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Adjunct Faculty, Research Investigator, Bastyr University, Seattle
Dr. Pantuso reports no financial relationships relevant to this field of study.
SYNOPSIS: This secondary analysis of Effects of Aspirin in Gestation and Reproduction trial found that women with sufficient 25-hydroxyvitamin D levels (≥ 30 ng/mL) were more likely to become pregnant and have a live birth than women with insufficient concentrations of vitamin D.
SOURCE: Mumford SL, Garbose RA, Kim K, et al. Association of preconception serum hydroxyvitamin D concentrations with live birth and pregnancy loss: A prospective cohort study. Lancet Diabetes Endocrinol 2018;6:725-732.
The current body of research concerning the role of vitamin D and pregnancy has been focused on women undergoing in vitro fertilization (IVF).1 In these women, increased preconception serum vitamin D concentrations are associated with increased implantation rates and clinical pregnancy.1 Adverse pregnancy outcomes have been associated with vitamin D deficiency. To further understand the relationship of preconception vitamin D levels with live birth and pregnancy loss, Mumford et al performed a secondary analysis on the prospective cohort, block-randomized, double-blind, placebo-
controlled Effects of Aspirin in Gestation and Reproduction (EAGeR) trial.2 The authors of the EAGeR trial assessed the effect of daily low-dose aspirin on reproductive outcomes in women with a history of pregnancy loss, but the researchers collected other information from the cohort. From June 15, 2007, to July 15, 2011, investigators recruited participants from four clinical sites: Buffalo, NY; Denver; Salt Lake City; and Scranton PA. The participants were followed for six menstrual cycles while attempting pregnancy; in the case of conception, they were followed throughout pregnancy. Fertility monitors that measure estrogen and luteinizing hormones were used to assist in scheduling visits and timing intercourse. Serum samples of vitamin D were measured at baseline before randomization and at eight weeks of gestation. Outcome measures were pregnancy detected by human chorionic gonadotropin (hCG), clinical pregnancy, time to pregnancy, pregnancy loss, and live birth. The investigators measured hCG by both daily first morning urine collection and spot urine pregnancy tests at monthly visits. Ultrasound was performed to confirm clinical pregnancies at six to seven weeks of gestation. The number of menstrual cycles until hCG detected pregnancy was measured to define time to pregnancy. Pregnancy loss was defined as positive urine hCG detected at home or in a clinic followed by the absence of clinical pregnancy signs during the study ultrasound or loss after ultrasound. The authors defined live birth as an infant born after 23 weeks of gestation. They obtained demographic characteristics and reproductive history through questionnaires.
The EAGeR trial included 1,228 women between 18 and 40 years of age who had one to two pregnancy losses. The women were predominately (95%) white, with an average age of 28.7 years. The secondary analysis included 1,191 of the 1,228 women who had measured baseline vitamin D levels. Exclusion criteria included infertility treatment, pelvic inflammatory disease, tubal occlusion, endometriosis, anovulation, polycystic ovarian syndrome, or uterine abnormality. Of the 1,191 women, 555 had sufficient vitamin D levels (≥ 30 ng/mL) and 636 women had insufficient concentrations.3 The mean vitamin D level was 30.8 ng/mL (standard deviation, 30.5; interquartile range [IQR], 89.9-57.7) and the median was 29.2 ng/mL (IQR, 89.9-57.7).
Women who had sufficient preconception vitamin D levels were more likely to be white, have higher than a high school education, and be employed than women who had insufficient preconception vitamin D levels. Age, multivitamin use, smoking, or number of previous live births were not associated with preconception vitamin D levels. Women with sufficient vitamin D had a higher likelihood of clinical pregnancy (relative risk [RR], 1.10; 95% confidence interval [CI], 1.01-1.20) and live birth (RR, 1.15; 95% CI, 1.02-1.29) than those with insufficient levels. Increasing vitamin D concentrations was associated with a reduced risk of pregnancy loss per 10 ng/mL (RR per 10 ng/mL, 0.88; 95% CI, 0.77-0.99).
This study is important because it is the first to investigate the association between preconception vitamin D serum levels and pregnancy loss and live birth in women not undergoing IVF treatments. Although the study authors did not determine cause and effect, they set the stage for further investigations into the role of vitamin D in the biology of the reproductive system. Previous research in IVF populations has demonstrated that vitamin D may improve endometrial receptivity of the embryo increasing implantation rates.1 However, more research is underway to elucidate the role of vitamin D in fertility.
The strengths of the study include the prospective trial design and the ability to capture early pregnancy losses. There are a number of study limitations, including the secondary analysis that was performed on the EAGeR study data set and the low numbers of pregnancy losses detected, which limits the power of the study to capture statistically significant changes. Secondary analyses do not always control for important variables, such as genetic variation in key proteins involved in vitamin D metabolism that affect circulating concentrations of vitamin D metabolites.4 The cutoffs for vitamin D sufficiency and insufficiency were determined by the Endocrine Society and may not be relevant to levels needed for healthy reproductive function.3 The cutoffs for vitamin D sufficiency and insufficiency were based on studies investigating the association with bone health and not with reproductive immune function.1,3,4 Also, other studies have demonstrated that the relationship between vitamin D serum levels and bone indices are weaker than previously thought and not consistent across races.3 In addition, there are increasing concerns that vitamin D levels measured by 25-OH serum levels may not be the best indicator of vitamin D status.
An interesting finding from this study is that vitamin D levels were found to be lower in non-white women with a lower education status, while age, smoking status, multivitamin use, and previous live births were not associated with insufficient vitamin D levels. Ninety-one percent of the total participants reported multivitamin use, which was not evaluated for amounts of vitamin D. This lack of information is important because individual genetic variation has been shown to affect circulating concentrations of vitamin D metabolites.4 Since the amount of vitamin D in the multivitamins was not measured and the estimated dietary intake is unknown, we do not know if there is a large variation in the quality and amount of vitamin D within the multivitamins that women in this study consumed. Also, the finding that vitamin D levels were lower in non-white women may be related to findings from other research that has shown African-American populations have a lower serum vitamin D levels than white populations without increased rates of osteoporotic fracture.4 However, since this was a secondary analysis, these variables were not measured.
Although Mumford et al demonstrated that there may be an association between vitamin D levels and pregnancy loss and live birth, the American College of Obstetricians and Gynecologists does not recommend physicians routinely assess vitamin D levels in women desiring to become pregnant.5 More research is needed to further understand the role of vitamin D in the reproductive system and to determine the efficacy and dose of vitamin D in women desiring to become pregnant. Since evidence demonstrating that serum vitamin D levels may not be the best indicator of vitamin D status, particularly in non-white populations, ordering vitamin D serum levels and treating patients with vitamin D supplementation for indications other than bone health may be premature.
Although the role of vitamin D in pregnancy is unclear, we do know that sufficient vitamin D levels are essential for women's bone health.3 Women who have had multiple pregnancy losses need to have further workup, and vitamin D is a reasonable test. Treating patients with insufficient vitamin D levels will protect their bone health and also may improve their pregnancy outcomes.
Financial Disclosure: Integrative Medicine Alert’s Executive Editor David Kiefer, MD; Peer Reviewer Suhani Bora, MD; Relias Media Executive Editor Leslie Coplin; Editor Jonathan Springston; Editorial Group Manager Terrey L. Hatcher; and Accreditations Manager Amy M. Johnson, MSN, RN, CPN, report no financial relationships relevant to this field of study.