Vitamin D and gestational diabetes

REVIEW URRENT C OPINION Vitamin D and gestational diabetes: an update Jan S. Joergensen a, Ronald F. Lamont a,b, and Maria R. Torloni c,d Purpose of review Vitamin D status (which is involved in glucose homeostasis) is related to gestational diabetes mellitus (GDM). GDM is characterized by increased resistance to and impaired secretion of insulin and results in higher risk of adverse pregnancy outcomes including operative delivery, macrosomia, shoulder dystocia and neonatal hypoglycemia. Women with GDM and their babies are at increased risk for developing type II diabetes. Recent findings International definitions of vitamin D deficiency and normality are inconsistent. Vitamin D deficiency is common in pregnant women particularly those with poor diets and who have dark skins living in temperate climes with lack of exposure to sunlight. Summary Few interventional studies indicate that supplementation optimizes maternal vitamin D status or improves maternal glucose metabolism. Observational studies about maternal vitamin D status and risk of GDM are conflicting. This could be because of measurement of vitamin D or differences in population characteristics such as ethnicity, geographic location, gestational age at sampling and diagnostic criteria for GDM. Good-quality randomized controlled trials are required to determine whether vitamin D supplementation decreases the risk of GDM or improves glucose tolerance in diabetic women. Keywords gestational diabetes, insulin resistance, pregnancy complications, supplementation, vitamin D INTRODUCTION Vitamin D is a secosteroid obtained from diet as D2-ergocalciferol from vegetables and D3-cholecalciferol from foodstuffs such as oily fish and dairy products. In addition, vitamin D may be obtained through supplementation or synthesized subcutaneously by exposure to sunlight. The gold standard for the measurement of vitamin D is gas chromatography-mass spectrometry, but in clinical settings, it is usually measured by commercial immunoassays [1,2]. Although it is possible to measure several forms of vitamin D, most studies measure its major circulating form, 25-hydroxy vitamin D (25[OH]D), which is typically expressed in nanomoles per liter or nanograms per liter. There is inconsistency in international definitions of vitamin D deficiency, insufficiency, sufficiency and what is regarded as ‘normal’. Table 1 presents the standards that are typically used [3,4 ]. Vitamin D deficiency (VDD) or insufficiency (VDI) is common in women of reproductive age and during pregnancy, particularly in dark-skinned races at temperate climes where there are long dark winters and less exposure to sunlight, or where & www.co-clinicalnutrition.com women because of the ambient temperature or religious custom wear protective clothing. Apart from being essential for calcium and bone metabolism, vitamin D also plays a role in many other physiological mechanisms and vitamin D receptors are present in many extraskeletal tissues. Vitamin D is involved in glucose homeostasis by facilitating the secretion and action of insulin [5]. This specific effect of vitamin D led to the hypothesis that its deficiency could predispose pregnant women to develop gestational diabetes mellitus (GDM). a Department of Gynecology and Obstetrics, Clinical Institute, University of Southern Denmark, Odense University Hospital, Odense, Denmark, b Division of Surgery, University College, London, Northwick Park Institute of Medical Research Campus, London, UK, cBrazilian Cochrane Centre and dDepartment of Internal Medicine, São Paulo Federal University, São Paulo, Brazil Correspondence to Jan S. Joergensen, PhD, MD, Associate Professor, Department of Gynaecology and Obstetrics, Odense University Hospital, Odense 5000, Denmark. Tel: +45 65415154; fax: +45 24228323; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2014, 17:360–367 DOI:10.1097/MCO.0000000000000064 Volume 17
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July 2014 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Vitamin D and gestational diabetes: an update Joergensen et al. KEY POINTS GDM, maternal obesity and adverse maternal, neonatal and infant outcome [12 ]. As VDD and VDI have been shown to be treatable by simple vitamin D supplementation [13], there have been calls for interventional randomized controlled trials (RCTs), but only a few RCTs have recently been published. The incidence of VDD and VDI differs [14] according to geographic location, ethnicity and skin pigmentation, clothing, cultural habits, exposure to sunlight, nutrition and supplementation [3]. The percentage of pregnant women with VDI can vary from 96% in rural China where there is low exposure to sunlight and low vitamin D supplementation, to 1% close to the equator in Tanzanian women. Differences in 25(OH)D serum levels can be striking. Although mean serum levels of 25(OH)D in Tanzanian women are 138.5 nmol/l, they are 10 times lower (12.8 nmol/l) in Iranian women because of their lack of exposure to sunlight and low vitamin D intake [4 ]. Seasonality also plays an important role in the levels of vitamin D [15] and this could help to explain differences in the incidence of GDM [16]. &
Good-quality RCTs are required to determine whether vitamin D supplementation decreases the risk of GDM or improves glucose tolerance in diabetic women.
