Table of contents
- Maternal vitamin D insufficiency and risk of adverse pregnancy and birth outcomes: A systematic review and meta-analysis of longitudinal studies.
- Vitamin D supplementation in pregnancy, prenatal 25(OH)D levels, race, and subsequent asthma or recurrent wheeze in offspring: Secondary analyses from the Vitamin D Antenatal Asthma Reduction Trial.
- Vitamin D and autism, what's new?
- Maternal Vitamin D Status in the Late Second Trimester and the Risk of Severe Preeclampsia in Southeastern China.
- Vitamin D administration during pregnancy as prevention for pregnancy, neonatal and postnatal complications.
- Vitamin D supplementation during pregnancy: Improvements in birth outcomes and complications through direct genomic alteration.
- Adverse Perinatal Outcomes and Postpartum Multi-Systemic Dysregulation: Adding Vitamin D Deficiency to the Allostatic Load Index.
- Infant Respiratory Tract Infections or Wheeze and Maternal Vitamin D in Pregnancy: A Systematic Review.
- The effect of vitamin D supplementation on gestational diabetes in high-risk women: Results from a randomized placebo-controlled trial.
- Relationship between vitamin D deficiency and early-onset neonatal sepsis.
- Relationship between newborn craniotabes and vitamin D status.
- Vitamin D and risk of preterm birth: Up-to-date meta-analysis of randomized controlled trials and observational studies.
- Maternal vitamin D levels during pregnancy and neonatal health: evidence to date and clinical implications.
- Does Maternal Vitamin D Deficiency Increase the Risk of Preterm Birth: A Meta-Analysis of Observational Studies.
- Vitamin D and Autism Spectrum Disorder: A Literature Review.
- Micronutrient deficiencies in pregnancy worldwide: health effects and prevention.
- Post-hoc comparison of vitamin D status at three timepoints during pregnancy demonstrates lower risk of preterm birth with higher vitamin D closer to delivery.
- Post-hoc analysis of vitamin D status and reduced risk of preterm birth in two vitamin D pregnancycohorts compared with South Carolina March of Dimes 2009-2011 rates.
- Maternal and Pediatric Health Outcomes in relation to Gestational Vitamin D Sufficiency.
- Vitamin D Deficiency Increases the Risk of Gestational Diabetes Mellitus: A Meta-Analysis of Observational Studies.
- Maternal vitamin D status and spontaneous preterm birth by placental histology in the US Collaborative Perinatal Project.
- Vitamin D may be a link to black-white disparities in adverse birth outcomes.
- Association between vitamin D deficiency and primary cesarean section.
- Sunlight and Vitamin D: Necessary for Public Health.
- A randomized trial of vitamin D supplementation in 2 community health center networks in South Carolina.
- Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness.
PLoS One. 2017 Mar 17;12(3):e0173605. doi: 10.1371/journal.pone.0173605. eCollection 2017.
Maternal vitamin D insufficiency and risk of adverse pregnancy and birth outcomes: A systematic review and meta-analysis of longitudinal studies.
Amegah AK1, Klevor MK2, Wagner CL3.
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.
J Allergy Clin Immunol. 2017 Mar 9. pii: S0091-6749(17)30217-8. doi: 10.1016/j.jaci.2017.01.013. [Epub ahead of print]
Vitamin D supplementation in pregnancy, prenatal 25(OH)D levels, race, and subsequent asthma or recurrent wheeze in offspring: Secondary analyses from the Vitamin D Antenatal Asthma Reduction Trial.
Wolsk HM1, Harshfield BJ2, Laranjo N2, Carey VJ3, O'Connor G4, Sandel M5, Strunk RC6, Bacharier LB6, Zeiger RS7, Schatz M7, Hollis BW8, Weiss ST3, Litonjua AA9.
Nutrient trials differ from drug trials because participants have varying circulating levels at entry into the trial.
We sought to study the effect of a vitamin D intervention in pregnancy between subjects of different races and the association between 25-hydroxyvitamin D3 (25[OH]D) levels in pregnancy and the risk of asthma/recurrent wheeze in offspring.
The Vitamin D Antenatal Asthma Reduction Trial is a randomized trial of pregnant women at risk of having children with asthma randomized to 4400 international units/d vitamin D or placebo plus 400 international units/d vitamin D. Asthma and recurrent wheezing until age 3 years were recorded.
African American (AA) women (n = 312) had lower initial levels of 25(OH)D (mean [SD], 17.6 ng/mL [8.3 ng/mL]) compared with non-AA women (n = 400; 27.1 ng/mL [9.7 ng/mL], P < .001). No racial difference was found from vitamin D supplementation in pregnancy on asthma/recurrent wheezing in offspring (P for interaction = .77). Having an initial level of greater than 30 ng/mL and being randomized to the intervention group was associated with the lowest risk for asthma/recurrent wheeze by age 3 years compared with having an initial level of less than 20 ng/mL and receiving placebo (adjusted odds ratio, 0.42; 95% CI, 0.19-0.91).
We did not find differences between AA and non-AA mothers in the effect of maternal vitamin D supplementation and asthma/recurrent wheeze in offspring at 3 years. Maternal supplementation of vitamin D, particularly in mothers with initial 25(OH)D levels of greater than 30 ng/mL, reduced asthma/recurrent wheeze in the offspring through age 3 years, suggesting that higher vitamin D status beginning in early pregnancy is necessary for asthma/recurrent wheeze prevention in early life.
Rev Endocr Metab Disord. 2017 Feb 20. doi: 10.1007/s11154-017-9409-0. [Epub ahead of print]
Vitamin D and autism, what's new?
