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Vitamin D deficiency co-exists in patients with COVID-19. At this time, dark skin color, increased age, the presence of pre-existing illnesses and vitamin D deficiency are features of severe COVID disease. Of these, only vitamin D deficiency is modifiable. Through its interactions with a multitude of cells, vitamin D may have several ways to reduce the risk of acute respiratory tract infections and COVID-19: reducing the survival and replication of viruses, reducing risk of inflammatory cytokine production, increasing angiotensin-converting enzyme 2 concentrations, and maintaining endothelial integrity. Fourteen observational studies offer evidence that serum 25-hydroxyvitamin D concentrations are inversely correlated with the incidence or severity of COVID-19. The evidence to date generally satisfies Hill’s criteria for causality in a biological system, namely, strength of association, consistency, temporality, biological gradient, plausibility (e.g., mechanisms), and coherence, although experimental verification is lacking. Thus, the evidence seems strong enough that people and physicians can use or recommend vitamin D supplements to prevent or treat COVID-19 in light of their safety and wide therapeutic window. In view of public health policy, however, results of large-scale vitamin D randomized controlled trials are required and are currently in progress.

Three previous reviews on the association of vitamin D insufficiency in pregnancy with preterm birth (PTB) and stillbirth were limited in scope and deemed inconclusive. With important new evidence accumulating, there is the need to update the previous estimates and assess evidence on other clinically important outcomes such as spontaneous abortion and Apgar score. We conducted a systematic review and meta-analysis to evaluate the quality and strength of the available evidence on the relations between vitamin D nutritional status, and pregnancy and birth outcomes. PubMed and Scopus databases were searched from their inception to June, 2015 with no language restrictions imposed. Eighteen longitudinal studies satisfied the inclusion criteria. Random effects model was applied in computing the summary effect estimates and their corresponding 95% confidence intervals. Serum 25(OH)D levels <75 nmol/l was associated with 83% (95% CI: 1.23, 2.74) and 13% (95% CI: 0.94, 1.36) increased risk of PTB measured at <32-34 weeks and <35-37 weeks, respectively. An inverse dose-response relation was observed for both PTB outcome. Serum 25(OH)D levels <75 nmol/l was also associated with 11% increased risk of spontaneous PTB (<35-37 weeks; RR = 1.11; 95% CI: 0.75, 1.65) with a dose-response relation also noted. Vitamin D insufficiency was not associated with risk of spontaneous abortion and stillbirth (RR of 1.04 [95% CI: 0.95, 1.13] and 1.02 [95% CI: 0.96, 1.09], respectively), as well as short gestational length (ES = -0.24, 95% CI: -0.69, 0.22), and low Apgar score. We found vitamin D insufficiency to be associated with risk of PTB. Regarding spontaneous abortion and stillbirth, the available evidence suggest no association with low vitamin D levels. The evidence on vitamin D nutrition and Apgar score is conflicting and controversial. Overall, the experimental evidence uncovered was small and weak. Hence, the benefits of vitamin D supplementation during pregnancy should be further evaluated through rigorous intervention studies.

Studies have indicated that 25-hydroxyvitamin D (25(OH)D) level in obese is lower than normal weight subjects; however, results of studies that investigated relationship between 25(OH)D and fat mass are inconsistent. In addition, several randomized clinical trials (RCTs) have studied the influence of cholecalciferol supplement on percentage fat mass (PFM) but their results are conflicting. The objectives were to investigate the association between vitamin D3 and PFM pooling together observational studies and RCTs. PubMed/MEDLINE, Cochrane, and Scopus were comprehensively searched from inception to September 2016. The Fisher’s Z (SE) of correlation coefficient and mean (SD) of changes in PFM from baseline were used to perform meta-analysis in observational studies and RCTs, respectively. To determine potential source of heterogeneity, subgroup and meta-regression analyses were conducted. Pooling correlation coefficients showed an inverse association between PFM (Fisher’s Z: − 0.24, 95% CI: − 0.30 to −0 .18) and FM (Fisher’s Z: − 0.32, 95% CI: − 0.43 to − 0.22) and 25(OH)D. Subgroup analysis revealed continent but not gender influence on the effect size. Meta-regression analysis indicated that age, latitude, and longitude are not sources of heterogeneity. Combining trials showed vitamin D3 supplementation had a mild but insignificant effect on PFM (− 0.31%, 95% CI: − 1.07 to 0.44). Subgroup analyses indicated that type of cholecalciferol and treatment regimens explain source of heterogeneity. Age, baseline body mass index, dose of cholecalciferol, length of study, female (%), and baseline 25(OH)D are not source of heterogeneity. In conclusion, our results state that 25(OH)D level is inversely correlated with PFM but cholecalciferol supplementation had no effect on PFM.