Results from observational studies about maternal vitamin D status and risk of GDM are conflicting.
International definitions of vitamin D deficiency and normality are inconsistent. GDM is defined as ‘carbohydrate intolerance of varying degrees of severity which first presents during pregnancy’ and is characterized by temporary maternal hyperglycemia and carbohydrate intolerance primarily because of increased insulin resistance and also impaired insulin secretion [6]. The prevalence of GDM is increasing worldwide with an incidence that typically ranges from 2 to 10% in high-income countries and up to 20%, depending on the characteristics of the populations and the diagnostic criteria used [7,8,9 ]. GDM exposes both mother and baby to short-term risks such as cesarean and operative vaginal delivery, macrosomia, shoulder dystocia, neonatal hypoglycemia and hyperbilirubinemia. Women with a history of GDM are also at increased risk for developing type II diabetes in the years that follow their pregnancy and their children have a higher risk of becoming obese or developing type II diabetes in early life. This is mediated through intrauterine exposure to hyperglycemia, and later development of obesity and diabetes [10]. ‘Globesity’ (the worldwide epidemic of obesity) contributes to this increasing incidence of GDM and carries many of the same risk factors for mother and baby [11]. A growing body of epidemiological evidence suggests a possible association between VDD or VDI and & & Table 1. Classification of vitamin D status (typically used standards) [3,4 ] & Serum 25(OH)D level (nmmol/l) Serum 25(OH)D level (ng/l) Severe deficiency (sVDD) <12.5 <5 Deficiency (VDD) <25 <10 Insufficiency (VDI) <50 <20 50–75 20–30 >75 (80) >30 (32) Vitamin D Sufficiency Normal 25 (OH)D, 25 hydroxy vitamin D; sVDD, severe vitamin D deficiency; VDD, vitamin D deficiency; VDI, vitamin D insufficiency. VITAMIN D EFFECTS ON CARBOHYDRATE METABOLISM The molecular and cellular mechanisms with respect to the interaction between vitamin D and GDM are only partly understood. It would appear that vitamin D acts directly on pancreatic b-cells by expression of the vitamin D receptors as well as the enzyme 25(OH)D-1-a-hydroxylase, through regulation of intracellular calcium to reduce insulin resistance, which facilitates the transport of glucose in target tissues and by attenuating systemic inflammation associated with insulin resistance in diabetes [17]. RECENT SYSTEMATIC REVIEWS AND OBSERVATIONAL STUDIES ON VITAMIN D STATUS VERSUS RISK FOR GESTATIONAL DIABETES MELLITUS The association between vitamin D and glucose metabolism has been thoroughly investigated in seven observational studies from 2007 to 2011 [12 ]. These comprised 2146 women from different countries and ethnicities of whom 433 had GDM. Adjusting for maternal BMI, age and ethnicity, there was a significant inverse relationship between serum 25(OH)D and the incidence of GDM. However, there was high heterogeneity between the studies and it was questioned whether this relationship might be because of seasonality or methodological factors 1363-1950 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins & www.co-clinicalnutrition.com 361 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Carbohydrates such as selection bias, differences in the diagnostic criteria for GDM or in the measurement of vitamin D levels. Furthermore, the studies differed with respect to the trimester in which the samples were taken. In 2013, these conclusions were confirmed in systematic reviews [18,19 ] and a narrative review [20 ]. Although the findings conflicted and the studies were observational in design, they do suggest an inverse association between vitamin D status and GDM. It remains to be determined whether vitamin D supplementation for all pregnant women can reduce the risk of developing GDM and whether supplementing diabetic women with VDD could improve their glucose tolerance. The most comprehensive systematic review included data from observational studies on the serum level of 25(OH)D during pregnancy and adverse outcomes on more than 22 000 pregnant women and demonstrated a relationship between VDD/VDI and adverse maternal and neonatal outcome including a modest association with GDM [19 ]. The authors found no heterogeneity across the studies reporting on GDM and they adjusted for confounding factors such as country of origin, 25(OH)D cutoff levels (<50 and <75 nmol/l), gestational age at sampling (<16 or >16 weeks), study design, 25(OH)D quantification methods (chromatography-mass spectrometry or