By: Danielle Dowell, MD
Editor’s Note: October marks Pregnancy and Infant Loss Awareness Month and October 15th is World Pregnancy and Infant Loss Remembrance Day. It’s estimated that 1 in 4 women will lose a baby during pregnancy, delivery or infancy. Despite how common miscarriage, stillbirth and infant loss may be, there is still so much to learn about the factors that may play a role. For this research review, Dr. Danielle Dowell, a resident physician and former FACTS elective student, summarized a 2018 study by Mumford et al. that considers the importance of sufficient vitamin D levels in women to reduce risk of pregnancy loss.
Introduction
Vitamin D (25-hydroxyvitamin D, or 25(OH)D) has been identified as a critical factor for the proper function of numerous processes in the body, with receptors found all along the hypothalamus-pituitary-ovarian (HPO) axis. Due to the role of the HPO axis in reproductive health, vitamin D levels are thus relevant to fertility research. Previous studies have demonstrated that adequate vitamin D levels during pregnancy are associated with better pregnancy outcomes. However, such studies usually recruit participants during early pregnancy, which may exclude very early pregnancy losses and fail to account for preconception health and its possible effects on pregnancy outcomes. To bridge this knowledge gap, researchers Mumford et al [1] attempted to examine the relationship between preconception vitamin D levels and pregnancy outcomes.
“Previous studies have demonstrated that adequate vitamin D levels during pregnancy are associated with better pregnancy outcomes.”
Methods
This study utilized a prospective cohort pulled from a larger study entitled, “Effects of Aspirin in Gestation and Reproduction.” [2] In this study, women were part of a randomized, double-blind trial to evaluate effects of low dose aspirin (LDA) started during preconception on pregnancy and fertility outcomes. Women from both arms of the LDA study were used in this study and possible effects of the LDA therapy was accounted for in the analysis.
The cohort included 1,991 women, aged 18-40, actively attempting to conceive and with a history of 1-2 prior pregnancy losses. The study excluded women with history of infertility treatment, pelvic inflammatory disease, tubal occlusion, endometriosis, anovulation and polycystic ovarian syndrome, or uterine abnormality. The participants were followed for six cycles of attempting pregnancy and throughout pregnancy if achieved. All participants were given ClearBlue Fertility Monitors to help time intercourse effectively. Serum 25(OH)D was measured at baseline (preconception, operationalized as the beginning of cycles attempting conception) and again at 8 weeks gestation if the participant conceived during the six cycles.
Results
The study participants were classified as either vitamin D insufficient (<75 nmol/L 25(OH)D) or sufficient (≥75 nmol/L 25(OH)D). 46.6% of women (n=555/1191) had sufficient vitamin D concentrations ≥75 nmol/L. Women with sufficient preconception vitamin D concentrations, on average, had a lower BMI and were more likely to be white, have more than a high school education, and be employed. Vitamin D level was not associated with age, vitamin use, smoking, or number of previous live births.
Women with sufficient serum concentrations of Vitamin D were more likely to achieve live birth (RR 1·15) and clinical pregnancy (RR 1·10). Sufficient preconception vitamin D levels was associated with a lower risk of pregnancy loss (RR 0·88) while vitamin D level at 8 weeks of pregnancy was not (RR 0·98). There was no association between fecundability and vitamin D levels, at either preconception or at 8 weeks pregnancy. The percentage of pregnancy losses was similar between women with sufficient and insufficient vitamin D levels, with a mean difference of just −0.6% (95% CI −5%, 4%). However, vitamin D levels were lower overall in women who experienced pregnancy losses during the study; and, after adjusting for confounders, higher vitamin D concentrations were significantly associated with reduced risk of pregnancy loss (RR 0·88).
“Vitamin D levels were lower overall in women who experienced pregnancy losses during the study; and, after adjusting for confounders, higher vitamin D concentrations were significantly associated with reduced risk of pregnancy loss.”
Discussion
The results of this study confirm the findings of prior studies: higher vitamin D levels are associated with better pregnancy outcomes. However, this study specifically highlights the importance of sufficient preconception vitamin D levels to improve fertility and pregnancy outcomes. Vitamin D receptors are located all throughout the HPO axis, which again supports the conclusion that sufficient vitamin D levels are crucial for optimal ovarian function. Studies of women undergoing IVF treatment have also suggested that sufficient vitamin D levels are necessary for endometrial receptivity and implantation of a fertilized egg, and may even prevent early pregnancy loss by boosting maternal immune tolerance due to the inherent immune-modulating effects of vitamin D. Results of this study therefore suggest that vitamin D screening and supplementation should occur before pregnancy is achieved, especially in populations at high risk of vitamin D deficiency.
“This study confirms the findings of prior studies: higher vitamin D levels are associated with better pregnancy outcomes.”
This study does have a few limitations, including the fact that participant vitamin D levels ranged from 50-112 nmol/L. These are values that are typically considered in the normal to high range by most healthcare professionals and do not reflect the average population of truly vitamin D deficient patients, making the data less generalizable. Participant selection criteria also make the results less generalizable by including only women with a history of 1-2 prior pregnancy losses. Lastly, the study fails to consider the role of male vitamin D levels* in conception. More research is needed to further clarify the impact of both male and female vitamin D levels on fertility and pregnancy outcomes.
* Editor’s Note: As part of National Men’s Health Month this past June, we featured a research summary by Abby Koski investigating the impact of vitamin D3 on sperm parameters in infertile men. Please be sure to read it!
References
[1] Mumford SL, Garbose RA, Kim K, et al. Association of preconception serum 25-hydroxyvitamin D concentrations with livebirth and pregnancy loss: a prospective cohort study. Lancet Diabetes Endocrinol. 2018;6(9):725-732. doi:10.1016/S2213-8587(18)30153-0
[2] Connell MT, Sjaarda LA, Radin RG, et al. The Effects of Aspirin in Gestation and Reproduction (EAGeR) Trial: A Story of Discovery. Semin Reprod Med. 2017;35(4):344-352. doi:10.1055/s-0037-1606384
ABOUT THE AUTHOR
Danielle Dowell, MD
Danielle Dowell, MD is an Internal Medicine resident physician at the University of Arizona College of Medicine – Phoenix. She has always had a special interest in women’s health but found the standard curriculum in medical school to be lacking, which led her to the FACTS elective on FABMs for Family Planning and Restorative Reproductive Women’s Healthcare. Since taking the course, Dr. Dowell has been able to incorporate the knowledge she has gained regarding NFP to not only guide many women in their family planning journeys, but also help teach and empower her patients to understand and treat their reproductive health in a more comprehensive and natural way.
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