An increasing amount of evidence points to the possibility that gestational and early childhood vitamin D deficiency [25(OH)D < 40 ng/ml] cause some cases of autism. Vitamin D is metabolized into a seco-steroid hormone that regulates about 3% of the 26,000 genes in the coding human genome. It is also a neurosteroid that is active in brain development, having effects on cellular proliferation, differentiation, calcium signaling, neurotrophic and neuroprotective actions; it also appears to have an effect on neurotransmission and synaptic plasticity. Children who are, or who are destined to become, autistic have lower 25(OH)D levels at 3 months of gestation, at birth and at age 8 compared to their unaffected siblings. Two open label trials found high dose vitamin D improves the core symptoms of autism in about 75% of autistic children. A few of the improvements were remarkable. The vitamin D doses used in these children were 300 IU/KG/day up to a maximum of 5000 IU/day (highest final 25(OH)D level reached was 45 ng/ml). The other study used 150,000 IU/month IM as well as 400 IU/day [highest final 25(OH)D level was 52 ng/ml]. These two open label trials were recently confirmed with a randomized controlled trial (RCT) using 300 IU/kg/day with a maximum of 5000 IU/day and resulted in effects similar to the two open label studies. In terms of prevention, a recent small study showed vitamin D supplementation during pregnancy (5000 IU/day) and during infancy and early childhood (1000 IU/day) significantly reduced the expected incidence of autism in mothers who already had one autistic child from 20% to 5%. Vitamin D is safe; for example, over the last 15 years, Poison Control reports there have been approximately 15,000 cases of vitamin D overdose. However only three of these 15,000 people developed clinical toxicity and no one died. Given those facts, practitioners might consider treating autism with 300 IU/kg/day, and seek to prevent autism by supplementing pregnant and lactating women (5000 IU/day) and infants and young children (150 IU/kg/day) checking 25(OH)D levels every 3 months. These doses will increase 25(OH)D blood levels to those recommended by the Endocrine Society. As the American Academy of Pediatrics recommends vitamin D supplementation during infancy and childhood, pediatricians and family practitioners should evaluate the current evidence on autism and vitamin D and act accordingly.
Nutrients. 2017 Feb 14;9(2). pii: E138. doi: 10.3390/nu9020138.
Maternal Vitamin D Status in the Late Second Trimester and the Risk of Severe Preeclampsia in Southeastern China.
Zhao X1,2, Fang R3, Yu R4, Chen D5, Zhao J6, Xiao J7.
The association between maternal vitamin D deficiency and the risk of severe preeclampsia is still debated. In the present study, we aimed to evaluate vitamin D status in Chinese pregnant women and investigate its correlation with the odds of developing severe preeclampsia. A cohort study was performed on 13,806 pregnant women who routinely visited the antenatal care clinics and subsequently delivered at the Wuxi Maternity and Child Health Hospital. All the subjects in the cohort had their serum 25-hydroxyvitamin D (25(OH)D) concentrations measured during pregnancy. A high prevalence of maternal vitamin D deficiency (25(OH)D < 50 nmol/L) was found. Pregnant women who had different BMIs before pregnancy had significantly different serum concentrations of 25(OH)D. There was also a significant difference in the serum 25(OH)D concentration among pregnant women of different ages. The serum 25(OH)D concentration was significantly lower in pregnant women who subsequently developed severe preeclampsia compared with those who did not. Maternal vitamin D deficiency at 23-28 weeks of gestation was strongly associated with increased odds for severe preeclampsia after adjusting for relevant confounders (adjusted OR, 3.16; 95% CI, 1.77-5.65). Further studies are required to investigate whether vitamin D supplementation would reduce the risk of severe preeclampsia and improve pregnancy outcomes.
Rev Endocr Metab Disord. 2017 Feb 18. doi: 10.1007/s11154-017-9414-3. [Epub ahead of print]
Vitamin D administration during pregnancy as prevention for pregnancy, neonatal and postnatal complications.
Wagner CL1, Hollis BW1, Kotsa K2, Fakhoury H3, Karras SN4.
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.
Mol Cell Endocrinol. 2017 Feb 7. pii: S0303-7207(17)30052-7. doi: 10.1016/j.mce.2017.01.039. [Epub ahead of print]
Vitamin D supplementation during pregnancy: Improvements in birth outcomes and complications through direct genomic alteration.
Hollis BW1, Wagner CL2.
Pregnancy represents a time of rapid change, including dramatic shifts in vitamin D metabolism. Circulating concentrations of the active form of vitamin D-1,25(OH)2D skyrocket early in pregnancy to levels that would be toxic to a nonpregnant adult, signaling a decoupling of vitamin D from the classic endocrine calcium metabolic pathway, likely serving an immunomodulatory function in the mother and her developing fetus. In this review, we summarize the unique aspects of vitamin D metabolism and the data surrounding vitamin D requirements during this important period. Both observational and clinical trials are reviewed in the context of vitamin D's health effects during pregnancy that include preeclampsia, preterm birth, and later disease states such as asthma and multiple sclerosis. With enhanced knowledge about vitamin D's role as a preprohormone, it is clear that recommendations about supplementation must mirror what is clinically relevant and evidence-based. Future research that focuses on the critical period(s) leading up to conception and during pregnancy to correct deficiency or maintain optimal vitamin D status remains to be studied. In addition, what effects vitamin D has on genetic signatures that minimize the risk to the mother and her developing fetus have not been elucidated. Clearly, while there is much more research that needs to be performed, our understanding of vitamin D requirements during pregnancy has advanced significantly during the last few decades.
Matern Child Health J. 2017 Mar;21(3):398-406. doi: 10.1007/s10995-016-2226-3.
Adverse Perinatal Outcomes and Postpartum Multi-Systemic Dysregulation: Adding Vitamin D Deficiency to the Allostatic Load Index.
Accortt EE1, Mirocha J2, Dunkel Schetter C3, Hobel CJ4.