radioimmunoassay). After adjustment, the pooled odds ratio for the association between GDM and VDI was 1.98 [95% confidence interval (CI) 1.23–3.23]. By including pregnant women of diverse ethnicity with a wide range of 25(OH)D values from 11 countries, these findings are widely generalizable. Furthermore, the evidence lends support to the suggestion that vitamin D doses sufficient to elevate serum 25(OH)D concentrations more than 75 nmol/l (corresponding to 4000 IU/day) may provide additional benefit, and should be tested in ongoing RCTs [21]. Subsequently, seven new observational studies on vitamin D and GDM that enrolled 5065 pregnant women have been published (Table 2) [22,23 ,24– 26,27 ,28 ]. In countries with a high prevalence of VDD in pregnant women like Korea, China, Iran and Arabic countries, there was a significant association with GDM. Vitamin D deficiency has been reported to be correlated with high placental expression of CYP24A1 – a vitamin D catabolic enzyme [22]. In several of the studies, there appeared to be an inverse dose–response relationship between vitamin D and GDM. This relationship could contribute to the determination of an optimal vitamin D status and hence supplementation for women with GDM [23 ]. Canadian women with GDM also have a higher incidence of VDD compared with women with normal glucose tolerance and have && & && & & && & 362 www.co-clinicalnutrition.com lower serum levels of anti-inflammatory and metabolic regulators such as adiponectin, resistin and plasminogen activator inhibitor-1. This association has also been found in the cord blood of their offspring [24]. In Turkey, where VVD among pregnant women is predominant, GDM is significantly not only associated with sVDD but also with higher parathyroid hormone (PTH) levels. Vitamin D and PTH are both responsible for maintaining extracellular calcium homeostasis, and secondary hyperparathyroidism has been suggested to increase the risk of diabetes mellitus [27 ]. Among obese, African-American, first-trimester pregnant women who were multiparous, married, and socially deprived, 11% had GDM and there was a significant inverse relationship in those who were smokers, but no such association in nonsmokers [25]. Conversely, a strong association between serum calcium and fasting insulin and GDM was reported and needs further investigation [26]. Causality has been addressed in a large prospective cohort (n ¼ 655) of pregnant women of whom 54 developed GDM [28 ]. Rigorous selection criteria were used and adjustment was made for confounding factors such as maternal age, ethnicity, gestational age, smoking, medication, vitamin D supplementation, diet, exposure to sunlight and sunscreen use, outdoor clothing coverage, tanning salon visits, travel to warmer climes, (outdoor) physical activity, BMI, percentage of body fat and waist circumference. Vitamin D was measured at 6–13 weeks’ gestation, and blood glucose and insulin were measured three times over the course of a 2 h oral glucose tolerance test (OGTT) at 24–28 weeks’ gestation to calculate insulin resistance using homeostatic model assessment of insulin resistance, dynamic indices of insulin sensitivity and b-cell secretion. The conclusion was that lower vitamin D levels in the first trimester is an independent risk factor for developing GDM [Adjusted odds ratio (OR) 1.48 per decrease of one standard deviation (18.8 nmol/l)] and is associated with insulin resistance in second trimester, and that these observations provide additional evidence in favor of vitamin D supplementation early in pregnancy to prevent GDM. Many authors of observational studies are enthusiastic about their findings and speculate about the possible benefits of vitamin D supplementation. However, this needs to be tested in adequately powered intervention trials, in different settings with both high and low prevalence of VDD, before clinical guidelines can recommend general vitamin D supplementation in pregnancy for women with GDM. & && Volume 17