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) D 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 (40 ng·mL ). 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.

The placenta plays an important role in how vitamin D is metabolized and supplied to the fetus.

Vitamin D is an endocrine regulator of calcium and bone metabolism. Yet, its effects include other systems, such as innate and adaptive immunity. Unique to pregnancy, circulating 1,25-dihydroxyvitamin D (1,25[OH] 2 D) increases early on to concentrations that are 2–3 times prepregnant values. At no other time during the lifecycle is the conversion of 25-hydroxyvitamin D (25[OH]D) to 1,25(OH) 2 D directly related and optimized at ≥100 nmol/L. Vitamin D deficiency appears to affect pregnancy outcomes, yet randomized controlled trials of vitamin D supplementation achieve mixed results depending on when supplementation is initiated during pregnancy, the dose and dosing interval, and the degree of deficiency at the onset of pregnancy. Analysis of trials on an intention-to-treat basis as opposed to the use of 25(OH)D as the intermediary biomarker of vitamin D metabolism yields differing results, with treatment effects often noted only in the most deficient women. Immediately after delivery, maternal circulating 1,25(OH) 2 D concentrations return to prepregnancy baseline, at a time when a breastfeeding woman has increased demands of calcium, beyond what was needed during the last trimester of pregnancy, making one question why 1,25(OH) 2 D increases so significantly during pregnancy. Is it to serve as an immune modulator? The vitamin D content of mother’s milk is directly related to maternal vitamin D status, and if a woman was deficient during pregnancy, her milk will be deficient unless she is taking higher doses of vitamin D. Because of this relative “deficiency,” there is a recommendation that all breastfed infants receive 400 IU vitamin D 3 /day starting a few days after birth. The alternative – maternal supplementation with 6,400 IU vitamin D 3 /day, effective in safely raising maternal circulating vitamin D, that of her breast milk, and effective in achieving sufficiency in her recipient breastfeeding infant – remains a viable option. Additional research is needed to understand vitamin D’s influence on pregnancy health and the effect of maternal supplementation on breast milk’s immune signaling.

Given the high rate of preterm birth (PTB) nationwide and data from RCTs demonstrating risk reduction with vitamin D supplementation, the Medical University of South Carolina (MUSC) implemented a new standard of care for pregnant women to receive vitamin D testing and supplementation. To determine if the reported inverse relationship between maternal 25(OH)D and PTB risk could be replicated at MUSC, an urban medical center treating a large, diverse population. Medical record data were obtained for pregnant patients aged 18-45 years between September 2015 and December 2016. During this time, a protocol that included 25(OH)D testing at first prenatal visit with recommended follow-up testing was initiated. Free vitamin D supplements were offered and the treatment goal was ≥40 ng/mL. PTB rates (<37 weeks) were calculated, and logistic regression and locally weighted regression (LOESS) were used to explore the association between 25(OH)D and PTB. Subgroup analyses were also conducted. Among women with a live, singleton birth and at least one 25(OH)D test during pregnancy (N = 1,064), the overall PTB rate was 13%. The LOESS curve showed gestational age rising with increasing 25(OH)D. Women with 25(OH)D ≥40 ng/mL had a 62% lower risk of PTB compared to those <20 ng/mL (p<0.0001). After adjusting for socioeconomic variables, this lower risk remained (OR = 0.41, p = 0.002). Similar decreases in PTB risk were observed for PTB subtypes (spontaneous: 58%, p = 0.02; indicated: 61%, p = 0.006), by race/ethnicity (white: 65%, p = 0.03; non-white: 68%, p = 0.008), and among women with a prior PTB (80%, p = 0.02). Among women with initial 25(OH)D <40 ng/mL, PTB rates were 60% lower for those with ≥40 vs. <40 ng/mL on a follow-up test (p = 0.006); 38% for whites (p = 0.33) and 78% for non-whites (p = 0.01). Maternal 25(OH)D concentrations ≥40 ng/mL were associated with substantial reduction in PTB risk in a large, diverse population of women.

