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RE: Supplementation and Preterm Birth

Posted by suzanc on 17 Jul 2009 at 03:32 GMT

The recent study by Bukowski et al. (1) found that maternal intake of folic acid-containing supplements for at least a year before conception was associated with large reductions in the risk of very preterm birth (< 32 weeks). In an accompanying commentary, Callaway et al. (2) pointed out some reasons for cautious interpretation – the small numbers of exposed very preterm births (n=16) and absence of information on dose, frequency and formulation of the supplements. We would like to point out several additional considerations that in our opinion further suggest a cautious interpretation of this study’s findings.
1) Alternative explanations. As noted by Callaway et al., the actual formulation of the supplements women took was unknown. We would like to point out that it is likely that the supplements contained additional multiple vitamins and minerals. For example, based on detailed maternal interview data, among the control mothers from the National Birth Defects Prevention Study (NBDPS), a multi-state, population-based case-control study of deliveries from 1997-2005 (3) who took folic acid-containing supplements during the three months before pregnancy, 93% took formulas that contained multiple vitamins/minerals. Therefore, focusing on the exposure as “folic acid” is misleading. Studies often emphasize folic acid but largely ignore potential effects of the other component nutrients that are part of the supplement. We recommend that the interpretation of the findings by Bukowski and colleagues rest more on the “multiple nutrient” aspect of supplements rather than solely on folic acid. The data do not permit one to disentangle folic acid-specific effects.
2) Exposure misclassification. The Bukowski study did not consider women’s supplement behavior after conception; women who took supplements during early pregnancy were considered “non-users.” Also, it is unclear how the information on supplement intake was collected, and therefore uncertain how well or how consistently this information was obtained. Supplement intake behavior is quite dynamic during the periconceptional period. For example, 45% of NBDPS control mothers started taking folic acid-containing supplements during the first or second month after conception (4). The critical time window of supplementation for the potential prevention of preterm delivery is uncertain but may include these early weeks of fetal development. Classifying women who took supplements in early pregnancy as non-users may have just attenuated risk estimates in the Bukowski study, but certainly this point has broader implications for the biologic and clinical interpretations of the results. If the authors have information on early pregnancy intake (e.g., at the time of study enrollment), incorporation of that information into the analysis would have been helpful (e.g., stratify on early pregnancy users / non-users).
3) Outcome heterogeneity. It appears that the only malformation excluded from their study was anencephaly. Infants with many other structural malformations are more likely to be delivered preterm than non-malformed infants (5;6). Indeed, a previous study of the cohort analyzed by Bukowski et al. reported that liveborn infants with a structural malformation or chromosomal abnormality were 11.5 times more likely to be very preterm than unaffected infants (7). It seems particularly important to know whether the inclusion of malformed infants affected the results since the strongest findings were among the very preterm births. It would have been quite informative for the investigators to report the number of infants with structural malformations among the 16 very preterm infants that contributed to the observed findings, and to report the association of supplements with very preterm birth separately for infants with and without malformations; the stratified results may lead to different interpretations of the data. 4) Generalizability. In the Bukowski study, 56% of women were taking folic acid supplements in the year before conception, which is high relative to population-based studies in the U.S. (4;8). Supplement intake is correlated with many other health-related conditions and behaviors. Therefore, in extending these results to the general population, one needs to proceed with caution, considering carefully how applicable are the observed results for an apparently highly motivated group of women to all women who become pregnant.
Certainly many clues point toward a protective effect of folic acid and other nutrients against adverse reproductive outcomes. In our excitement to extend the potential benefits of folic acid supplementation, we encourage equal consideration of plausible alternative explanations, especially more careful attention to the complexities of nutritional exposures, which are seldom limited to folic acid.

Suzan L. Carmichael, PhD
California Research Division, March of Dimes, Oakland, CA

Gary M. Shaw, DrPH
Stanford University, Palo Alto, CA

Reference List

(1) Bukowski R, Malone FD, Porter FT, Nyberg DA, Comstock CH, Hankins GD et al. Preconceptional folate supplementation and the risk of spontaneous preterm birth: a cohort study. PLoS Med 2009; 6(5):e1000061.
(2) Callaway L, Colditz PB, Fisk NM. Folic acid supplementation and spontaneous preterm birth: adding grist to the mill? PLoS Med 2009; 6(5):e1000077.
(3) Yoon PW, Rasmussen SA, Lynberg MC, Moore CA, Anderka M, Carmichael SL et al. The National Birth Defect Prevention Study. Public Health Rep 2001; 116(Suppl 2):32-40.
(4) Carmichael SL, Shaw GM, Yang W, Laurent C, Herring A, Royle M et al. Correlates of intake of folic acid-containing supplements among pregnant women. Am J Obstet Gynecol 2006; 194(1):203-210.
(5) Rasmussen SA, Moore CA, Paulozzi LJ, Rhodenhiser EP. Risk for birth defects among premature infants: a population-based study. J Pediatr 2001; 138(5):668-673.
(6) Shaw GM, Savitz DA, Nelson V, Thorp JM, Jr. Role of structural birth defects in preterm delivery. Paediatr Perinat Epidemiol 2001; 15(2):106-109.
(7) Dolan SM, Gross SJ, Merkatz IR, Faber V, Sullivan LM, Malone FD et al. The contribution of birth defects to preterm birth and low birth weight. Obstet Gynecol 2007; 110(2 Pt 1):318-324.
(8) Williams LM, Morrow B, Lansky A, Beck LF, Barfield W, Helms K et al. Surveillance for selected maternal behaviors and experiences before, during, and after pregnancy. Pregnancy Risk Assessment Monitoring System (PRAMS), 2000. MMWR Surveill Summ 2003; 52:1-14.

No competing interests declared.