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July 2014 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Author/year/ venue Type Total N (n with GDM) 60 (n ¼ 20) Gestational age at vitamin D sampling (weeks) Population characteristics (controls/with GDM) Vitamin D levels in controls  GDM Adjustments Main conclusions (risk of GDM) 24 to 28 weeks Mean age 32.7 vs. 33.5 years, ethnicity 100% Asian, parity (0.6/0.5) % nullips, % obese BMI (26.5/28.4) 34.5  19.7 vs. 11.7  9.2 (ng/nl) Age, BMI, parity, birthweight, sex, total calcium level Women with VDD (<20 mg/ml nmol): Adj. OR for GDM 30.78 (4.7–203.99) þ association to higher levels of CYP24A1 in the placenta 20 weeks Not specified VDD in controls (<37.5 nmol/ml): 18.7% not reported for GDM) BMI, age, education, season and gestational age of sampling Adj. OR for GDM: 3.1 (1.6–6.2), 2.4 (1.2–4.7)and 1.9 (1.0–3.7) for 25(OH) levels >37.5, 37.5– 49.9 and 50–74.9 respectively relative to >75 nmol/l. VitD status inversely associated with GDM in a dose-response manner 31 weeks Mean age 30.2 vs. 31.6 years , prepregnancy BMI (27.2/28.7) 93.2  19.2 vs. 77.3  4.3 nmol/ml Age, prepregnancy BMI and sun-exposure Lower Vit D levels in maternal serum and lower anti-inflammatory and metabolic regulators such as adiponectin, resistin and PAI-1 in GDM mothers and their offspring (cord blood) www.co-clinicalnutrition.com Cho et al., 2013 [22], Korea Case–control Dodds et al., 2013 & [23 ], Canada Nested case– control from two cohorts McManus et al., 2013 [24], Canada Case-control Zuhur et al., 2013 & [27 ], Turkey Cross-sectional 402 (n ¼ 234) 24–28 weeks Mean age 29.8 vs. 31.6 years , ethnicity 100% Turkish, parity: Multips 60.7/ 85.9% Nullips: 39./14.1/ % , BMI 24.4/26.7, previous history of GDM: 2.4/19.7% 36.0  16.2 vs. 30.8  16.3 nmol/ml; sVDD: 7.7 vs.21.8%; VDD: 20.2 vs. 19.2; sVDD: 7.7 vs.21.8%; VDI: 51.2 vs. 47%; sufficiency: 20.8 vs. 12.0% Age, season, previous history of GDM, family history of diabetes, prepregnancy BMI Significant association with sVDD – and significantly higher PTH in GDM mothers Tomedi et al., 2013 [25], USA Cohort 429 (n ¼ 12) <16 weeks All: 61% black, 36% obese,45% smokers, 88% <high school degree, 79% multiparous, history of diabetes 38% Hyperglycemia (postload glucose conc. >7.5 mmol/l); smokers: 45.1 vs. 28.4%; nonsmokers: 41.1 vs. 46.3% Age, parity, ethnicity, smoking status, marital income and employment -status, education, family history of diabetes, prepregnancy BMI, season of sampling, gestational age at diabetes screening Low vitamin D status increases risk of GDM only in smokers Whitelaw et al., 2014 [25], UK? Cross-sectional 26 weeks 53% South Asian, 47% white European and ethnicity: BMI 27.2 (24.1–31.1); age 27 (23–31) All (ng/ml): 9.3 (5.2–16.9) South Asian: 5.9 (3.9–9.4) European: 15.2 (10.7–23.5) Age, ethnicity, BMI, smoking, education, maternal deprivation, gestation at OGTT, vitamin D supplementation, sun-exposure and physical activity No association between vitamin D status  GDM but association to serum calcium levels Lacroix et al., 2013 && [28 ], xxx Prospective cohort 6-13 weeks Age 28.2  4.4 vs. 30.4  5.4, White European 97.8 vs. 94.4%, smoking 8.5 vs. 14.8%, history of GDM diabetes or macrosomial baby 7.7 vs. 29.6%, family history of diabetes 18.4 vs. 29.6%, primiparous: 52.3 vs. 37.0, BMI: 23.8 vs. 27.3 63.5  18.9 vs. 57.5  17.2 nmol/ml Age, ethnicity, gestational age, smoking, medication, vitamin D supp., diet, exposure to sunlight, sunscreen, clothing, tanning, travel, physical activity, BMI, body fat and waist measure Low 25(OH) D levels in first trimester is an independent risk factor for developing GDM and associated with insulin resistance in the second trimesters 1979 (n ¼ 399) 73 (n ¼ 36) 1467 (n ¼ 137) 655 (n ¼ 54) 363 25 (OH)D, 25 hydroxy vitamin D; GDM, gestational diabetes mellitus; OGTT, oral glucose tolerance test; PAI-1, plasminogen activator inhibitor-1; PTH, parathyroid hormone; sVDD, severe vitamin D deficiency; VDD, vitamin D deficiency; VDI, vitamin D insufficiency. Vitamin D and gestational diabetes: an update Joergensen et al. 1363-1950 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Table 2. Characteristics of recent observational studies on maternal vitamin D status and GDM www.co-clinicalnutrition.com Author/year/ venue Gestational age at supplementation (weeks) Volume 17
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July 2014 Population characteristics (controls/with GDM) Baseline vitamin D status controls  GDM Vitamin D dose, and schedule Outcomes Main conclusions 25 weeks Age 24.8  3.6 vs. 25.3  4.2, 100% Iranian, BMI at baseline 25.2  3.5 vs. 25.23.8 14.5  1.2 vs. 17.8  1.3 mg/ml; sVDD: 45.8%; VDD: 88.3% 400 IU/day during 9 weeks from gestational age 25–34 weeks Reduction in FPG and insulin concentration and increase insulin sensitivity Vitamin D supplementation for 9 weeks in pregnant women has beneficial effects on metabolic status; GDM incidence not reported 504 12–16 weeks (Control/2000 IU/4000 IU); in age 27(18–41) 26(16–41) 26 (17–44); ethnicity: black Americans 25.5, 32.7, 40.9 %; caucasian 32.7, 20.9, 23.8%; hispanics 40.9, 42.3, 38.9% parity: 2 (0–5), 