The Role of Vitamin D in the Development of Gestational

DiabetesRenée Guida

MSPH/RDJohns Hopkins Bloomberg School of Public Health

Overview Vitamin D Gestational diabetes Studies:

Vitamin D status & risk for GDM Vitamin D status & glycemic control Supplementation effects

Mechanisms Clinical Implications Contradictory findings Conclusions

Vitamin D Fat-soluble vitamin Found naturally in limited foods; fortified in milk and

orange juice Produced endogenously through skin from ultraviolet

rays. Vitamin D converted to 25-OHD in the liver, and in

the kidney hydroxylated to 1,25-(OH2)D (active form) Functions:

Enhances calcium absorption in gut, necessary for bone health

Modulates cell growth Immune function Reduces inflammation Gene regulation 1

https://www.inlifehealthcare.com/blog/health-benefits-of-vitamin-d/

Vitamin D Assessment Assessed through serum 25(OH)D concentrations, most common

circulating form of vitamin D 2

nmol/L ng/mL Status<30 <12 Deficiency, rickets in

infants and children, osteomalacia in adults

30 to <50 12 to <20 Inadequate for bone health

≥50 ≥20 Adequate for bone health

>125 >50 High levels, potential for toxicity, especially when >150 nmol/L (>60 ng/mL)(NIH)

Vitamin D Deficiency Deficiency common in women and pregnant women 2

Characteristics of those with deficiency: Breastfed infants Limited exposure to sun Old age Darker skin tone Obesity (BMI > 30 kg/m2) 2

During pregnancy, RDA remains the same for women 14-50 years old at 600 IU (15 mcg/day) 2

Gestational Diabetes CDC definition: “impaired glucose tolerance and hyperglycemia with

onset or first recognition during pregnancy, caused by imbalance between insulin resistance and insulin secretion” 3

Affects approximately 1 – 14% pregnancies in US and is increasing with rising rates of type 2 diabetes and obesity 3

Consequences: Infant macrosomia (>9 lb) Hypoglycemia in infant Cesarean delivery Type 2 diabetes post-partum 4

Gestational Diabetes Risk Factors Overweight/Obesity (BMI>25) Previously delivered a baby > 9 lbs. Previous diagnosis of gestational diabetes mellitus Polycystic ovarian syndrome A1C ≥ 5.7% 4

**Women with risk factors should be screened for undiagnosed type 2 diabetes at first prenatal visit

A1C ≥ 6.5% Fasting plasma glucose ≥ 126 mg/dL 2-hr post 75 g load (OGTT) ≥ 200 mg/dL 4

Gestational Diabetes Diagnosis Pregnant women not known to have diabetes tested at 24-28 weeks

using one or two step approach:

American Diabetes Association: One-step: 75 gram oral glucose tolerance test with fasting plasma glucose

measurements at 1 and 2 hours. Fasting: ≥ 92 mg/dL (5.1 mmol/L) 1 hour: ≥ 180 mg/dL (10.0 mmol/L) 2 hours: ≥ 153 mg/dL (8.5 mmol/L) 4

Two-step: Non-fasting: 50 g glucose load measured at 1 hour. If >140 mg/dL, 100-g OGTT performed (fasting)

3 hours post load: cutoff of > 140 mg/dL used for diagnosis of GDM4

Different diagnostic criteria 4

Vitamin D Status and Risk for GDM Meta analysis: 20 observational studies, 9,209 participants, 24-35 years, BMI: 21.9

- 31 6 out of 20 studies showed significant associations between vitamin D

deficiency and risk of GDM Pooled results: women with deficiency had significantly increased risk for

developing GDM (OR = 1.53, 95% CI 1.33 – 1.75) 5

Zhang 2008Baker (2011)Parildar (2012)Wang 2012Zuhur (2013)Bener (2013)Makgoba (2011)Arnold (2015)Pleskacvoa (2015)Burris (2012)

.5 1 10

OR (95% CI)3.06 (1.43, 6.57)1.27 (0.40, 4.7)2.35 (1.10, 5.00)33.51 (1.99,563.96)1.94 (1.13, 3.33)1.38 (1.05, 1.82)1.24 (0.73, 2.11)1.93 (1.28, 2.89)1.67 (0.22, 12.531.27 (0.77, 2.11)

Meta: Random-effects model 16 studies, 5,449 participants,

comparing mean difference of 25(OH)D levels and GDM

10 studies reported women with GDM had significantly decreased serum 25OHD levels

Pooled effect: -4.93 nmol/L (p=.001)

Conclusions:1. Serum 25(OH)D level was

significantly lower in participants with GDM than control.

2. Vit. D deficiency is significantly associated with risk for GDM 5

(Zhang et al, 2015)

Meta- Limitations Not all of these studies reported adjusted odds ratios so this

could not be taken into consideration when pooling results.