Background Allostatic load (AL) is an index of multi-system physiological "wear-and-tear," operationalizing emergent chronic disease risk and predicting morbidity and mortality. AL has been proposed as an organizing framework for studying pregnancy outcomes and additional AL biomarkers for the study of maternal health would be valuable. Objectives To test whether adverse perinatal outcomes are associated with postpartum AL and if including vitamin D deficiency (serum 25(OH)D < 20 ng/ml) as an additional marker of postpartum AL increases the association. Methods The Community Child Health Network is a community-based participatory research network that enrolled women at birth and followed them for 2 years measuring ten biomarkers (body mass index, waist: hip ratio, pulse, systolic and diastolic blood pressures, cortisol slope, c-reactive protein, hgbA1c, HDL, and total cholesterol) at 6 and 12 months postpartum. A composite of four adverse perinatal outcomes (low birth weight, preterm birth, preeclampsia, and gestational diabetes) was collected from medical charts in a sample of 164 women from one site and serum 25(OH)D status was measured 24-39 weeks postpartum in this cohort. Results Twenty-nine percent experienced one or more of the four adverse perinatal outcomes. Serum 25(OH)D was significantly inversely correlated with the AL index (Spearman's r = -0.247, p = 0.002). Logistic regression results adjusting for maternal age and race showed that adverse outcome was significantly associated with higher postpartum AL (OR 1.53 for a 1-unit increase in AL, 95% CI 1.24-1.89). Adding 25(OH)D deficiency as an 11th component to the AL index improved the model fit (Delta (-2LogL) = 3.955, p = 0.047), and improved the Akaike information criterion (180.32 vs. 184.27). Conclusion Women with adverse perinatal outcomes have higher postpartum AL and adding vitamin D deficiency to the AL index strengthens this association.
Pediatr Infect Dis J. 2017 Apr;36(4):384-391. doi: 10.1097/INF.0000000000001452.
Infant Respiratory Tract Infections or Wheeze and Maternal Vitamin D in Pregnancy: A Systematic Review.
Christensen N1, Søndergaard J, Fisker N, Christesen HT.
Respiratory tract infections (RTIs) are a common cause of morbidity and mortality in young children and can be associated with wheeze. Vitamin D can have a protective role against RTI.
MATERIALS AND METHODS:
A systematic search of PubMed, Embase and the Cochrane library was performed. Titles and abstracts were evaluated, and selected articles were reviewed by 2 authors. We included randomized controlled trials (RCTs) investigating the effect of vitamin D supplementation during pregnancy on RTIs or wheeze in children of 5 years of age or younger. Observational studies on the association between serum 25-hydroxyvitamin D during pregnancy, or at birth, and RTIs and/or wheeze were included. The protocol was registered on PROSPERO (Registration number: CRD42015019183).
Of 4 RCTs, 1 showed a protective effect of a high daily dose (2000 IU) of vitamin D during pregnancy on offspring RTI doctor visits (P = 0.004; the RCT also included 800 IU/d supplement to the infants until 6 months). Meta-analysis of 3 RCTs showed a reduced relative risk for offspring wheeze when mothers were supplemented with vitamin D during pregnancy [relative risk: 0.81 (95% confidence interval: 0.68-0.97), P = 0.025]. In 3 of 4 strong-quality, and 5 of 10 moderate-quality observational studies, an inverse association between pregnancy and cord 25-hydroxyvitamin D and subsequent wheeze and/or RTI was seen.
Growing evidence supports a preventive role of vitamin D during pregnancy on offspring wheeze and/or RTI. Recommendations in future intervention studies may need to exceed current recommendations of vitamin D supplementation during pregnancy to show benefit against childhood wheeze or infections.
J Res Med Sci. 2016 Jan 28;21:2. eCollection 2016.
The effect of vitamin D supplementation on gestational diabetes in high-risk women: Results from a randomized placebo-controlled trial.
Shahgheibi S1, Farhadifar F1, Pouya B1.
Vitamin D deficiency is common in pregnancy, leading to increase in the frequency of preeclampsia, cesarean delivery, neonatal bacterial vaginosis, and gestational diabetes. The current study was designed and implemented to investigate the effect of vitamin D during the first and second trimesters of pregnancy in reducing the risk of gestational diabetes mellitus (GDM) in women who are at high risk [history of GDM, birth macrosomia, family history, and high body mass index (BMI)].
MATERIALS AND METHODS:
In a randomized, double-blind, and placebo-controlled trial, 90 pregnant women who had at least one risk factor for GDM were randomized into intervention (46 participants) and control (44 participants) groups. Participants in the intervention group took 5000 units of vitamin D daily and the control group took placebo until the 26th week of pregnancy. Then the glucose challenge test (GCT) and the glucose tolerance test (GTT) were performed to evaluate GDM.
Mean ± standard deviation (SD) age was 31.28 ± 6.38 years and 29 ± 6.24 years for the intervention group and the placebo group, respectively, (P > 0.05). In addition, there were no significant differences between two groups in terms of vitamin D levels and GCT (P > 0.05), and the difference was not significant. The incidence of diabetes in the intervention groups was statistically lower than in control group (11.4% vs 34.8; P < 0.01). The results showed that abnormal GCT in the placebo group was statistically higher than in intervention group (35.9% vs 10.9 P < 0.005).
The results of the current study showed that the prescription of vitamin D supplementation in the first and second trimesters of pregnancy was effective in reducing GDM and controlling GTT and GTC.
Zhongguo Dang Dai Er Ke Za Zhi. 2016 Sep;18(9):791-795.
[Relationship between vitamin D deficiency and early-onset neonatal sepsis].
[Article in Chinese]
Yang LR1, Li H, Yang TY, Zhang T, Zhao RC.
