1 Department of Maternal and Child Health, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC.
2 Department of Nutrition, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC.
3 Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.
4 Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC.
5 Department of Obstetrics and Gynecology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Received for publication October 8, 2002; accepted for publication November 20, 2003.
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ABSTRACT |
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delivery, obstetric; infant, premature; pregnancy; vitamins
Abbreviations: Abbreviations: CI, confidence interval; PIN, Pregnancy, Infection, and Nutrition.
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INTRODUCTION |
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Although the relation with neural tube defects and folic acid is established, it is unclear whether preconceptional and prenatal multivitamin use affects other birth outcomes. Previous research suggests that multivitamin use before and during pregnancy can diminish diet-related deficiencies of certain micronutrients (e.g., folate and iron) and potentially prevent preterm birth (7). Specifically, supplementation studies with folic acid suggest an association between higher folate levels and longer gestation (8, 9). It is hypothesized that folate supplementation promotes a cell-rich placenta, which is beneficial for fetal growth in the last trimester of pregnancy (9, 10). A recent randomized controlled trial of iron supplementation showed that the prevalence of preterm birth was lower with universal supplementation of 30 mg of iron compared with placebo among women with sufficient iron stores at the start of pregnancy (Siega-Riz et al., University of North Carolina at Chapel Hill, unpublished manuscript), and one other study showed a beneficial effect on reducing the incidence of preterm low-birth-weight infants (11).
To our knowledge, only three studies to date have examined the relation between the timing of multivitamin supplement use and the risk of preterm birth (7, 12, 13). However, the findings from these studies are inconsistent. A randomized controlled trial found a higher, but not significantly different rate of preterm birth among periconceptional multivitamin users compared with those who took a trace element (13). In comparison, a retrospective analysis reported an inverse association between periconceptional use and preterm birth, compared with nonuse, with an adjusted odds ratio of 0.72 (95 percent confidence interval (CI): 0.40, 1.30) (12). A third, prospective analysis reported an inverse association between prenatal use, compared with nonuse, and both preterm and very preterm (<33 completed weeks of gestation) birth, with adjusted odds ratios on the order of 0.550.66 for preterm and 0.210.44 for very preterm birth, depending on whether gestational age was based on date of the last menstrual period or an obstetric estimate (7).
In each analysis, the authors defined the exposure and outcome of interest as a dichotomous variable. Generally, multivitamin use was defined as either periconceptional or prenatal use versus nonuse (12, 13), with the periconceptional period ranging from 1 month prior to conception through 23 months of pregnancy. With regard to preterm birth, we know of only one study that looked at early versus late preterm birth as well (7). Thus, our study sought to fill in the gaps related to the exposure time window and preterm birth subtypes by exploring the relation between multivitamin use and the risk of preterm birth using data from the Pregnancy, Infection, and Nutrition (PIN) Study.
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MATERIALS AND METHODS |
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Blood, urine, and genital tract specimens were collected from participants at the time of recruitment; in addition, a food frequency questionnaire assessed preconceptional supplement use and dietary intake in the second trimester. A telephone interview was conducted shortly afterwards to collect information on sociodemographic characteristics, the current pregnancy, reproductive and medical histories, and health behaviors. Delivery logs were examined to determine birth outcome information on all participants. The PIN Study was approved by the institutional review boards of the University of North Carolina School of Medicine and Wake Medical Center.
Women were recruited for this study from August 1995 to June 2000. During this time, 5,194 women were identified as eligible for participation, and 3,163 (61 percent) were recruited successfully. Slightly more White women than Black women were recruited into the PIN Study in comparison to the women who refused to participate. More notable differences were found when the different study sites were compared; the health department clinics had a greater proportion of refusals and more women who could not be contacted than the teaching hospital did. The study had somewhat greater success in recruiting highly educated (>16 years of education) and older (age >35 years) women. The risk of preterm birth was similar among the successfully recruited women compared with those who refused (14). Of those women recruited successfully, 2,586 completed both the food frequency questionnaire and the telephone interview. Excluded from this analysis were 180 women who reported incomplete information on multivitamin intake and 396 women who did not report complete information on potential confounders. Thus, this analysis was limited to women for whom information from these sources was complete (n = 2,010). Compared with the original study population, this sample included a higher proportion of White, more highly educated, and married women.