1 (0–7), 1 (0– –9); BMI: not specified; add education Total 25(OH)D ng/ml, mean (SD): 24.6 (10.9), 23.2 (8.6) and 22.8 (9.7) Controls/2000 IU/ 4000 IU (capsules) from 12–16 weeks Controls/2000 IU/ 4000 IU. Maternal 25(OH)D; >32 ng/ml: 51.8, 68.7 and 76.2%. >40 ng/ml: 35.5, 48.8 and 62.7% and 76.2% Consistent differences in maternal and cord blood 25(OH)D concentrations achieved with higher rates of sufficiency using 4000 IU/day. No differences found in pregnancy adverse events but not a significant trend of lower GDM in the 4000-IU group RCT double blind – 3 interventional arms); stratified block design (season) 162 12–16 weeks 400 IU/2000 IU/4000 IU; mean age (SD) 27.5 (5.5), 27.3 (16– 41) and 25.6 (5.5); BMI 25.8 (6.3), 26.3 (6.4) and 27.3 (5.4) Mean total 25(OH)D, 8.2 ng/ml Tablets 400 IU/ 2000 IU/4000 IU Mothers achieving 25(OH)D >32 ng/ml (>80 nmol/l): 9.5, 24.4 and 65.1%; 25(OH)D >20 ng/ml (>50 nmol/l): 47.6, 75.6 and 90.7% Very low serum 25(OH)D levels at enrollment. Very low mean 25(OH)D, levels and percentage reaching a level higher than 32 ng/ml and 20 ng/ml at delivery significantly higher in 2000 and 4000 IU groups. GDM incidence not reported; safety measurements similar in all groups RCT open label 120 <12 weeks A: 200 (controls) IU daily/B: 50 000 IU monthly and C: 50 000 IU every second week; BMI (A/B/C): 26.2  4.5, 25  3.8 and 25.9  4.6; age: 25  4.3, 26.5  4.5 and 26.3 years; parity 1.3  0.6, 1.6  0.8 and 1.7  0.9 Mean total 25(OH)D, ng/ml; 8.3  7.8, 7.3  5.3 and 7.3  5.9 A: 200 IU daily (controls )/B: 50 000 IU monthly and C: 50 000 IU every second week Mean  SD of 25(OH)D ng/ml increase; in group C: 7.3  5.3 to 34.1  11.5 n and group B: 7.3  5.3 to 27.2  10.7 ng/ml Very low serum 25(OH)D levels at enrollment, the best improvement in 25(OH)D levels achieved with high-dose regimen. Insulin resistance improved significantly. GDM incidence not reported 45 Postpartum Mean age 29.5 vs. 30.7, 100% Iranian – no differences in BMI, GDM treatment, delivery mode <35 nmol/l: 76.2 vs. 79.2%; > 35 nmol/l: 23.8 vs. 20.8% 300 000 IU i.m. single injection Vit D levels after supplementation: <35 nmol/l: 71.4 (controls) vs. 4.2% (GDM); b-cell function increase, insulin sensitivity increase Significant increase in mean vit D level; improvement of insulin resistance Type of trial Total N Asemi et al., [29], 2013, Iran RCT, (placebo controlled) 48 Wagner & Hollis, && [30 ], 2013, US RCT (double blind – 3 interventional arms) Dawodu 2013, [31], United Arab Emirates and US Soheilykhah et al., & [32 ], 2013, Iran Vit D supplementation to improve glucose metabolism in order to prevent GDM Vit D supplementation to improve treatment GDM Hosseinzadeh-ShamsiAnar et al., [33], 2012, Iran RCT (placebo controlled) in GDM mothers postpartum Carbohydrates 364 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Table 3. Characteristics of recent trials on supplementation of vitamin D for GDM RANDOMIZED CONTROLLED TRIALS ON VITAMIN D SUPPLEMENTATION 25 (OH)D, 25 hydroxy vitamin D; FBG, fasting blood glucose; FPG, fasting plasma glucose; GDM, gestational diabetes mellitus; HOMA-IR, homeostatic model assessment of insulin resistance; RCT, randomized controlled trial. & Asemi et al., [34 ], 2013, Iran RCT, (placebo controlled) 54 24–28 weeks Age 31.8  6.6 vs. 31.7  5.6, 100% Iranian, BMI at baseline 30.7  4.5 vs. 30.9  4.5 20.4  13.4 vs. 20.4  14.3 ng/ml 50 000 IU capsules two times – 21 days’ interval 25(OH)D increased in intervention group compared with placebo: 18.5  20.4 vs. 0.5  6.1 ng/ml; decrease in FBG 17.1  14.8, serum insulin 3.08  6.6 and HOMA-IR 1.28  1.1; reduction in total and low-density lipoprotein (11.0  23.5 vs. þ9.5  36.5 and 10.8  22,4 vs. þ10.4  28.0 mg/dl) respectively Vit D supplementation in pregnant GDM women had beneficial effects on glycemia, insulin sensitivity, lipid profile and did not affect inflammatory and oxidative stress factors Vitamin D and gestational diabetes: an update Joergensen et al. Recently, six articles reporting on seven RCTs using vitamin D supplementation comprising 933 pregnant women have been reported (Table 3). Four trials focused on preventing GDM [29,30 ,31,32 ], and two on improving metabolic status in women with GDM [33,34 ]. Four of the trials were conducted in Iran, which have a very high prevalence of VVD (83.3%), sVVD (45.8%) and a GDM prevalence of 4.7% [29]. && & & PREVENTION OF GESTATIONAL DIABETES MELLITUS Vitamin D supplementation in pregnant women has beneficial effects on metabolic status [29] and significantly improves insulin resistance [32 ]. Consistent differences in