To evaluate the effect of vitamin D level on early-onset sepsis (EOS) in neonates.
Seventy-eight full-term neonates with EOS were used as the research group (EOS group). sixty healthy full-term neonates without clinical and/or laboratory features related to infections were used as the control group. Blood samples of the neonates and their mothers in both groups were collected within 72 hours of delivery to determine 25-hydroxyvitamin D(25-OHD) levels. The rate of vitamin D deficiency in the neonates and the level of 25-OHD supplemented to their mothers during pregnancy were compared between the two groups.
There was a significant positive correlation between the serum level of 25-OHD of the mothers and that of the neonates in both groups (EOS group: r=0.797, P<0.01; control group: r=0.929, P<0.01). The neonates and their mothers in the EOS group had significantly lower 25-OHD levels than those in the control group (P<0.01). The rate of vitamin D deficiency among the neonates in the EOS group was significantly higher than that of the control group (P<0.01). The level of vitamin D supplemented to the mothers during the last 3 months of pregnancy in the EOS group was significantly lower than that in the control group (P<0.01).
Low serum level of 25-OHD is associated with the development of early-onset sepsis in full-term neonates.
North Clin Istanb. 2016 May 2;3(1):15-21. doi: 10.14744/nci.2016.48403. eCollection 2016.
Relationship between newborn craniotabes and vitamin D status.
Ercan M1, Ozcetin M2, Karaci M3, Ozgurhan G2, Yasar A3, Guven B4.
In recent studies, vitamin D deficiency during pregnancy and early infancy has been reported to predispose children to many chronic diseases, except those of the skeletal system. The aim of this study was to investigate whether craniotabes in otherwise healthy newborns is physiological, its relationship to vitamin D deficiency and whether or not it requires treatment.
A total of 150 healthy newborns with a weight of over 2000 g were included. Newborns were divided into two groups during postnatal discharge (1-3.'s day): those with and without craniotabes. The 25-hydroxy (OH) vitamin D levels of the newborns' mothers were measured, and all infants were re-evaluated for craniotabes, as well as tested to determine levels of serum calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), parathyroid hormone (PTH) and 25(OH) vitamin D, urine calcium and creatinine.
Craniotabes was present in 45 (30%) of newborns enrolled in the study. Craniotabes of the newborns born during the winter months was significantly higher. PTH level was significantly higher in 1-month-old newborns with craniotabes than those without craniotabes. No relationship was observed between diet and craniotabes, but in exclusively breastfed infants, vitamin D level was statistically significantly lower. No statistically significant difference was found in the occurrence of craniotabes in newborns with or without vitamin D support.
The relationship between newborn craniotabes and maternal vitamin D deficiency is not clear. However, the present study illustrates that maternal vitamin D deficiency is still a major problem. Therefore, measures to prevent maternal vitamin D deficiency should be strengthened.
J Obstet Gynaecol Res. 2017 Feb;43(2):247-256. doi: 10.1111/jog.13239.
Vitamin D and risk of preterm birth: Up-to-date meta-analysis of randomized controlled trials and observational studies.
Zhou SS1, Tao YH2, Huang K2, Zhu BB2, Tao FB2.
We performed a meta-analysis of randomized controlled trials (RCT) and observational studies to answer the two following questions: (i) whether low maternal circulating 25 hydroxyvitamin D (25-OHD) is associated with an increased risk of preterm birth (PTB ) or spontaneous PTB (sPTB ); and (ii) whether vitamin D supplementation alone during pregnancy can reduce the risk of PTB.
Literature search was carried out using Pubmed, Web of Science and Embase databases up to June 2016. Pooled OR or relative risk (RR) with 95%CI were computed using fixed or random effects models depending on the size of heterogeneity. Subgroup analysis was used to explore potential sources of between-study heterogeneity. Publication bias was evaluated using Egger's test and Begg's test.
Twenty-four articles (six RCT and 18 observational studies) were identified. Maternal circulating 25-OHD deficiency (pooled OR, 1.25; 95%CI: 1.13-1.38) rather than insufficiency (pooled OR, 1.09; 95%CI: 0.89-1.35) was associated with an increased risk of PTB, and vitamin D supplementation alone during pregnancy could reduce the risk of PTB (pooled RR, 0.57; 95%CI: 0.36-0.91). This was also the case for the sPTB subgroup (circulating 25-OHD <50 vs >50 nmol/L; pooled OR, 1.45; 95%CI: 1.20-1.75).
Maternal circulating 25-OHD deficiency could increase PTB risk and vitamin D supplementation alone during pregnancy could reduce PTB risk. Extrapolation of the results, however, must be done with caution, and there is urgent need for larger, better-designed RCT to confirm this effect.
Ther Adv Musculoskelet Dis. 2016 Aug;8(4):124-35. doi: 10.1177/1759720X16656810. Epub 2016 Jul 13.
Maternal vitamin D levels during pregnancy and neonatal health: evidence to date and clinical implications.
Karras SN1, Fakhoury H2, Muscogiuri G3, Grant WB4, van den Ouweland JM5, Colao AM6, Kotsa K7.
Low maternal vitamin D levels during pregnancy have been associated with a plethora of adverse neonatal outcomes, including small for gestational age and preterm births, detrimental effect on offspring bone and teeth development, and risk of infectious diseases. Although most observational studies indicate a significant linear relationship between maternal 25-hydroxyvitamin D and the above outcomes, some randomized controlled trials to date are inconclusive, mostly due to differences in study design and supplementation regimen. The currently available results indicate that vitamin D supplementation during pregnancy reduces the risk of preterm birth, low birth weight, dental caries of infancy, and neonatal infectious diseases such as respiratory infections and sepsis. This narrative review aims to summarize available trial results regarding the effect of low maternal vitamin D levels during pregnancy, in conjunction with neonatal outcomes on the field, with a discourse on the appropriate clinical approach of this important issue.