Birth outcome
The outcome of interest for this analysis was preterm birth, defined as a delivery prior to 37 completed weeks of gestation. Gestational age was determined on the basis of a self-reported estimate of the date of the last menstrual period or an estimate derived from an ultrasound examination when the date of the last menstrual period was unknown. When the two estimates were within 14 days of each other, the estimated date of the last menstrual period was used. However, if the estimates differed by more than 14 days, the ultrasound estimate was used. One of three obstetricians examined the charts for all preterm deliveries to determine whether the delivery was spontaneous or medically indicated. For additional insight, preterm deliveries were subdivided into spontaneous and medically indicated preterm as well as early (<35 completed weeks of gestation) and late (3536 completed weeks of gestation) preterm. A medically indicated preterm delivery was defined as induction of labor or cesarean section without labor before 37 weeks of gestation based on the health of the mother or fetus.
Exposure of interest and selected covariates
Multivitamin use was the exposure of interest for this analysis. This variable was constructed based on responses from both the screening/telephone interview (at the time of the screener at 2429 weeks or telephone interview, which was at 2729 weeks) and the food frequency questionnaire, and it consisted of four levels of the exposure time window: preconceptional use only, prenatal use only, periconceptional (preconceptional and prenatal) use, and nonuse. Together, these categories represented all possible combinations of multivitamin intake prior to and during pregnancy. The food frequency questionnaire ascertained preconceptional use, while the main telephone interview or screener established prenatal use. For this analysis, preconceptional use referred to intake anytime before pregnancy, while prenatal use referred to intake anytime during pregnancy up until the time of interview or recruitment. Women who responded that they did not take multivitamins before or during pregnancy were identified as nonusers. Information regarding potential confounders was obtained from the medical record, the telephone interview, the diet questionnaire, and specimen collection at the time of recruitment.
Statistical analysis
Descriptive analyses were conducted to assess the distributions of the various covariates across each of the four levels of multivitamin use. Students t tests or chi-square tests were used to assess statistical significance (p < 0.05). The proportion of preterm births in this sample was 11.5 percent. Thus, log-linear regression models were used to compute crude and adjusted risk ratios and 95 percent confidence intervals for the effect of multivitamin use on the risk of preterm birth, because an odds ratio would overestimate the risk ratio when the outcome is common (>10 percent). To isolate spontaneous preterm births, we repeated this analysis after excluding medically indicated preterm births.
We did not include interaction terms in the full model because previously published studies did not suggest the presence of effect modification by maternal race and stratified analyses did not reveal any effect modification. Potential confounders were included in the full model if they were risk factors for preterm birth and were associated with multivitamin use in the source population, based on a p value of 0.20. These covariates included maternal race, parity, marital status, maternal health during pregnancy, vomiting during pregnancy, estimated energy intake, and estimated vitamin A, vitamin C, calcium, iron, folate, and zinc intake per 1,000 kcal. However, only those covariates that changed the beta coefficient of the multivitamin variable by more than 10 percent were retained in the final model. These covariates included maternal race, parity, marital status, maternal health status during pregnancy, vomiting during pregnancy, estimated energy intake, and estimated iron and folate intake per 1,000 kcal. Logistic regression models examined the effect of multivitamin use on early and late preterm birth, and crude and adjusted odds ratios and 95 percent confidence intervals were computed because the proportions of early (4.7 percent) and late (7.4 percent) preterm births in this sample were less than 10 percent. All analyses were performed by using the Statistical Analysis System (SAS), version 8.1 (SAS Institute, Inc., Cary, North Carolina).
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RESULTS |
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DISCUSSION |
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Scholl et al. (7) conducted a prospective cohort study of low-income, urban women in New Jersey who participated in the Camden Study from 1985 to 1995. The sample was restricted to women with singleton pregnancies who entered prenatal care during their first and second trimesters of pregnancy. The authors reported an odds ratio of 0.66 (95 percent CI: 0.47, 0.93) for women who used vitamins during the first and second trimester of pregnancy, compared with nonusers, and after adjusting for multiple confounders similar to those in our study. However, the focus of their study was prenatal use; preconceptional use was assessed as a potential confounder only. Moreover, the authors studied a very low income population of young women (mean age of 18 years).