maternal and cord blood 25(OH)D concentrations can be achieved with higher rates of sufficiency by using high doses of vitamin D supplementation such as 4000 IU/day. No differences were found in pregnancy adverse events, but a nonsignificant trend of lower GDM (OR 0.75; 95% CI 0.82– 1.33) occurred with high-dose vitamin D supplementation [30 ] (Table 3). These studies constitute the overriding part of the current body of evidence on high-dose vitamin D supplementation in ‘normal’ pregnant women with VDD. The effects were most obvious in populations with a higher prevalence of VDD and VDI. Three of the studies did not report on, or did not have sufficient power to demonstrate, a reduction in GDM. & && VITAMIN D SUPPLEMENTATION TO IMPROVE TREATMENT OF GESTATIONAL DIABETES MELLITUS Two small RCTs (Table 3) have reported on the effect of vitamin D supplementation in women with GDM. All women received high-dose vitamin D, either as 300 000 IU (single intramuscular injection) [33] or 50 000 IU (capsules) on two occasions 3 weeks apart [34 ]. This treatment resulted in a remarkably effective improvement of vitamin D levels and reduction of VDD in postpartum women with GDM [vitamin D levels after supplementation <35 nmol/l ¼ 71.4% (controls) vs. 4.2% (GDM)]. Furthermore, metabolic measures were improved as b-cell function and insulin sensitivity increased [33]. With intervention in the second trimester, beneficial effects were demonstrated on glycemia, insulin sensitivity and lipid profile, whereas inflammatory and oxidative stress factors were not affected [34 ] (Table 3). The intervention seemed well tolerated, as there were no signs of hypervitaminosis in either of these studies. 1363-1950 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins & & www.co-clinicalnutrition.com 365 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Carbohydrates ONGOING OR PLANNED TRIALS ON VITAMIN D SUPPLEMENTATION FOR PREVENTION OR TREATMENT OF GESTATIONAL DIABETES MELLITUS A recent search (March 27, 2014) for ongoing clinical trials at www.clinicaltrials.gov yielded only one RCT from Penang in Malaysia (reported as completed) that aims to test the effectiveness of high dose supplementation of vitamin D3 (4000 IU/day for 6 months) to improve the glycemic control of 26 women with previous gestational diabetes. A search on the Australian register for trials www.anzctr. org.au (http://www.anzctr.org.au/TrialSearch.aspx) yielded no results, but we identified a large ongoing European trial at https://www.clinicaltrialsregister. eu that is testing lifestyle interventions and/or vitamin D supplementation for the prevention of GDM in high-risk women (BMI 29 kg/m2). This is an European project that involves 13 partners from 10 countries. Women are enrolled after a normal OGTT in early pregnancy (gestational age <18 weeks). Randomization assigns the participants to one of the eight intervention arms using a 2  2  2 factorial design: healthy eating; physical activity; healthy eating þ physical activity; Control; healthy eating þ physical activity þ vitamin D; healthy eating þ physical activity þ placebo; vitamin D alone; placebo alone. Women randomized to vitamin D intervention receive either 1600 IU vitamin D or placebo daily until delivery. Data are collected at baseline (before 20 weeks), at 24–28 weeks, at 35–37 weeks of gestation and at delivery. In total, 880 women will be included with 110 women allocated to each arm. A central bio bank containing samples of maternal blood, cord blood and placenta will be established. The primary outcomes are gestational weight gain, fasting glucose and insulin sensitivity, and the aim is that this study will collect data on the prevalence of GDM and gain insight into preventive measures against the development of GDM [9 ]. & CONCLUSION AND CURRENT OPINION Recently gathered evidence suggests that lower maternal plasma levels of vitamin D in the two first trimesters of pregnancy increase the risks of insulin resistance and therefore the risk of developing GDM. This association seems to be dose-responsive and is more pronounced in areas with endemic vitamin D deficiency. However, these conclusions come mainly from observational studies of heterogeneous quality and methodologies and hence with poor evidence of causality. Vitamin D has oxidative properties and is involved in the mechanisms of both impaired 366 www.co-clinicalnutrition.com glucose metabolism and obesity through many pathways, which is strongly associated to VDD as well as GDM. The conflicting results between maternal vitamin D status and the