirometer (Figure 4B and 4C). On average, FEV1 increased by 19 ml (95% CI, 3 to 35) and FVC increased by 16 ml (95% CI, −1 to 32) for every 1-SD increase in postpartum serum retinol level (1 SD = 0.510 μmol per liter). Postpartum serum beta-carotene levels were measured in 594 mothers. We did not find a significant association between postpartum serum beta-carotene levels in the mothers and either FEV1 or FVC in their children.Discussion
In a population with chronic vitamin A deficiency, maternal supplementation with vitamin A at recommended dietary levels before, during, and after pregnancy resulted in improved lung function in the offspring 9 to 13 years later. Improvement in lung function was probably due to supplementation received in utero because this population of children was subsequently exposed — starting at 6 months of age and extending through their preschool years — to high-coverage, semiannual vitamin A supplementation as part of a national program.28 The benefit from maternal supplementation with vitamin A was limited to children whose mothers received preformed vitamin A and was not seen in those whose mothers received beta carotene, possibly because beta carotene is a less efficient source of vitamin A than the preformed ester.29-31 We previously reported that supplementation with preformed vitamin A, but not beta carotene, corrected abnormal dark-adaptation thresholds in pregnant and lactating women32 and reduced the rate of death among infants born to mothers with night blindness.33 The greater bioefficacy of preformed vitamin A as compared with beta carotene may stem from differences in absorption and metabolism. In the gut, the preformed ester is hydrolyzed to retinol and efficiently absorbed, re-esterified, and delivered through circulating chylomicrons to the liver for storage, although extrahepatic pathways for tissue delivery of vitamin A also exist.34 Once hepatic retinol is bound to retinol binding protein, it is released into the circulation to meet tissue needs, including those of the placenta and the developing fetus.35 On the other hand, beta carotene is less well absorbed than the preformed ester and must be cleaved and hydrolyzed to retinol in the intestines before becoming available as vitamin A.29 Beta carotene can also be directly absorbed and may be converted to vitamin A in tissues other than the intestine,31 including the maternal–placental interface.35 The lower bioefficacy of the beta-carotene supplement as a source of vitamin A in the mothers and their offspring in our trial was also evident in the finding that serum retinol concentrations in mothers at mid-pregnancy and post partum7 and in their infants at 3 months of age24 were lower among those in the beta-carotene group than they were among those in the preformed–vitamin A group.
There is a wealth of data from studies in animals13,20,36,37 and from observational studies involving children38,39 and adults40-43 suggesting that there is a positive functional relationship between vitamin A status and lung function. Studies have shown that defects in pulmonary development such as bronchopulmonary dysplasia may be linked to vitamin A deficiency.44,45 Vitamin A mediates alveolar formation and septation through the binding of its active metabolite, retinoic acid, to nuclear receptors.21 Thus, conditions that lead to vitamin A deficiency, to deletions in nuclear receptors for retinoic acid, or to improper signaling of these receptors have been associated with abnormalities in lung development.13,14,21 In animals, prenatal vitamin A supplementation after induced maternal deficiency prevents abnormal lung development in offspring.14 Postnatal treatment with retinoic acid, even in the presence of inhibitors of alveolar formation, induces alveolarization.20,37 However, retinoic acid is an intracellular metabolic intermediate of retinol, and unlike naturally occurring retinoids such as preformed vitamin A, it is not available as a supplement for common use.
Our study provides data from a cohort of children in an undernourished population whose mothers were assigned at random to receive antenatal vitamin A supplementation or placebo. We controlled for potential imbalances that may have resulted from incomplete follow-up, since not all of the 2055 children who were born alive to the subsample of women enrolled in the original trial were available for study. The absence of confounders or imbalances across maternal supplement groups in predictors of lung function strengthens the likelihood that the observed association between maternal vitamin A supplementation and increased lung function in offspring was causal. Data regarding nutrition from birth to the time lung function was measured, retinol levels at the time lung function was measured, and the history with respect to pneumonia after infancy were not available.
The effects of enhanced vitamin A status early in human life extend beyond the pulmonary system. Vitamin A supplementation in early childhood prevents xerophthalmia, a condition attributable to keratinization and necrosis of the corneal epithelium.46 Routine administration of vitamin A strengthens host defenses against infection, which can favor child survival in undernourished populations.46 Randomized trials in Indonesia, India, and Bangladesh showed that oral supplementation with 50,000 IU of vitamin A in oil shortly after birth reduced the rates of death during the first year of life by 64%,47 23%,48 and 16%,49 respectively. At sites in which specific causes of death were analyzed, the largest reductions were in diarrhea-related deaths.50
It is important to recognize that a mean increase of 46 ml in FEV1 (3% of the mean FEV1 in this study population) and in FVC (3% of the mean FVC) corresponds to a change in the distribution of values in this study population of children and does not predict the level of benefit that is expected in an individual child. However, the magnitude of the effect observed in this study is slightly greater than that associated with preventing exposure to parental smoking in school-aged children.51 Because FEV1 correlates with overall longevity in the general adult population,52-54 any improvement in the distribution of values of FEV1 in a population may provide long-term health benefits.
In summary, in an area in which there was chronic vitamin A deficiency, maternal supplementation with vitamin A before, during, and after pregnancy was a critical determinant of lung maturation among offspring 9 to 13 years later. Early interventions involving vitamin A supplementation in communities where undernutrition is highly prevalent may have long-lasting consequences for lung health.
Supported by a grant (no. 614) from the Bill and Melinda Gates Foundation and by a grant from the Sight and Life Research Institute, Baltimore. The original maternal vitamin A or beta-carotene supplementation trial (1994–1997) was conducted under the Vitamin A for Health Cooperative Agreement (HRN-A-0097-00015-00) between Johns Hopkins University and the Office of Health, Infectious Diseases and Nutrition of the U.S. Agency for International Development, with additional support from Task Force Sight and Life, Basel, Switzerland. Dr. Checkley is the recipient of a Clinician Scientist Award from Johns Hopkins University and a K99/R00 Pathway to Independence Award (K99HL096955) from the National Heart, Lung, and Blood Institute, National Institutes of Health.
No potential conflict of interest relevant to this article was reported.
This article (10.1056/NEJMoa0907441) was last updated on December 29, 2010, at NEJM.org.
We are grateful for the dedicated contributions of Sharada Ram Shrestha (deceased) to the field study.
Source Information
From the Division of Pulmonary and Critical Care, School of Medicine (W.C., R.A.W., M.R.B.), the Program in Global Disease Epidemiology and Control (W.C., J.K., J.M.T.) and the Center for Human Nutrition (K.P.W., L.W., S.C.L., P.C., J.K., J.M.T.), Department of International Health, and the Department of Epidemiology (A.S.), Bloomberg School of Public Health, Johns Hopkins University, Baltimore; and the Nepal Nutrition Intervention Project Sarlahi, National Society for the Prevention of Blindness, Kathmandu, Nepal (S.C.L., S.K.).
Address reprint requests to Dr. Checkley at Johns Hopkins University School of Medicine, Division of Pulmonary and Critical Care, 1830 Monument St., 5th Fl., Baltimore, MD 21205, or at wcheckl1@jhmi.edu.
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