Folate and reproductive health. An epidemiologic study of folic acid supplement use and its relation to birth outcomes in Norwegian pregnant women
Nilsen, Roy Miodini
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Background: Randomized trials and observational studies have consistently shown that maternal intake of folic acid supplements before and early in pregnancy reduces the risk of neural tube defects in infants. These reports constitute the basis for recommending fertile women to use folic acid supplements before and during early pregnancy and for introducing food fortification programs with folic acid in numerous countries. Furthermore, increasing evidence suggests that prenatal use of vitamins including folic acid may also have a protective effect on other adverse pregnancy outcomes and complications as well. Objectives: In Norway, periconceptional folic acid supplement use is low, despite official recommendations and information campaigns to fertile women. This thesis aimed to examine the patterns of folic acid supplement use in Norwegian pregnant women and to identify important predictors of periconceptional use 1 month before pregnancy and throughout the first 3 months of pregnancy. We also tested whether various folate indicators, including prenatal folic acid supplement use, were associated with placental abruption and infant birth size. These outcomes have been linked to folate in previous studies, but results are inconsistent, possibly due to small sample sizes and methodological limitations. Materials: For the purpose of this thesis, we used observational data from two wellestablished data bases: the Medical Birth Registry of Norway (MBRN) and the Norwegian Mother and Child Cohort Study (MoBa). MBRN is a national health registry in which registration of all live births and stillbirths in Norway has been compulsory since 1967 (50,000-60,000 births per year), whereas MoBa is a population-based prospective study of Norwegian pregnant women which includes more than 100,000 pregnancies between 1999 and 2008. Results: Our first paper (based on MoBa) showed that 71.6 percent of the MoBa participants in 2000-2003 had taken folic acid-containing supplements at some time before or during pregnancy. Of these, more than 70 percent had started use after becoming pregnant, the majority during the first and second month of pregnancy. Only 10.2 percent of the participating women had used folic acid-containing supplements regularly from 1 month before pregnancy throughout the 3 first months of pregnancy. Women who had used folic acid supplements regularly during the periconceptional period were more likely to be older, to be married or living together, to be non-smokers, to have higher incomes, to have higher education, to have lower parity, to have planned their pregnancy, and to have received fertility treatments. Demographic and socioeconomic factors were the strongest predictors. Our second paper (based on MoBa) showed that food folate intake, supplemental folic acid use, total dietary folate intake, and maternal plasma folate and homocysteine concentrations were not significantly associated with gestational age, infant birth weight, head circumference, crown-heel length, or small for gestational age (SGA). Consistent with previous studies, infant birth size was strongly predicted by maternal smoking (adjusted odds ratio (OR) for SGA = 2.3; 95 percent confidence interval (CI): 1.6, 3.3). Our third paper (based on MBRN) showed that intake of folic acid and other vitamin supplements before and during pregnancy statistically significantly reduced the risk for placental abruption by up to 30 percent. Associations between vitamin supplement use and placental abruption were strongest for women using both folic acid and multivitamin supplements (adjusted OR = 0.68; 95 percent CI: 0.56, 0.83), followed by multivitamins alone (adjusted OR = 0.72; 95 percent CI: 0.57, 0.91) and folic acid alone (adjusted OR = 0.81; 95 percent CI: 0.68, 0.98). Because the response rate of MoBa is low (43 percent), there is concern as to which extent the results of MoBa are valid for the total Norwegian population. To evaluate potential bias due to self-selection in MoBa, our fourth paper aimed to study differences in prevalence estimates and association measures between study participants and all women giving birth in Norway, using data from the MBRN. We found no bias in 8 studied exposure-outcome associations, even though several exposures and outcomes were overrepresented or underrepresented in MoBa. Conclusions: Most women started folic acid supplementation too late with respect to the prevention of NTDs. Demographic and socioeconomic factors were the strongest predictors for periconceptional folic acid use 1 month before pregnancy throughout the 3 first months of pregnancy. This thesis further supports the old hypothesis that folate deficiency can be involved in development of placental abruption. Maternal intake and status of folate during second trimester appeared not to be associated with infant birth size, possibly due to the low number of individuals with low folate status in MoBa.
Paper 1: The American Journal of Clinical Nutrition 84(5), Nilsen, R. M.; Vollset, S. E.; Gjessing, H. K.; Magnus, P.; Meltzer, H. M.; Haugen, M.; Ueland, P. M., Patterns and predictors of folic acid supplement use among pregnant women: the Norwegian Mother and Child Cohort Study, pp. 1134-1141. Copyright 2006 American Society for Nutrition. Full text not available in BORA due to publisher restrictions. The published version is available at: http://www.ajcn.org/cgi/content/abstract/84/5/1134Paper 2: Journal of Nutrition 140(3), Nilsen, R. M.; Vollset, S. E.; Monsen, A. L.; Ulvik, A.; Haugen, M.; Meltzer, H. M.; Magnus, P.; Ueland, P. M., Infant birth size is not associated with maternal intake and status of folate during second trimester in Norwegian pregnant women, pp. 572-579. Copyright 2010 by the American Society for Nutrition. Full text not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.3945/jn.109.118158Paper 3: American Journal of Epidemiology 167(7), Nilsen, R. M.; Vollset, S. E.; Rasmussen, S. A.; Ueland, P. M.; Daltveit, A. K., Folic acid and multivitamin supplement use and risk of placental abruption: a population-based registry study, pp. 867-874. Copyright 2008 The Author. Published by the Johns Hopkins Bloomberg School of Public Health. Full text not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1093/aje/kwm373Paper 4: Paediatric and perinatal epidemiology 23(6), Nilsen, R. M.; Vollset, S. E.; Gjessing, H. K.; Skjærven, R.; Melve, K. K.; Schreuder, P.; Alsaker, E. R.; Haug, K.; Daltveit, A. K.; Magnus, P., Self-selection and bias in a large prospective pregnancy cohort in Norway, pp. 597-608.Copyright 2009 Blackwell Publishing. Full text not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1111/j.1365-3016.2009.01062.x