In our study, preconceptional users had higher rates of nausea and vomiting compared with prenatal, periconceptional, and nonusers. They also had the lowest rate of preterm births. It is possible that the nausea and vomiting prevented women from continuing their supplement use during pregnancy; vomiting has been associated with a lack of multivitamin supplementation early in pregnancy (15). Moreover, previous research indicates that women who experience nausea and vomiting early in pregnancy are less likely to deliver preterm (1618). Huxley suggests that "a reduced nutrient intake in early pregnancy lowers maternal levels of the anabolic hormones, insulin, and IGF-1 [insulin-like growth factor-1]. This helps to ensure that nutrient delivery to the placenta is sufficient to ensure adequate placental growth" (19, pp. 780781). The etiology of nausea and vomiting is not well understood, but it is thought that the hormonal response to the pregnancy state may cause the nausea and vomiting and as such serve as an indication that the body is accepting the pregnancy state.
In our analysis, vomiting during pregnancy was retained as a confounder in modeling the association between multivitamin use and preterm birth. In contrast, nausea during pregnancy did not meet the criteria for confounding. The PIN Study assessed vomiting during pregnancy based on responses to the following two questions: "Have you vomited five or more days in a row during this pregnancy because of nausea?" and "Have you vomited during this pregnancy because of nausea?". Thus, this covariate measured the frequency of vomiting specific to nausea during pregnancy rather than from a condition irrespective of the current pregnancy. In multivariate analyses, adjustment for this covariate had a minimal effect on the risk ratios for preterm birth for any exposure group and only slightly increased the odds of early preterm birth for periconceptional (from 1.50 to 1.56) and prenatal (from 1.39 to 1.41) users. The reduction in the risk of preterm birth for preconceptional users remained after adjustment and merits further study.
Strengths of this analysis include a comprehensive definition of multivitamin use that assessed preconceptional, prenatal, and periconceptional intake as separate categories. In addition, multiple sociodemographic, behavioral, dietary, and medical factors were considered as potential confounders. However, the small number of women categorized as preconceptional users, compared with the other exposure levels, was a limitation of this observational study, as reflected in the wide confidence intervals.
The findings of our study must be interpreted with recognition of its other limitations. Generalizability may be limited to low- and moderate-income women receiving prenatal care. Since the recruitment period for this study occurred at 2429 weeks of pregnancy, women who entered prenatal care in the third trimester or not at all were excluded from this analysis. This approach could have introduced selection bias because women at higher risk of adverse birth outcomes were excluded from the sample; this loss may have been differential by vitamin use.
Dietary data were assessed by using a semiquantitative food frequency questionnaire and are subject to the errors inherent in this mode of data collection. Information on supplement use was collected separately for each time period. However, within those time periods, we know that compliance with taking the supplements is less than ideal; thus, our assumption of a constant level during the time period is imperfect. Information on dietary intake and supplement use during the third trimester was lacking.
Lastly, because of the observational nature of our data, we cannot entirely exclude the possibility that important confounders were omitted from the analysis or that adjustment for confounders was incomplete. Moreover, we acknowledge that the patterns observed in our data may have been the result of random error, given the small numbers in some cells and the lack of statistical significance, and may have added some uncertainty to our findings.
Women who use multivitamin supplements prior to conception, compared with nonusers, may have a reduced risk of preterm birth. However, this protective effect may be limited to late preterm deliveries, although the precision of these estimates diminished in subgroup analyses. It is thought that the determinants between early and late preterm birth differ. Romero et al. (20) reported that at least 40 percent of all preterm deliveries occur among mothers who have an intrauterine infection. Moreover, among early preterm deliveries, there is a greater frequency of intrauterine infection (21). Whereas early preterm birth is more than likely pathologic, late preterm birth without growth restriction may be related to medical complications during pregnancy, error associated with the measurement of gestational age, or other unknown factors. It is difficult to interpret our results for preconceptional multivitamin use and late preterm birth because only five of 93 preconceptional users delivered preterm; of those five women, three delivered a late preterm infant. While this modest sample is a limitation of our analysis of subsets of preterm birth, this association merits further study with a larger sample of preconceptional users. Finally, we recognize that preconceptional use may be a proxy for overall healthiness; previous research suggests that supplement use is generally higher among those who perceive their health as excellent or very good (22). In this analysis, women who used multivitamins prior to conception, compared with nonusers, were more likely to report their health status as excellent or good and had higher levels of most nutrients (per 1,000 kcal).
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ACKNOWLEDGMENTS |
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The authors appreciate the cooperation and support of all study staff members and prenatal care providers.
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NOTES |
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REFERENCES |
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