BackgroundLittle is known about how maternal obesity impacts breast milk (BM) composition and how BM composition may impact growth. We sought to determine the role of maternal body mass index (BMI) on BM inflammatory and oxidative stress markers and to delineate the role of these BM markers on infant growth.MethodsThis was a secondary analysis of 40 mother-infant dyads. We first assessed the association between maternal BMI and BM marker (omega-6:omega-3 polyunsaturated fatty acid ratio (n-6:n-3 PUFA), leptin, interleukin (IL)-8, IL-6, IL-1β and malondialdehyde (MDA)) concentration at one (V1) and four (V4) months postpartum. We then examined the association between BM markers on infant growth trajectory from birth to seven months.ResultsHigher maternal BMI was associated with higher BM n-6:n-3 PUFA (V1 β = 0.12, 95% CI 0.01, 0.2; V4 β = 0.13, 95% CI 0.01, 0.3) and leptin (V1 β = 107, 95% CI 29, 184; V4 β = 254, 95% CI 105, 403) concentrations. Infants exposed to high BM n-6:n-3 PUFA had higher BMI z-scores over time (p = 0.01). Higher BM leptin was associated with lower infant percent fat mass at V4 (β = −9, 95% CI −17, −0.6). Infants exposed to high BM IL-8, IL-6, or IL-1β had higher weight z-scores over time (IL-8 p < 0.001; IL-6 p < 0.001; IL-1β p = 0.02). There was no association between BM MDA and maternal BMI or infant growth.ConclusionsHigher maternal BMI is associated with higher BM n-6:n-3 PUFA and leptin concentrations. In addition, higher BM n-6:n-3 PUFA and inflammatory cytokines were associated with accelerated weight gain in infancy.

Pregnancy represents a time of rapid bodily change, which includes physical proportions, physiology and responsibility. At this context, maternal vitamin D stores have been the objective of extensive scientific research during the last decades, focusing on their potential effects on maternal an neonatal health. A growing body of observational studies indicated that maternal hypovitaminosis D (as defined by maternal 25-hydroxyvitamin D [25(OH)D] levels <20 ng/ml or <50 nmol/l) is a significant risk factor for adverse neonatal outcomes including asthma, multiple sclerosis and other neurological disorders. On that basis, this review aims to provide to the reader new insights into the vitamin D requirements and function during pregnancy supported by recent data and will not discuss the classical roles of vitamin D and skeletal function during pregnancy. In addition, we will focus on recent results that demonstrate that maternal vitamin D supplementation could reduce neonatal respiratory and neurological complications, suggesting that available guidelines should be updated, since it remains unclear why these recommendations are not updated according to recent results. Also, with regard to randomized controlled trials (RCT’s) for vitamin D, we consider that they are largely doomed to fail. The reasons for this are many and specific cases of this failure will be presented in this text.

The level of serum 25-hydroxyvitamin D (25(OH)D) at which intact parathyroid hormone (iPTH) is maximally suppressed (suppression point) and below which PTH begins to rise (inflection point) has been used to define optimum 25(OH)D concentration. We aimed to study the association of circulating iPTH with 25(OH)D concentrations and to determine a 25(OH)D threshold associated with a significant iPTH suppression. This cross-sectional study was conducted on 198 boys and 180 girls, aged 6-13 years with BMI ≥ 1SD (WHO criteria) recruited from primary schools. Adjusted iPTH for BMI z-score, pubertal status, and dietary calcium was used. Nonlinear regression was used to model the relationship between 25(OH)D and iPTH and identify a suppression point for 25(OH)D at which iPTH reached a plateau. Piecewise regression analysis with a single knot for all possible values of 25(OH)D were fitted. Furthermore, 95% confidence intervals (95%CI) for those point had been calculated. The mean age (SD) of girls and boys was 9.1 (1.6) and 9.4 (1.7) years, respectively. Median 25(OH)D and iPTH were 13.8 ng/mL and 33.9 pg/mL in boys and 9.9 ng/mL and 47.8 ng/mL in girls, respectively. The equation in girls was: log-iPTH = 3.598+0.868 exp[(-0.190×25(OH)D. The point for near maximal suppression of iPTH by 25(OH)D for girls occurred at a 25(OH)D concentration of 20 ng/mL (95% CI: 7.1 to 32.2). No point of maximal suppression was found for boys. We also found a 25(OH)D threshold of 10 ng/mL (95% CI: 4.6 to 22.5) for girls (f: 9.8) by linear piecewise regression modeling of adjusted iPTH. No significant inflection point for boys was observed. In overweight/obese girls, when the concentration of 25(OH)D was higher than 20 ng/mL, an iPTH mean plateau level is reached, and when its concentrations approach 10 ng/mL, the slope of iPTH concentration has been accelerated.