1 Epidemic Intelligence Service, Division of Applied Public Health Training, Epidemiology Program Office, Centers for Disease Control and Prevention, Atlanta, GA.
2 National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA.
3 National Center for Maternal and Infant Health, Peking University Health Sciences Center, Beijing, People's Republic of China.
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ABSTRACT |
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abnormalities; anus, imperforate; folic acid; maternal age; pregnancy; primary prevention; risk
Abbreviations: CI, confidence interval; RR, risk ratio.
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INTRODUCTION |
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Daily consumption of folic acid with or without multivi-tamins before pregnancy and during early pregnancy can reduce a woman's risk for having an infant with a neural tube defect (68
). Recent studies have also suggested that supplementation with multivitamins containing folic acid before and during early pregnancy may reduce the risk for some non-neural-tube birth defects, including cardiovascular defects (9
11
), orofacial clefts (12
14
), urinary tract defects (10
, 14
, 15
), and limb-reduction defects (9
, 16
). In these studies, it was not clear whether folic acid or another component of the multivitamins was associated with the reduced risk for these birth defects. None of these studies addressed the effect of the use of folic acid or multivitamins before and during early pregnancy on the risk for imperforate anus.
A public health campaign in China using a folic acid pill without other vitamins to prevent neural tube defects began in October 1993 (8). We used pill-taking and birth-defects surveillance data from this large cohort study to evaluate the effect of maternal daily consumption of 400 µg of folic acid before and during early pregnancy on the risk for imperforate anus.
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MATERIALS AND METHODS |
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Cohort
The campaign was conducted in one northern province (Hebei) and two southern provinces (Zhejiang and Jiangsu) of China. All pregnant women and women who were preparing for marriage registered with a pregnancy monitoring system that serves as the principal record of prenatal care and delivery in all three provinces. Subjects for this evaluation were all women who registered with this monitoring system between October 1, 1993, and September 30, 1995, and had an informative pregnancy (i.e., one in which the presence or absence of a birth defect could be ascertained). The project was approved by the institutional review boards of the US Centers for Disease Control and Prevention and Peking University.
Use of folic acid supplements
Beginning in October 1993, all women who registered with the pregnancy monitoring system were asked to purchase pills containing 400 µg of folic acid without other vitamins and to take one of these pills every day through the end of the first trimester of pregnancy. Women used one bottle containing 31 folic acid pills for each calendar month. At the end of each month, village health care workers collected the bottles and counted and recorded the number of pills consumed by each woman and the dates on which the women had started and stopped taking folic acid. For each woman, we computed compliance with pill-taking as the percentage of folic acid pills taken compared with the number that could have been taken.
For this study, we used the classification and pattern of pill-taking defined by Berry et al. (8). Women taking any folic acid pills before or during their first trimester of pregnancy were classified as folic acid users. Women with periconceptional use were defined as those who started taking folic acid on or before the date of their last menstrual period prior to conception and who stopped taking folic acid at the end of their first trimester. Women with late use were those who started taking folic acid during their first trimester but after their last menstrual period. Women who discontinued folic acid early were those who started and stopped taking the pills before their last menstrual period prior to conception. Women with missing dates were considered unclassifiable and were not assigned to any group. Women who either were already in their second trimester of pregnancy at registration (i.e., never had the opportunity to start taking folic acid by the end of their first trimester) or did not agree to take folic acid pills at the time of registration were considered not to have taken folic acid.
Case ascertainment
We identified infants with imperforate anus through a birth defects surveillance system that was established in January 1993. This system collects detailed data about infants and fetuses with external structural birth defects. Included in the surveillance system were liveborn and stillborn infants of at least 20 weeks' gestation who had a birth defect that was diagnosed by 6 weeks of age (17). We also collected information about all pregnancies, even those with gestations of less than 20 weeks, that were electively terminated after the prenatal diagnosis of any birth defect. Three pediatricians who were unaware of the mothers' folic acid status independently reviewed the reports and photographs and assigned diagnostic codes, and a clinical geneticist validated the diagnoses. In this evaluation, the definition of imperforate anus included the absence of an anal opening. Case infants with anal stenosis or anteriorly displaced but patent anus were not included in this study.
Classification of case infants
We attempted to classify infants into the three groups typically used in epidemiologic studies of birth defects: infants in whom the defect was the only defect or was associated with other, minor anomalies (isolated defect); infants in whom the defect was associated with other, major defects in seemingly unrelated organ systems (multiple defects); and infants in whom the defect was part of a recognized single gene or chromosomal condition (a syndrome). For this study, classification using this method was difficult, because only data on external birth defects were collected by the surveillance system, and imperforate anus is often a component of conditions characterized by anomalous development of caudal body structures, such as cloacal exstrophy and sirenomelia. Thus, we divided the case infants into 1) those with imperforate anus and no other major external birth defects; 2) those with imperforate anus and other major external birth defects only in the caudal region; 3) those with imperforate anus and major external birth defects outside of the caudal region; and 4) those with a recognized syndrome that has imperforate anus as a component. Because imperforate anus with and without other, more severe caudal defects could be part of a spectrum of anomalies varying in severity, we also analyzed infants in the first two groups together.