risk for GDM of various observational studies could be because of measurement of vitamin D as well as differences in population characteristics such as ethnicity, geographic location, gestational age at sampling and diagnostic criteria for GDM. There are still very few trials on vitamin D supplementation to prevent or improve the treatment of GDM. The results of these studies indicate that supplementation is effective in optimizing maternal vitamin D status and may also improve maternal glucose metabolism by reducing insulin resistance in both normal and pregnant women with GDM. Whether vitamin D supplementation in pregnant women can reduce the risk of developing GDM and reduce adverse pregnancy outcome in women with GDM remains unproven and largescale RCTs focusing on carefully selected and comparable core maternal and offspring parameters are needed. Acknowledgements The authors would like to thank Tove Faber Frandsen, chief librarian at ’Videncentret’, Odense University Hospital, Denmark, for her hard work and help in designing and conducting the systematic literature search. Conflicts of interest There are no conflicts of interest. REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Wootton AM. Improving the measurement of 25-hydroxyvitamin D. Clin Biochem Rev 2005; 26:33–36. 2. Heijboer AC, Blankenstein MA, Kema IP, Buijs MM. Accuracy of 6 routine 25-hydroxyvitamin D assays: Influence of vitamin D binding protein concentration. Clin Chem 2012; 58:543–548. 3. Christesen HT, Falkenberg T, Lamont RF, Jorgensen JS. The impact of vitamin D on pregnancy: a systematic review. Acta Obstet Gynecol Scand 2012; 91:1357–1367. 4. Dawodu A, Akinbi H. Vitamin D nutrition in pregnancy: current opinion. Int J & Womens Health 2013; 5:333–343. This is a current review of vitamin D nutrition in pregnancy. 5. Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab 2007; 92:2017–2029. 6. Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 2007; 30 (Suppl 2):S251–S260. 7. Coustan DR, Lowe LP, Metzger BE, Dyer AR. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study: paving the way for new diagnostic criteria for gestational diabetes mellitus. Am J Obstet Gynecol 2010; 202:654; e1–e6. 8. Skouteris H, Morris H, Nagle C, Nankervis A. Behavior modification techniques used to prevent gestational diabetes: a systematic review of the literature. Curr Diab Rep 2014; 14:480. Volume 17
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July 2014 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Vitamin D and gestational diabetes: an update Joergensen et al. 9. Jelsma JG, van Poppel MN, Galjaard S, et al. DALI: Vitamin D and lifestyle & intervention for gestational diabetes mellitus (GDM) prevention: an European multicentre, randomised trial - study protocol. BMC Pregnancy Childbirth 2013; 13:142. This is a study protocol for the largest ever RCT on vitamin D (and lifestyle intervention) to prevent GDM. 10. HAPO Study Cooperative Research Group. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Int J Gynaecol Obstet 2002; 78:69–77. 11. Ovesen P, Rasmussen S, Kesmodel U. Effect of prepregnancy maternal overweight and obesity on pregnancy outcome. Obstet Gynecol 2011; 118 (2 Pt 1):305–312. 12. Poel YHM, Hummel P, Lips P, et al. Vitamin D and gestational diabetes: A & systematic review and meta-analysis. Eur J Intern Med 2012; 23:465–469. This is a recent systematic review and meta-analysis on vitamin D and GDM. 13. Heaney RP, Davies KM, Chen TC, et al. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003; 77:204–210. 14. Mulligan ML, Felton SK, Riek AE, Bernal-Mizrachi C. Implications of vitamin D deficiency in pregnancy and lactation. Am J Obstet Gynecol 2010; 202:429; e1- e9. 15. Andersen LB, Abrahamsen B, Dalgard C, et al. Parity and tanned white skin as novel predictors of vitamin D status in early pregnancy: a population-based cohort study. Clin Endocrinol 2013; 79:333–341. 16. Verburg P, Tucker G, Scheil W, et al. Seasonality of gestational diabetes mellitus based on date of conception in South Australiaea retrospective population study 2006-2011. Am J Obstet Gynecol 2014; 1:; S165. 17. Alvarez JA, Ashraf A. Role of vitamin d in insulin secretion and insulin sensitivity for glucose homeostasis. Int J EndocrinolV 2010 2010; 351385. 18. Wei SQ, Qi HP, Luo ZC, Fraser WD. Maternal vitamin D status and adverse pregnancy outcomes: a systematic review and meta-analysis. J Matern Fetal Neonatal Med 2013; 26:889–899. 