Nutrients. 2016 May 20;8(5). pii: E301. doi: 10.3390/nu8050301.
Does Maternal Vitamin D Deficiency Increase the Risk of Preterm Birth: A Meta-Analysis of Observational Studies.
Qin LL1,2, Lu FG3, Yang SH4, Xu HL5, Luo BA6.
There are disagreements among researchers about the association between vitamin D deficiency during pregnancy and preterm birth (PTB ). Therefore, we conducted a meta-analysis of observational studies to evaluate this association. We performed a systematic literature search of PubMed, MEDLINE and the Cochrane Library through August 2015 with the following keywords: "vitamin D" or "cholecalciferol" or "25-hydroxyvitamin D" or "25(OH)D" in combination with "premature birth" or "preterm birth" or "PTB" or "preterm delivery" or "PTD" or "prematurity". Our meta-analysis of 10 studies included 10,098 participants and found that pregnant women with vitamin D deficiency (maternal serum 25 (OH) D levels < 20 ng/mL) experienced a significantly increased risk of PTB (odds ratio (OR) = 1.29, 95% confidence intervals(CI): 1.16, 1.45) with low heterogeneity (I² = 25%, p = 0.21). Sensitivity analysis showed that exclusion of any single study did not materially alter the overall combined effect. In the subgroup analyses, we found that heterogeneity was obvious in prospective cohort studies (I² = 60%, p = 0.06). In conclusion, pregnant women with vitamin D deficiency during pregnancy have an increasing risk of PTB.
Nutrients. 2016 Apr 21;8(4):236. doi: 10.3390/nu8040236.
Vitamin D and Autism Spectrum Disorder: A Literature Review.
Mazahery H1, Camargo CA Jr2, Conlon C3, Beck KL4, Kruger MC5, von Hurst PR6.
Low vitamin D status in early development has been hypothesised as an environmental risk factor for Autism Spectrum Disorder (ASD), given the concurrent increase in the prevalence of these two conditions, and the association of vitamin D with many ASD-associated medical conditions. Identification of vitamin D-ASD factors may provide indications for primary and secondary prevention interventions. We systematically reviewed the literature for studies on vitamin D-ASD relationship, including potential mechanistic pathways. We identified seven specific areas, including: latitude, season of conception/birth, maternal migration/ethnicity, vitamin Dstatus of mothers and ASD patients, and vitamin D intervention to prevent and treat ASD. Due to differences in the methodological procedures and inconsistent results, drawing conclusions from the first three areas is difficult. Using a more direct measure of vitamin D status- - that is, serum 25(OH)D level during pregnancy or childhood- we found growing evidence for a relationship between vitamin D and ASD. These findings are supported by convincing evidence from experimental studies investigating the mechanistic pathways. However, with few primary and secondary prevention intervention trials, this relationship cannot be determined, unless randomised placebo-controlled trials of vitamin D as a preventive or disease-modifying measure in ASD patients are available.
Nat Rev Endocrinol. 2016 May;12(5):274-89. doi: 10.1038/nrendo.2016.37. Epub 2016 Apr 1.
Micronutrient deficiencies in pregnancy worldwide: health effects and prevention.
Gernand AD1, Schulze KJ2, Stewart CP3, West KP Jr2, Christian P2.
Micronutrients, vitamins and minerals accessible from the diet, are essential for biologic activity. Micronutrient status varies widely throughout pregnancy and across populations. Women in low-income countries often enter pregnancy malnourished, and the demands of gestation can exacerbate micronutrient deficiencies with health consequences for the fetus. Examples of efficacious single micronutrient interventions include folic acid to prevent neural tube defects, iodine to prevent cretinism, zinc to reduce risk of preterm birth, and iron to reduce the risk of low birth weight. Folic acid and vitamin D might also increase birth weight. While extensive mechanistic and association research links multiple antenatal micronutrients with plausible materno-fetal health advantages, hypothesized benefits have often been absent, minimal or unexpected in trials. These findings suggest a role for population context in determining health responses and filling extensive gaps in knowledge. Multiple micronutrient supplements reduce the risks of being born with low birth weight, small for gestational age or stillborn in undernourished settings, and justify micronutrient interventions with antenatal care. Measurable health effects of gestational micronutrient exposure might persist into childhood but few data exists on potential long-term benefits. In this Review, we discuss micronutrient intake recommendations, risks and consequences of deficiencies, and the effects of interventions with a particular emphasis on offspring.
J Steroid Biochem Mol Biol. 2015 Apr;148:256-60. doi: 10.1016/j.jsbmb.2014.11.013. Epub 2014 Nov 13.
Post-hoc comparison of vitamin D status at three timepoints during pregnancy demonstrates lower risk of preterm birth with higher vitamin D closer to delivery.
Wagner CL1, Baggerly C2, McDonnell SL2, Baggerly L2, Hamilton SA3, Winkler J3, Warner G3, Rodriguez C3, Shary JR4, Smith PG4, Hollis BW4.