Statistical analysis
Any woman registering with the pregnancy monitoring system on or after October 1, 1993, was asked to take folic acid. We expected most women from this cohort to deliver after July 1, 1994. Therefore, our analysis of pregnancy outcomes was limited to the period from July 1, 1994, through December 31, 1996. Each woman contributed only one informative pregnancy to the study. For this cohort, we compared the numbers of women who took folic acid pills and the number who did not in each region (northern and southern) according to maternal age, parity, body mass index (weight (kg)/height (m)2), ethnicity, educational level, and occupation. For each region, we calculated the rate of imperforate anus (the number of cases per 10,000 pregnancies of at least 20 weeks' gestation) according to the use of folic acid. We estimated risk ratios by dividing the risk for imperforate anus among the fetuses or infants of all women who took folic acid by the risk among the fetuses or infants of women who did not take folic acid. Logistic regression was used to examine the effects of folic acid use (any; none), maternal education (elementary school or none; junior high school; high school or college), maternal occupation (farmer; factory worker; other), parity (no previous births; one or more previous births), and maternal age at delivery (1524 years; 2529 years; 30 years) on the risk for imperforate anus. We used SPSS statistical software (SPSS Base 10 for Windows; SPSS, Inc., Chicago, Illinois) for all analyses.
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RESULTS |
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Use of folic acid supplements
Among women who registered with the pregnancy monitoring system within 6 weeks after their last menstrual period, 88 percent bought and took folic acid pills, and 90 percent of these women continued using the pills until the end of their first trimester. Among all women who did not take folic acid pills, 67 percent did not take folic acid because they registered with the health authorities after the first trimester of pregnancy, and 3 percent refused to take folic acid.
Once women began taking folic acid supplements, compliance with pill-taking remained high (overall mean compliance was more than 90 percent). The most common pattern of use of folic acid pills was periconceptional use in both the northern region (71 percent) and the southern region (54 percent) (table 2).
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DISCUSSION |
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Many of the strengths and limitations of the data obtained from this public health campaign have been previously discussed (8). Strengths include the population-based nature of the study, with nearly complete ascertainment of outcomes among large numbers of women whose pregnancies lasted at least 20 weeks, and the prospective monthly recording of folic acid use before the outcome of pregnancy was known. Other strengths are the use of a system of prospective surveillance for birth defects, which was established before our evaluation began, and the establishment of diagnoses on the basis of photographs taken at birth and reviews of reports and photographs by several clinicians.
One limitation of the study was that folic acid use was not randomized, and the women who took folic acid pills may have differed systematically from those who did not in terms of factors that could influence the frequency of imperforate anus. Controlling for region, education, and occupation did not change our findings. Because parity and maternal age were correlated, we could not control for their independent effects. However, controlling for either of these covariates had a small effect on the magnitude of the relative risk estimate. We did not collect information on maternal smoking, alcohol drinking, or use of other nutritional supplements. However, smoking and alcohol drinking are uncommon among women in China. At the time of this study, prenatal vitamins were not part of routine prenatal care in China, and multivitamin supplements were not available for purchase. Although we do not have data on other potential confounders, the population studied was relatively homogeneous. The general lifestyle among women in rural China, including local housing, access to health care, and health-seeking behavior, tends to be uniform.
Imperforate anus is a birth defect that requires surgical correction and is associated with significant infant morbidity. Prognosis is most favorable for low lesions and is variable for intermediate and high lesions (1). It has been postulated that imperforate anus and other caudal birth defects result from abnormal development of the umbilical arteries in the form of a single umbilical artery of vitelline rather than allantoic origin (1
). However, the etiology of imperforate anus, like that of most birth defects, has remained ill-defined. Recent observations that maternal prenatal consumption of folic acid may reduce the risk for neural tube defects both with and without other major birth defects (18
) suggest that the pathways through which folic acid works to reduce birth defect risk may be nonspecific and that folic acid may also have a protective effect against other birth defects. Our finding that maternal folic acid consumption may reduce the risk for imperforate anus with and without other anomalies is consistent with this idea.
The US Public Health Service has recommended that all women who might become pregnant take 400 µg of folic acid daily to reduce the risk for neural tube defects (19). Other countries have adopted this recommendation (20
). Our results suggest that the implementation of such recommendations may also help reduce the risk for other, non-neural-tube birth defects. The preventive effect of folic acid use before and during early pregnancy on non-neural-tube birth defects requires further exploration.
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ACKNOWLEDGMENTS |
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The authors are indebted to the leaders of the Chinese Ministry of Health, Peking University Health Sciences Center, and the US Embassy in Beijing for their support and assistance. The authors thank Yecai Liu for assistance with data management and analysis.
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NOTES |
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REFERENCES |
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