New insights into the vitamin D requirements during pregnancy

Abstract

Pregnancy represents a dynamic period with physical and physiological changes in both the mother and her developing fetus. The dramatic 2-3 fold increase in the active hormone 1,25(OH)₂D concentrations during the early weeks of pregnancy despite minimal increased calcium demands during that time of gestation and which are sustained throughout pregnancy in both the mother and fetus suggests an immunomodulatory role in preventing fetal rejection by the mother. While there have been numerous observational studies that support the premise of vitamin D's role in maintaining maternal and fetal well-being, until recently, there have been few randomized clinical trials with vitamin D supplementation. One has to exhibit caution, however, even with RCTs, whose results can be problematic when analyzed on an intent-to-treat basis and when there is high non-adherence to protocol (as if often the case), thereby diluting the potential good or harm of a given treatment at higher doses. As such, a biomarker of a drug or in this case "vitamin" or pre-prohormone is better served. For these reasons, the effect of vitamin D therapies using the biomarker circulating 25(OH)D is a far better indicator of true "effect." When pregnancy outcomes are analyzed using the biomarker 25(OH)D instead of treatment dose, there are notable differences in maternal and fetal outcomes across diverse racial/ethnic groups, with improved health in those women who attain a circulating 25(OH)D concentration of at least 100 nmol·L^-1 (40 ng·mL^-1). Because an important issue is the timing or initiation of vitamin D treatment/supplementation, and given the potential effect of vitamin D on placental gene expression and its effects on inflammation within the placenta, it appears crucial to start vitamin D treatment before placentation (and trophoblast invasion); however, this question remains unanswered. Additional work is needed to decipher the vitamin D requirements of pregnant women and the optimal timing of supplementation, taking into account a variety of lifestyles, body types, baseline vitamin D status, and maternal and fetal vitamin D receptor (VDR) and vitamin D binding protein (VDBP) genotypes. Determining the role of vitamin D in nonclassical, immune pathways continues to be a challenge that once answered will substantiate recommendations and public health policies.

Figure 1

Diagram of the metabolic processes providing vitamin D and its metabolites to various tissues in the body. Tissue distribution of vitamin D and 25(OH)D based on simple diffusion (red arrows) or endocytosis (green arrows). Endocytosis requires the tissue-specific meglin-cubilin system, whereas simple diffusion is primarily controlled by the dissociation constant of the vitamin D compound for the VDBP. Bolder red lines indicate greater diffusion rates due to higher dissociation constant. t_½, half-life.

Figure 2

Effect of vitamin D supplementation starting at 20 weeks of pregnancy with respect to the development of complications of pregnancy. Pregnancy complication in the form of preterm labor (PTL), gestational hypertension (GHTN)/preeclampsia (PE) or gestational diabetes mellitus (GDM) were observed in 25/57 (44%) women taking placebo compared to 22/108 (20.4%) women being supplemented with vitamin D. Significance between groups was P<0.02. Reproduced with permission from Sablok et al.

Figure 3

Kaplan–Meier survival estimates for the effect of vitamin D treatment during pregnancy on the development of asthma/recurrent wheeze by age 3 year analyzed in an intent-to-treat format. The hazard ratio for the time to first event of asthma or recurrent wheeze was 0.8 at 3 years, P=0.051. Reproduced with permission from Litonjua et al.

Figure 4

Kaplan–Meier survival estimates for the effect of vitamin D treatment during pregnancy on the development of asthma/recurrent wheeze by age 3 year analyzed stratified by third trimester maternal level of circulating 25(OH)D as an estimate of study compliance. The hazard ratio for the time to first event of asthma or recurrent wheeze now becomes 0.73 at 3 years, P<0.02. Reproduced with permission from Litonjua et al.

Figure 5

Circulating levels of maternal 25(OH)D with respect to birth staging. Reproduced with permisson from Wagner et al.

Figure 6

LOESS curve of 25(OH)D concentration and gestational age (weeks) at birth to show the change in average behavior with 1 and 2 s.d. windows superimposed (NICHD and TRF, n=509). Black line represents fitted LOESS curve; dark gray area represents 1 s.d.; and light gray area represents 2 s.d. Multivariable log-binomial regression found that 25(OH)D concentrations >40 ng·mL⁻¹ reduces the risk of preterm birth by 59% compared to <20.0 ng·mL⁻¹, adjusted for covariates. NICHD, National Institute of Child Health and Development. Reproduced with permission from Wagner et al.

Figure 7

Weighted Co-expression Network Analysis (WGCNA) was carried out on 5839 differentially expressed probes identified by SigGenes. 14 co-expression modules were identified and, correlated to various clinical traits. Gene network, represented by different colored coded co-expression modules (y axis) and their association with various clinical traits (x axis). The intensity of the colors indicates the strength of the relationships, as indicated by the scale to the right. The range of the scale (+1 to −1) indicates either positive (+1) or negative (−1) correlation with a specific clinical trait. Top number in each box corresponds to the Pearson’s correlation coefficient between a module and a specific trait, while the lower number represents its P-value. Traits: ppbmi=pre-pregnancy BMI; gestdays=gestational age; basev=vitamin D levels in first trimester; latev=vitamin D levels in third trimester; mother.race=maternal race (White/African-American); Child.gender+infant gender (boy/girl). Pearson’s correlation (P<0.05). Reproduced with permission from Al-Garawi et al.

Figure 8

CREB1 transcription factor network depicting CREB1 in center and known interactions among 72 genes demonstrating various functionality within the green module. Hypergeometric test adjusted for multiple comparisons using Benjamini and Hochberg (P<0.05). Reproduced with permission from Al-Garawi et al.