There have been observational reports that maternal vitamin D status at baseline and not closest to delivery is a better predictor of pregnancy outcomes, suggesting that a cascade of events is set into motion that is not modifiable by vitamin D supplementation during later pregnancy. To address this issue, in this exploratory post-hoc analysis using correlation and logistic regression, we sought to measure the strength of the association between serum 25(OH)D concentrations at 3 timepoints during pregnancy: baseline, 1st trimester (<16 weeks); 2nd trimester (16-26 weeks); and 3rd trimester (≥27 weeks) and preterm birth. It was hypothesized that the 25(OH)D value closest to delivery would be most significantly associated with preterm birth. To accomplish this objective, the datasets from NICHD (n=333) and Thrasher Research Fund (n=154) vitamin D supplementation pregnancy studies were combined. The results of this analysis were that 25(OH)D values closer to delivery were more strongly correlated with gestational age at delivery than earlier values: 1st trimester: r=0.11 (p=0.02); 2nd trimester: r=0.08 (p=0.09); and 3rd trimester: r=0.15 (p=0.001). When logistic regression was performed with preterm birth (<37 weeks) as the outcome and 25(OH)D quartiles as the predictor variable, adjusting for study and participant race/ethnicity, as with the correlation analysis, the measurements closer to delivery were more significantly associated and had a higher magnitude of effect. That is, at baseline, those who had serum concentrations <50nmol/L (20ng/mL) had 3.3 times of odds of a preterm birth compared to those with serum concentrations ≥100nmol/L (40ng/mL; p=0.27). At 2nd trimester, the odds were 2.0 fold (p=0.21) and at the end of pregnancy, the odds were 3.8 fold (p=0.01). The major findings from this exploratory analysis were: (1) maternal vitamin D status closest to delivery date was more significantly associated with preterm birth, suggesting that later intervention as a rescue treatment may positively impact the risk of preterm delivery, and (2) a serum concentration of 100nmol/L (40ng/mL) in the 3rd trimester was associated with a 47% reduction in preterm births. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.
J Steroid Biochem Mol Biol. 2016 Jan;155(Pt B ):245-51. doi: 10.1016/j.jsbmb.2015.10.022. Epub 2015 Nov 10.
Post-hoc analysis of vitamin D status and reduced risk of preterm birth in two vitamin D pregnancycohorts compared with South Carolina March of Dimes 2009-2011 rates.
Wagner CL1, Baggerly C2, McDonnell S2, Baggerly KA3, French CB2, Baggerly L2, Hamilton SA4, Hollis BW5.
Two vitamin D pregnancy supplementation trials were recently undertaken in South Carolina: The NICHD (n=346) and Thrasher Research Fund (TRF, n=163) studies. The findings suggest increased dosages of supplemental vitamin D were associated with improved health outcomes of both mother and newborn, including risk of preterm birth (<37 weeks gestation). How that risk was associated with 25(OH)D serum concentration, a better indicator of vitamin D status than dosage, by race/ethnic group and the potential impact in the community was not previously explored. While a recent IOM report suggested a concentration of 20 ng/mL should be targeted, more recent work suggests optimal conversion of 25(OH)D-1,25(OH)2D takes place at 40 ng/mL in pregnant women.
Post-hoc analysis of the relationship between 25(OH)D concentration and preterm birth rates in the NICHD and TRF studies with comparison to Charleston County, South Carolina March of Dimes (CC-MOD) published rates of preterm birth to assess potential risk reduction in the community.
Using the combined cohort datasets (n=509), preterm birth rates both for the overall population and for the subpopulations achieving 25(OH)D concentrations of ≤20 ng/mL, >20 to <40 ng/mL, and ≥40 ng/mL were calculated; subpopulations broken down by race/ethnicity were also examined. Log-binomial regression was used to test if an association between 25(OH)D serum concentration and preterm birth was present when adjusted for covariates; locally weighted regression (LOESS) was used to explore the relationship between 25(OH)D concentration and gestational age (weeks) at delivery in more detail. These rates were compared with 2009-2011 CC-MOD data to assess potential risk reductions in preterm birth.
Women with serum 25(OH)D concentrations ≥40 ng/mL (n=233) had a 57% lower risk of preterm birth compared to those with concentrations ≤20 ng/mL [n=82; RR=0.43, 95% confidence interval (CI)=0.22,0.83]; this lower risk was essentially unchanged after adjusting for covariates (RR=0.41, 95% CI=0.20,0.86). The fitted LOESS curve shows gestation week at birth initially rising steadily with increasing 25(OH)D and then plateauing at ∼40 ng/mL. Broken down by race/ethnicity, there was a 79% lower risk of preterm birth among Hispanic women with 25(OH)D concentrations ≥40 ng/mL (n=92) compared to those with 25(OH)D concentrations ≤20 ng/mL (n=29; RR=0.21, 95% CI=0.06,0.69) and a 45% lower risk among Black women (n=52 and n=50; RR=0.55, 95% CI=0.17,1.76). There were too few white women with low 25(OH)D concentrations for assessment (n=3). Differences by race/ethnicity were not statistically significant with 25(OH)D included as a covariate. Compared to the CC-MOD reference group, women with serum concentrations ≥40 ng/mL in the combined cohort had a 46% lower rate of preterm birth overall (n=233, p=0.004) with a 66% lower rate among Hispanic women (n=92, p=0.01) and a 58% lower rate among black women (n=52, p=0.04).
In this post-hoc analysis, achieving a 25(OH)D serum concentration ≥40 ng/mL significantly decreased the risk of preterm birth compared to ≤20 ng/mL. These findings suggest the importance of raising 25(OH)D levels substantially above 20 ng/mL; reaching 40 ng/mL during pregnancy would reduce the risk of preterm birth and achieve the maximal production of the active hormone.
Obstet Gynecol Int. 2015;2015:501829. doi: 10.1155/2015/501829. Epub 2015 Dec 6.
Maternal and Pediatric Health Outcomes in relation to Gestational Vitamin D Sufficiency.