19. Aghajafari F, Nagulesapillai T, Ronksley PE, et al. Association between && maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational Studies. BMJ 2013; 346:f1169. This is the largest, and most recent systematic review and meta-analysis on the association between vitamin D and pregnancy and neonatal outcomes, including more than 22 000 pregnant women. 20. Burris HH, Camargo CA Jr. Vitamin D and gestational diabetes mellitus. Curr & Diab Rep 2014; 14:451. This is the most recent review of vitamin D nutrition in pregnancy. 21. Martineau AR, Khan K. Maternal vitamin D insufficiency is associated with adverse pregnancy and neonatal outcomes. Evid Based Med 2014; 19:e4. 22. Cho GJ, Hong SC, Oh MJ, Kim HJ. Vitamin D deficiency in gestational diabetes mellitus and the role of the placenta. Am J Obstet Gynecol 2013; 209:560; e1–e8. 23. Dodds L, Giguere Y, Woolcott C, et al. Vitamin D status in early pregnancy and & development of gestational diabetes. Can J Diabetes 2013; 37:S80–S81. This is a recent and large nested case-control study from two cohorts (abstract). 24. McManus R, Summers K, de Vrijer B, et al. Maternal, umbilical arterial and umbilical venous 25-hydroxyvitamin D and adipocytokine concentrations in pregnancies with and without gestational diabetes. Clin Endocrinol (Oxf) 2014; 80:635–641. 25. Tomedi LE, Simhan HN, Bodnar LM. Early-pregnancy maternal vitamin D status and maternal hyperglycaemia. Diabet Med 2013; 30:1033–1039. 26. Whitelaw DC, Scally AJ, Tuffnell DJ, et al. Associations of circulating calcium and 25-hydroxyvitamin D with glucose metabolism in pregnancy: a cross-sectional study in European and South Asian women. J Clin Endocrinol Metab 2014. [Epub ahead of print]. doi: 10.1210/jc.20132896. 27. Zuhur SS, Erol RS, Kuzu I, Altuntas Y. The relationship between low maternal & serum 25-hydroxyvitamin D levels and gestational diabetes mellitus according to the severity of 25-hydroxyvitamin D deficiency. Clinics (Sao Paulo) 2013; 68:658–664. This is a recent cross-sectional study demonstrating a significant association between severe vitamin D insufficieny and GDM. 28. Lacroix M, Battista MC, Doyon M, et al. Lower levels of vitamin d at first && trimester of pregnancy are associated with higher risk of developing gestational diabetes mellitus. Can J Diabetes 2013; 37:61. This is a recent prospective cohort study clearly demonstrating low first trimester vitamin D as an independent risk factor for developing insulin resistance and GDM in second trimester. 29. Asemi Z, Samimi M, Tabassi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr 2013; 143:1432–1438; Available from: http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/166/CN00876166/frame.html. 30. Wagner CL, McNeil RB, Johnson DD, et al. Health characteristics and && outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis. J Steroid Biochem Mol Biol 2013; 136:313– 320. This is a combined analysis of two large RCT studies on vitamin D supplementation during pregnancy demonstrating effect of high dose vitamin D with lower risk of hypovitaminosis D and a nonsignificant trend toward a reduced risk of GDM. 31. Dawodu A, Saadi HF, Bekdache G, et al. Randomized controlled trial (RCT) of vitamin D supplementation in pregnancy in a population with endemic vitamin D deficiency. J Clin Endocrinol Metab 2013; 98:2337–2346. 32. Soheilykhah S, Mojibian M, Moghadam MJ, Shojaoddiny-Adrekani A. The & effect of different doses of vitamin D supplementation on insulin resistance during pregnancy. Gynaecol Endocrinol 2013; 29:396–399; Available from: http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/597/CN00877597/frame.html. This is a recent RCT study on high-dose vitamin D supplementation in a ‘normal’ pregnant population with endemically high incidence of vitamin D insufficieny and favorable impact on maternal insulin resistance. 33. Hosseinzadeh-Shamsi-Anar M, Mozaffari-Khosravi H, Salami MA, et al. The efficacy and safety of a high dose of vitamin D in mothers with gestational diabetes mellitus: a randomized controlled clinical trial. Iran J Med Sci 2012; 37:159–165. 34. Asemi Z, Hashemi T, Karamali M, et al. Effects of vitamin D supplementation & on glucose metabolism, lipid concentrations, inflammation, and oxidative stress in gestational diabetes: a double-blind randomized controlled clinical trial. Am J Clin Nutr 2013; 98:1425–1432. This is a recent RCT study on second trimester high-dose vitamin D supplementation in women with GDM demonstrating a favorable impact on maternal glucose metabolism and lipid profile. 1363-1950 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-clinicalnutrition.com 367 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.