Observed associations may be confounded by BMI and skin tone, especially since BMI and pre-pregnancy BMI increases risk for vitamin D deficiency and GDM.

However, after adjusting for maternal age, BMI, and ethnicity, there was still an association between vitamin D deficiency and GDM (OR 1.67, CI 1.31 to 2.13). 5

Vitamin D status and glycemic control -Study 1 Study: nested case control study based on a prospective cohort of normal

weight pregnant Chinese women 200 cases with GDM, 200 controls using frequency matching based on estimated

season of conception ADA criteria used for diagnosis of GDM

All pregnant women screened at 26-28 weeks if no previous diagnosis made with 50 g OGTT

Two step approach used if plasma glucose >7.8 mmol/L for 1 hour glucose load 100 g OGTT

Diagnosis: 2 or more Fasting glucose ≥ 5.3 mmol/L 1 h post-load ≥ 10 mmol/L 2 h post-load ≥ 8.6 mmol/L 3 h post-load ≥ 7.8 mmol/L

Considered normal glucose tolerant (NGT) if values were below thresholds 6

Results

Vitamin D Status GDM Group NGT GroupUnadjusted OR

(95% CI) Adjusted OR (95% CI)

Sufficiency(25OHD ≥ 25 nmol/L)

78 (42.2%)

107 (57.8%)

1.00 (reference) 1.00

(reference)Deficiency (25OHD <25 nmol/L)

122 (56.7%

)

93 (43.3%) 1.8 (1.21-2.68) 1.59 (1.03 –

2.44)

P-value - - 0.004 .035

*Each 1 nmol/L decrease in serum 25OHD concentrations increased the risk for GDM by 1.025-fold (p=.035, 95% CI: 1.002 – 1.049) adjusting for these confounders. 6

Adjusted for maternal age, family history of T2DM and TG

Results cont. 25(OH)D levels independently associated with HbA1c after

adjusting for pre-pregnancy BMI, fasting plasma insulin, family history of Type 2 diabetes, and triglycerides (p=.036).

Insulin resistance assessed through calculation of HOMA-IR ≥ 3, which was significantly higher in subjects with 25OHD <25 nmol/L compared to those ≥25 nmol/L (p=.04).

Serum 25(OH)D levels associated with reduced risk of insulin resistance after adjusting for maternal age, pre-pregnancy BMI, family history of Type 2 diabetes, and AUC-insulin (adjusted OR =0.935, 95% CI 0.877 -0.996, p=.039). 6

Vitamin D status and glycemic control- Study 2 Observation cross-sectional study 160 pregnant women, 20-40 years old, 3rd trimester Group 1: 80 women with GDM Group 2: 80 women with normal blood glucose levels Results:

Most women with insufficiency vs. deficiency.Group 1 had higher fasting insulin levels compared to group 2. 7

Vitamin D -0.492 0.001

Variables r p-value Variables r p-value

Correlation between HbA1C and Vitamin D

Correlation between Vitamin D and variables

Fasting blood sugar -.2450 0.000Fasting insulin -.357 0.000

Study 2 - Conclusion Significant negative correlation between glycemic control and

vitamin D levels.

Supplementation and adequate replacement not studied and further larger scale supplementation studies required. 7

Vitamin D Supplementation and Incidence of GDM Randomized controlled trial, 500 women, 12-16 weeks gestation

Serum 25(OH)D levels <30 ng/ml randomly categorized into 2 groups

Results: Incidence and odds of GDM in group B significantly lower than group A (6.7%

vs. 13.4%) and (OR=0.46, p=.01). Supplementation increased serum 25(OH)D above 30 ng/mL in mothers at

time of delivery and prevented neonatal vitamin D deficiency. Mean vitamin D levels in cord blood of group B significantly higher than in

group A (37.9 ng/mL vs. 27.2 ng/mL, p=.001).

Conclusion: 50,000IU vitamin D every 2 weeks decreased incidence of GDM with no

adverse toxicity effects 8

Group A (n=250) Group B (n=250)400 IU vitamin D daily 50,000 IU vitamin D every 2

weeks until delivery

Mechanisms1. Variants of nuclear vitamin D receptor associated with susceptibility to GDM 10

2. VDR expression found in pancreatic beta cells that affects local production of 1,25OH2D311

3. Vitamin D involved in calcium homeostasis and calcium flux through membranes (necessary for insulin release) 11

4. Vitamin D promotes insulin sensitivity by stimulating the expression of insulin receptors and enhancing insulin-dependent glucose transporters 6

5. Vitamin D improves insulin resistance through direct glucose absorption or increase in insulin sensitivity 8

https://www.researchgate.net/figure/46412881_fig1_Fig-3-Genomic-and-non-genomic-responses-of-vitamin-D-receptor-binding-to-125OH-2-D

Clinical Implications RD to emphasize importance of adequate vitamin D status in women who

are deficient, especially in those with risk factors or current diagnosis of diabetes