Juxtaposed with monumental improvement in maternal-fetal outcomes over the last century, there has been the recent emergence of rising rates of gestational complications including preterm birth, operative delivery, and gestational diabetes. At the same time, there has been a burgeoning problem with widespread vitamin D deficiency among populations of many developed nations. This paper provides a brief review of potential health outcomes recently linked to gestational vitamin D deficiency, including preterm birth, cesarean delivery, and gestational diabetes. Although immediate costs for obstetric complications related to gestational vitamin Dinsufficiency may be modest, the short- and long-term costs for pediatric healthcare resulting from such gestational complications may be enormous and present an enduring burden on healthcare systems. With increasing evidence pointing to fetal origins of some later life disease, securing vitamin D sufficiency in pregnancy appears to be a simple, safe, and cost-effective measure that can be incorporated into routine preconception and prenatal care in the offices of primary care clinicians. Education on gestational nutritional requirements should be a fundamental part of medical education and residency training, instruction that has been sorely lacking to date.
Nutrients. 2015 Oct 1;7(10):8366-75. doi: 10.3390/nu7105398.
Vitamin D Deficiency Increases the Risk of Gestational Diabetes Mellitus: A Meta-Analysis of Observational Studies.
Zhang MX1, Pan GT2, Guo JF3, Li BY4, Qin LQ5, Zhang ZL6.
The results investigating the relationship between vitamin D levels and gestational diabetes mellitus (GDM) are inconsistent. Thus, we focused on evaluating the association of vitamin D deficiency with GDM by conducting a meta-analysis of observed studies. A systematic literature search was conducted via PubMed, MEDLINE, and Cochrane library to identify eligible studies before August 2015. The meta-analysis of 20 studies including 9209 participants showed that women with vitamin D deficiency experienced a significantly increased risk for developing GDM (odds ratio (OR) = 1.53; 95% confidence intervals (CI), 1.33, 1.75) with a little heterogeneity (I² = 16.20%, p = 0.252). A noteworthy decrease of 4.93 nmol/L (95% CI, -6.73, -3.14) in serum 25(OH)D was demonstrated in the participants with GDM, and moderate heterogeneity was observed (I² = 61.40%, p = 0.001). Subgroup analysis with study design showed that there were obvious heterogeneities in nested case-control studies (I² > 52.5%, p < 0.07). Sensitivity analysis showed that exclusion of any single study did not materially alter the overall combined effect. In summary, the evidence from this meta-analysis indicates a consistent association between vitamin D deficiency and an increased risk of GDM. However, well-designed randomized controlled trials are needed to elicit the clear effect of vitamin D supplementation on prevention of GDM.
Am J Epidemiol. 2014 Jan 15;179(2):168-76. doi: 10.1093/aje/kwt237. Epub 2013 Oct 11.
Maternal vitamin D status and spontaneous preterm birth by placental histology in the US Collaborative Perinatal Project.
Bodnar LM, Klebanoff MA, Gernand AD, Platt RW, Parks WT, Catov JM, Simhan HN.
The objective of this study was to determine the association between maternal 25-hydroxyvitamin D ( 25(OH)D) and the risk of spontaneous preterm birth (sPTB ) before 35 weeks' gestation. A random subcohort from the US Collaborative Perinatal Project (1959-1965) was sampled (n = 2,629) and augmented with all remaining cases of sPTB before 35 weeks' gestation for a total of 767 cases. Banked serum samples collected at 26 weeks' gestation or earlier were assayed for 25(OH)D. Constructs for vascular histology and inflammatory histology were developed from placental pathology examinations. There was no relationship between 25(OH)D and sPTB among white women. Among nonwhite mothers, serum 25(OH)D levels of 30-<50, 50-<75, and ≥75 nmol/L were associated with reductions of 1.0-1.6 cases of sPTB per 100 live births and 20%-30% reductions in risk of sPTB compared with 25(OH)D levels less than 30 nmol/L after adjustment for prepregnancy body mass index (weight (kg)/height (m)(2)), season, and other confounders. This association was driven by inflammation-mediated cases of sPTB and sPTB cases without placental lesions. A sensitivity analysis for unmeasured confounding by exercise, fish intake, and skin color suggested some bias away from the null in the conventional results, but conclusions were generally supported. The vitamin D-sPTB relationship should be examined in modern cohorts with detailed data on skin pigmentation and other covariates.
Obstet Gynecol Surv. 2010 Apr;65(4):273-84. doi: 10.1097/OGX.0b013e3181dbc55b.
Vitamin D may be a link to black-white disparities in adverse birth outcomes.
Bodnar LM1, Simhan HN.
In the United States, significant, intractable disparities exist in rates of major pregnancy outcomes between non-Hispanic black and non-Hispanic white women. A previously unexplored candidate influence on the black-white disparity in adverse birth outcomes is maternal vitamin D status. This review summarizes the evidence relating maternal vitamin D to preeclampsia, spontaneous preterm birth, gestational diabetes, and fetal growth restriction, and addresses gaps in our understanding of the contribution of vitamin D to the intractable black-white disparity in these conditions. The literature reviewed highlights strong biologic plausibility of role for vitamin D in the pathophysiology of these poor pregnancy outcomes. Data also suggest that maternal vitamin D deficiency may increase the risk of preeclampsia and fetal growth restriction. Less research has been done in support of relations with spontaneous preterm birth and gestational diabetes, and fetal and infant survival have rarely been studied. Few trials of vitamin D supplementation have been conducted in pregnant women with adequate power to test effects on birth outcomes. Importantly, black pregnant women have rarely been studied in vitamin D-birth outcomes research. Although vitamin D is a promising candidate influence on black-white disparities in preeclampsia, spontaneous preterm birth, fetal growth restriction, and gestational diabetes, these associations require further study in large samples of black US women. Because vitamin D deficiency is widespread and black-white disparities in pregnancy outcomes and infant survival have been resistant to previous interventions, research to test vitamin D as a causal factor is of major public health significance.
J Clin Endocrinol Metab. 2009 Mar;94(3):940-5. doi: 10.1210/jc.2008-1217. Epub 2008 Dec 23.
Association between vitamin D deficiency and primary cesarean section.
Merewood A1, Mehta SD, Chen TC, Bauchner H, Holick MF.
