Preventing Health Disparities During Pregnancy Through Vitamin D Supplementation

This project, comprised of discrete studies, expert evaluation and translation for public health campaign, promotes racial health equity for pregnant women. A strong racial disparity in the US surrounds vitamin D status: African American women have 20-fold and Hispanic women 2.4-fold greater risk of deficiency than Caucasian women. In South Carolina, greater than 70% of African American, 33% of Hispanic and 12% of Caucasian pregnant women meet the Institute of Medicine's (IOM's) 2010 definition of vitamin D deficiency (1-3). Such disparity on the basis of race/ethnicity represents a serious public health issue. Yet, some-including the IOM-argue that vitamin D deficiency minimally affects maternal and fetal health and that no vitamin D supplementation study has shown improved pregnancy outcome (3, 4). Results of our two recently completed vitamin D trials involving 510 pregnant women throughout pregnancy suggest otherwise (5-7). In the NICHD trial, women supplemented with 400 IU vitamin D/day (the amount in most prenatal vitamins) vs. 2000 or 4000 IU/day not only had worse vitamin D status throughout pregnancy, but combined higher risk of comorbidities of pregnancy (gestational diabetes, hypertensive disorders, infection, preterm labor/birth and periodontal inflammation) (7). In trial 2, women at two South Carolina community health centers were supplemented with vitamin D and again, higher vitamin D status was associated with lower comorbidities of pregnancy risk (6, 8).

A novel finding from the NICHD trial was that serum levels of active, hormonal vitamin D (1,25(OH)2D) during pregnancy were optimized at twice the level normally observed in non-pregnant women, levels that would be considered toxic in nonpregnant individuals. At no other time in life does this relationship exist. Is the hormone at such levels driving some vital process during pregnancy? If so, what is that process? There are hints as to why 1,25(OH)2D is elevated in pregnant women. During pregnancy, the maternal immune system undergoes drastic changes for fetal protection. For example, if a solid organ composed of 50% mismatched cell markers (antigens) was transplanted into a new host, it would be rejected within hours; however, a fetus that is 50% mismatched with paternal antigens is protected from immune destruction through a process known as immune privilege. During pregnancy the body increases immune suppressive cells, reduces highly activated natural killer and cytotoxic T-cells with capacity to destroy the fetus and still has the capacity to fight off foreign pathogens. While the mechanisms that orchestrate this complex balance are unknown, we hypothesize that due to vitamin D's ability to regulate immune cells, vitamin D is responsible for many immune alterations associated with fetal immune privilege. We further hypothesize that correction of vitamin D deficiency during pregnancy will protect against immune-mediated disorders such as recurrent miscarriage, preterm birth, bacterial infections, periodontal inflammation and gestational diabetes. This premise, tested and confirmed by this project, will lead to public policy changes and equality in vitamin D status during pregnancy. To test the validity of these hypotheses, the goals of this project are as follows:

The central goal of this project is to realize racial equity for all pregnant women and their developing babies in the US. To achieve this goal, there are 3 specific objectives:

1. Determine how vitamin D deficiency leads to immune imbalance and subsequent disparities in pregnancy health outcomes;
2. Determine how vitamin D supplementation prevents such imbalance and disparities; and
3. Translate such findings into public health policy. By comparing women of diverse racial/ethnic backgrounds who receive the current vitamin D IOM standard of 400 IU/day compared to 4000 IU/day [daily dose shown to achieve optimal production of active vitamin D hormone (1,25(OH)2D)], the clear effects of vitamin D will be realized. Furthermore, these effects of sufficient vitamin D during pregnancy transcend the racial differences of the women.

Study Design: This is a randomized, placebo-controlled clinical trial of 450 pregnant women who will be enrolled between 10-14 weeks of gestation and followed until delivery. Following written, informed consent, each mother will be randomized to receive either placebo or 4000 IU/day vitamin D3 plus the standard prenatal vitamin (containing 400 IU vitamin D3). She will be followed monthly for a total of nine study visits. These visits will include the initial recruitment of mother at 10-14 weeks of pregnancy, monthly study visits, delivery study visit, and 18-month post-partum follow-up visit for mother and child. The primary outcome variable is maternal and neonatal health status as a function of maternal and infant vitamin D status. Secondary outcome variables to be analyzed, as a function of maternal vitamin D status during pregnancy will include: T-lymphocyte profile, immune function indicators, neonatal growth, inflammatory cytokine profile, methylation patterns of DNA of both mother and her neonate,