Supplementation in 1st trimester: to reduce incidence or development early in pregnancy

Supplementation in 2nd trimester: Study found that serum 25(OH)D levels were significantly lower in 2nd

trimester compared to 3rd trimester. Inverse relationship between serum 25(OH)D levels in 2nd trimester with

insulin (p=.047) and glucose concentrations 2 hours post 75 g OGGT at 24-28 weeks gestation. 12

RDA of 600 IU during pregnancy recommended 2

Contradictory Findings Study found replacement of vitamin D in women with

deficiency and GDM did not reverse glucose intolerance. 13

Two trials in meta analysis found no significant difference in risk of gestational diabetes with vitamin D supplementation. 14

Conclusions Association between vitamin D status and gestational diabetes Vitamin D deficiency may increase a woman’s risk for developing

gestational diabetes. Vitamin D’s role through gene regulation, calcium homeostasis and

insulin sensitivity may improve glycemic control

Importance of RCTs 7

Need for multiple studies using standardized assessment for deficiency and diagnostic criteria for GDM

Effectiveness of dose-response relationship of vitamin D on management of GDM symptoms

Address heterogeneity of population

References1. Benefits Of Vitamin D and its Significance In Our Daily Life!. Inlifehealthcarecom. 2014. Available at: https://www.inlifehealthcare.com/blog/health-benefits-of-vitamin-d/#.V6jBvJX2aJA. Accessed August 8, 2016.2. Office of Dietary Supplements - Vitamin D. Odsodnihgov. 2016. Available at: https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/. Accessed August 8, 2016.3. DeSisto C, Kim S, Sharma A. Prevalence Estimates of Gestational Diabetes Mellitus in the United States, Pregnancy Risk Assessment Monitoring System (PRAMS), 2007–2010. Preventing Chronic Disease. 2014;11. doi:10.5888/pcd11.130415.4. "ADA Diabetes Management Guidelines A1C Diagnosis | NDEI". Ndei.org. Web. 28 Aug. 2016.5. Zhang M, Pan G, Guo J, Li B, Qin L, Zhang Z. Vitamin D Deficiency Increases the Risk of Gestational Diabetes Mellitus: A Meta-Analysis of Observational Studies. Nutrients. 2015;7(10):8366-8375. doi:10.3390/nu7105398.6. Wang, O.; Nie, M.; Hu, Y.Y.; Zhang, K.; Li, W.; Ping, F.; Liu, J.T.; Chen, L.M.; Xing, X.P. Association between vitamin D insufficiency and the risk for gestational diabetes mellitus in pregnant Chinese women. Biomed. Environ. Sci. 2012, 25, 399–406.7. El Lithy A, Abdella R, El-Faissal Y, Sayed A, Samie R. The relationship between low maternal serum vitamin D levels and glycemic control in gestational diabetes assessed by HbA1c levels: an observational cross-sectional study. BMC Pregnancy Childbirth. 2014;14(1). doi:10.1186/1471-2393-14-362.8. The effects of vitamin D supplementation on maternal and neonatal outcome: A randomized clinical trial. Iran J Reprod Med Vol. 2015;13(11):687-696.

References cont.9. placenta V. Fig. 3. Genomic and non-genomic responses of vitamin D receptor binding... Researchgatenet. Available at: https://www.researchgate.net/figure/46412881_fig1_Fig-3-Genomic-and-non-genomic-responses-of-vitamin-D-receptor-binding-to-125OH-2-D. Accessed August 8, 2016. 10. Rahmannezhad G, Mashayekhi F, Goodarzi M, Rezvanfar M, Sadeghi A. Association between vitamin D receptor ApaI and TaqI gene polymorphisms and gestational diabetes mellitus in an Iranian pregnant women population. Gene. 2016;581(1):43-47. doi:10.1016/j.gene.2016.01.026. 11. Papandreou DHamid Z. The Role of Vitamin D in Diabetes and Cardiovascular Disease: An Updated Review of the Literature. Disease Markers. 2015;2015:1-15. doi:10.1155/2015/580474. 12. Jafarzadeh L, Motamedi A, Behradmanesh M, Hashemi R. A Comparison of Serum Levels of 25-hydroxy Vitamin D in Pregnant Women at Risk for Gestational Diabetes Mellitus and Women Without Risk Factors. Mater Sociomed. 2015;27(5):318. doi:10.5455/msm.2015.27.318-322.13. Muthukrishnan JDhruv G. Vitamin D status and gestational diabetes mellitus. Indian Journal of Endocrinology and Metabolism. 2015;19(5):616. doi:10.4103/2230-8210.163175.14. Palacios C, De-Regil L, Lombardo L, Peña-Rosas J. Vitamin D supplementation during pregnancy: Updated meta-analysis on maternal outcomes. The Journal of Steroid Biochemistry and Molecular Biology. 2016. doi:10.1016/j.jsbmb.2016.02.008.