At the turn of the 20th century, women commonly died in childbirth due to rachitic pelvis. Although rickets virtually disappeared with the discovery of the hormone vitamin D, recent reports suggest vitamin D deficiency is widespread in industrialized nations. Poor muscular performance is an established symptom of vitamin D deficiency. The current U.S. cesarean birth rate is at an all-time high of 30.2%. We analyzed the relationship between maternal serum 25-hydroxyvitamin D [25(OH)D] status, and prevalence of primary cesarean section.
Between 2005 and 2007, we measured maternal and infant serum 25(OH)D at birth and abstracted demographic and medical data from the maternal medical record at an urban teaching hospital (Boston, MA) with 2500 births per year. We enrolled 253 women, of whom 43 (17%) had a primary cesarean.
There was an inverse association with having a cesarean section and serum 25(OH)D levels. We found that 28% of women with serum 25(OH)D less than 37.5 nmol/liter had a cesarean section, compared with only 14% of women with 25(OH)D 37.5nmol/liter or greater (P = 0.012). In multivariable logistic regression analysis controlling for race, age, education level, insurance status, and alcohol use, women with 25(OH)D less than 37.5 nmol/liter were almost 4 times as likely to have a cesarean than women with 25(OH)D 37.5 nmol/liter or greater (adjusted odds ratio 3.84; 95% confidence interval 1.71 to 8.62).
Sunlight and Vitamin D: Necessary for Public Health.
Baggerly CA, Cuomo RE, French CB, Garland CF, Gorham ED, Grant WB, Heaney RP, Holick MF, Hollis BW, McDonnell SL, Pittaway M, Seaton P, Wagner CL, Wunsch A.
J Am Coll Nutr. 2015;34(4):359-65.
Am J Obstet Gynecol. 2013 Feb;208(2):137.e1-13. doi: 10.1016/j.ajog.2012.10.888. Epub 2012 Nov 3.
A randomized trial of vitamin D supplementation in 2 community health center networks in South Carolina.
Wagner CL1, McNeil R, Hamilton SA, Winkler J, Rodriguez Cook C, Warner G, Bivens B, Davis DJ, Smith PG, Murphy M, Shary JR, Hollis BW.
We sought to determine whether 4000 IU/d (vs 2000 IU/d) of vitamin D during pregnancy is safe and improves maternal/neonatal 25-hydroxyvitamin D [25(OH)D] in a dose-dependent manner.
A total of 257 pregnant women 12-16 weeks' gestation were enrolled. Randomization to 2000 vs 4000 IU/d followed 1-month run-in at 2000 IU/d. Participants were monitored for hypercalciuria, hypercalcemia, and 25(OH)D status.
Maternal 25(OH)D (n = 161) increased from 22.7 ng/mL (SD 9.7) at baseline to 36.2 ng/mL (SD 15) and 37.9 ng/mL (SD 13.5) in the 2000 and 4000 IU groups, respectively. While maternal 25(OH)D change from baseline did not differ between groups, 25(OH)D monthly increase differed between groups (P < .01). No supplementation-related adverse events occurred. Mean cord blood 25(OH)D was 22.1 ± 10.3 ng/mL in 2000 IU and 27.0 ± 13.3 ng/mL in 4000 IU groups (P = .024). After controlling for race and study site, preterm birth and labor were inversely associated with predelivery and mean 25(OH)D, but not baseline 25(OH)D.
Maternal supplementation with vitamin D 2000 and 4000 IU/d during pregnancy improved maternal/neonatal vitamin D status. Evidence of risk reduction in infection, preterm labor, and preterm birth was suggestive, requiring additional studies powered for these endpoints.
J Bone Miner Res. 2011 Oct;26(10):2341-57. doi: 10.1002/jbmr.463.
Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness.
Hollis BW1, Johnson D, Hulsey TC, Ebeling M, Wagner CL.
J Bone Miner Res. 2011 Dec; 26(12):3001.
The need, safety, and effectiveness of vitamin D supplementation during pregnancy remain controversial. In this randomized, controlled trial, women with a singleton pregnancy at 12 to 16 weeks' gestation received 400, 2000, or 4000 IU of vitamin D(3) per day until delivery. The primary outcome was maternal/neonatal circulating 25-hydroxyvitamin D [25(OH)D] concentration at delivery, with secondary outcomes of a 25(OH)D concentration of 80 nmol/L or greater achieved and the 25(OH)D concentration required to achieve maximal 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] production. Of the 494 women enrolled, 350 women continued until delivery: Mean 25(OH)D concentrations by group at delivery and 1 month before delivery were significantly different (p < 0.0001), and the percent who achieved sufficiency was significantly different by group, greatest in 4000-IU group (p < 0.0001). The relative risk (RR) for achieving a concentration of 80 nmol/L or greater within 1 month of delivery was significantly different between the 2000- and the 400-IU groups (RR = 1.52, 95% CI 1.24-1.86), the 4000- and the 400-IU groups (RR = 1.60, 95% CI 1.32-1.95) but not between the 4000- and. 2000-IU groups (RR = 1.06, 95% CI 0.93-1.19). Circulating 25(OH)D had a direct influence on circulating 1,25(OH)(2)D(3) concentrations throughout pregnancy (p < 0.0001), with maximal production of 1,25(OH)(2)D(3) in all strata in the 4000-IU group. There were no differences between groups on any safety measure. Not a single adverse event was attributed to vitamin D supplementation or circulating 25(OH)D levels. It is concluded that vitamin D supplementation of 4000 IU/d for pregnant women is safe and most effective in achieving sufficiency in all women and their neonates regardless of race, whereas the current estimated average requirement is comparatively ineffective at achieving adequate circulating 25(OH)D concentrations, especially in African Americans.