In this analysis, we found evidence of a reduction in the odds of miscarriage among women who used vitamins before and during pregnancy. The final adjusted and unadjusted models gave results of similar magnitude and precision.
Vitamin supplementation is widely recommended for all women who are pregnant or planning a pregnancy. Specific components of vitamin formulations are intended to cover gaps in maternal nutrition and to decrease the risk of adverse outcomes such as neural tube defects. The biologic mechanisms underlying these widespread recommendations remain unclear. The early embryo may require specific maternal nutrients at precise critical windows of development; however, little is known about nutritional requirements and exact time periods of importance. Detailed evidence of this nature is required before any conclusions can be drawn about a causal relation between vitamin use and adverse pregnancy outcomes.
Although there is some evidence of a beneficial effect of supplementation for women at risk of preeclampsia or preterm birth (7
), little is known about the effect of maternal nutrition on early pregnancy outcomes in a general population. Existing evidence suggests that vitamin supplementation may minimally affect the risk of miscarriage (13
) or may slightly increase the risk of miscarriage (11
). Given that miscarriage is a common pregnancy outcome, even a small increase in risk resulting from a common exposure may have far-reaching implications. In clinical studies of plasma folate measurements taken prior to or during pregnancy, investigators have reported an inverse relation between plasma folate levels and the risk of miscarriage (16
), a finding that is supported by our results. Plasma markers represent the effective dose of the supplement, which may be affected by actual supplement intake and individual genetic and dietary factors. To better understand the etiologic mechanism underlying the relation between vitamin use and miscarriage, biologic data would be required.
Our study examined the impact of supplementation itself, which may be related to the effect of pregnancy intendedness and other demographic, reproductive, and dietary characteristics associated with the decision to use vitamin supplements. We were unable to account for dietary intake, a limitation of this analysis. Because we assessed the effect of overall vitamin use, not the effect of specific supplement components, we may have actually been measuring a proxy for other health-conscious or preventive behaviors that are related to vitamin use, such as alcohol intake or physical activity during pregnancy. Of note, we found important demographic differences between participants who reported vitamin use and those who did not, suggesting that the results shown here may partly represent a constellation of lifestyle factors related to pregnancy intendedness and preconception care access, as well as self-selection into our study. The interplay of these dimensions of vitamin use requires further study, and such investigations would be enhanced by inclusion of both biologic and self-reported information. However, this study represents an initial step towards identifying modifiable factors that affect miscarriage risk, and it provides reassuring results suggesting that this very common early-pregnancy exposure does not have a detrimental relation with pregnancy loss.
More consistent vitamin use was associated with an odds ratio slightly closer to the null. This appears counterintuitive, but it could occur if women who are more vigilant about daily supplementation are at higher risk of miscarriage than women who are not as attentive to taking their daily vitamin. We had insufficient statistical power to evaluate the effect of beginning vitamin use prior to the time of conception versus afterwards. Odds ratios for miscarriages that occurred before and after the interview were somewhat different, although the overlap in confidence intervals indicates that the difference between the estimates remains within the bounds of random error. Regardless of when the interview occurred, vitamin use reduced the risk of miscarriage. Similar results were found when comparing early (≤10 weeks) and late (>10 weeks) miscarriage.
Our study had several strengths. Our nonclinical study population was recruited directly from the communities in which Right From the Start is active. Because of this, a more generalizable study population was recruited very early during pregnancy. Prior work has shown that clinic-based samples may be demographically different from population-based samples (23
). Analyses based on clinical samples may overestimate the occurrence of adverse outcomes. Our participants did not have to change any aspect of their usual prenatal care routine for the study; thus, it is unlikely that our enrollment procedures and study activities influenced our results. Although we recognize that the Right From the Start study population is highly educated and generally of high socioeconomic status, we believe that our results can be informative for pregnant women in the United States.
Because participants enroll in Right From the Start very early in pregnancy, we are able to observe a greater proportion of pregnancy losses in our study population than if prenatal clinic-based recruitment occurred. Our participants have an ultrasonogram conducted by a study sonographer early in pregnancy; thus, fetal viability is confirmed early in pregnancy and our gestational age assignment is accurate. A strength of Right From the Start is that we can accurately time the occurrence of events and exposures in pregnancy in time-varying models.
In conclusion, we found that use of vitamin supplements during early pregnancy was associated with reduced odds of miscarriage. Additional studies would be required to identify specific vitamin components that may have differential effects on early pregnancy outcomes. Further understanding of the interplay between vitamin exposure, biologic mechanisms, and pregnancy intendedness and health behaviors is also warranted.