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Special Article

Vitamin D and gestational diabetes mellitus

Maysa Alzaim and Richard J Wood
The incidence of gestational diabetes mellitus (GDM) is increasing worldwide. GDM can be responsible for an important proportion of adverse fetal and maternal outcomes during pregnancy, and it is associated with long-term health deterioration for both mother and child. Therefore, it is important to identify potentially modiable risk factors for GDM. Accumulating evidence links vitamin D deciency with abnormal glucose metabolism, and epidemiological studies have shown that women who develop GDM are more likely to be vitamin D decient. This review discusses the prevalence, risk factors, and outcomes of GDM and vitamin D deciency in pregnant women, outlines the possible mechanism of action of vitamin D in glucose homeostasis, and summarizes emerging evidence that associates vitamin D deciency with the risk of developing GDM. This critical review of the literature indicates there is a need for intervention trials to test the possible benecial eect of vitamin D supplementation in pregnant women with low vitamin D status to reduce the risk of developing GDM.
2013 International Life Sciences Institute

INTRODUCTION The American Diabetes Association (ADA) denes gestational diabetes mellitus (GDM) as carbohydrate intolerance of variable severity, with onset or rst recognition during pregnancy.1 Pregnancy is a diabetogenic condition in which gestational steroid hormones induce peripheral insulin resistance; thus, the stress on pancreatic b-cell function increases to levels typically associated with type 2 diabetes.2 Compared with normal pregnant women, women with GDM have impaired b-cell function and reduced b-cell adaptation, resulting in insucient insulin secretion to maintain normal glycemia.3 Usually, insulin resistance increases in mid-pregnancy and through the third trimester. For this reason, the ADA recommends that all pregnant women be screened for GDM between weeks 24 and 28 of gestation, with the exceptions of women with low risk status, including maternal age <25 years, normal body weight, not being members of a racial/ethnic group with a high prevalence of diabetes, no history of poor obstetric outcome, and no

family history of diabetes.1 Though varying criteria can be used, a diagnosis of GDM is characterized by a fasting plasma glucose level of >126 mg/dl (7.0 mmol/L) or a casual plasma glucose level of >200 mg/dl (11.1 mmol/L), if conrmed on a subsequent day, and precludes the need for any oral glucose tolerance test.1 The prevalence of GDM is increasing in parallel with the rising prevalence of type 2 diabetes (T2D) and the growing global obesity epidemic.4,5 This increase in GDM could be related to the obesity-associated increase in T2D, which, if undiagnosed before pregnancy,5 might explain the observed increasing GDM prevalence trends. Women at risk of T2D are also at risk of GDM.4 The prevalence of GDM around the world is from 1% to 14% of all pregnancies, depending on the ethnic mix of the population and the GDM diagnostic tests administered.6 In the United States, there is an increasing occurrence of GDM. One recent study reported that, between the time periods 19891990 and 20032004, the prevalence of GDM doubled from 1.9% to 4.2%.7 Annually, 135,000 cases of GDM, representing, on average, 38% of pregnancies, are

Aliations: M Alzaim and RJ Wood are with the Department of Nutrition, University of Massachusetts, Amherst, Massachusetts, USA. Correspondence: RJ Wood, PhD, Department of Nutrition, School of Public Health and Health Sciences, University of Massachusetts, 100 Holdsworth Way, 206 Chenoweth Labs, Amherst, MA 01003, USA. E-mail: rwood@nutrition.umass.edu. Phone: +1-413-545-1687. Fax: +1-413-545-1074. Key words: gestational diabetes, glucose metabolism, insulin resistance, vitamin D
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diagnosed in the United States with a higher prevalence seen among Native-American, Asian, African-American, and Hispanic populations than among non-Hispanic whites.5 A higher incidence of GDM has also been reported in Australia (610%)8 as well as in developing countries such as India (14.3%), China (13.9%),9 Saudi Arabia (12.5%),10 and Iran (7%).11 GDM imposes a signicant economic burden on society. In 2007, the shortterm annual medical costs associated with GDM in the United States were estimated at $636 million$596 million for maternal costs and $40 million for neonatal costs, excluding the long-term costs of adverse sequelae.12 GESTATIONAL DIABETES AND ADVERSE HEALTH OUTCOMES Maternal health eects GDM can also be responsible for an important proportion of fetal and maternal morbidity and mortality.7 During pregnancy, the short-term maternal health consequences of GDM include an increased risk of hypertension, preeclampsia, urinary tract infections, and caesarean delivery.7 Longitudinal studies of the long-term adverse health eects of GDM found that as many as 70% of women who experience GDM will develop T2D within 10 years after delivery.2 In addition to the increased risk of developing T2D later in life, women who have had GDM with one pregnancy are 3580% more likely to develop GDM again in future pregnancies.9 Ospring health eects

highest prevalence of type 2 diabetes, strikingly supports this relationship between GDM and T2D.5 The ospring born to mothers who were already diabetic upon pregnancy had a 45% likelihood of developing T2D by the age of 2024 years, whereas the likelihood amongst the ospring of mothers who developed diabetes after pregnancy was only approximately 9%.4 RISK FACTORS FOR GDM The known risk factors for GDM include maternal overweight and obesity, being of a particular race/ethnicity, prior history of GDM, family history of T2D, history of previous fetal death, previous delivery of a macrosomic infant, and increasing maternal age.15 Recent studies have also indicated that vitamin D deciency might also be a modiable risk factor for the development of GDM. This suggestion is of interest because vitamin D status is readily amenable to treatment with vitamin D supplements. Some additional points to consider are the following: vitamin D deciency and insuciency is quite common among pregnant women around the world; vitamin D deciency is associated with abnormal glucose metabolism in both nonpregnant and pregnant subjects; and women who develop GDM are more likely to be vitamin D decient compared to pregnant women who do not develop GDM.8,11,1619 The connection between poor vitamin D status and GDM may be confounded by the known association of obesity and vitamin D deciency, as well as the increased risk of vitamin D deciency in darker-skinned ethnic and racial groups. ROLE OF VITAMIN D IN PREGNANCY

Untreated hyperglycemia allows glucose to travel freely from the mother to the fetus, forcing the fetus to increase its own production of insulin.3 Excess insulin production by the fetus increases the risk of embryopathy, including the following: fetal macrosomia, birth trauma, increased risk of neonatal intensive care unit admission, and perinatal death.12 According to a study performed in Saudi Arabia, GDM was a major contributor to perinatal death, congenital malformation, and neonatal jaundice.13 Fetal macrosomia, or excessive birth weight, is present in 20% of newborns from mothers with GDM, but it occurs in only 12% of pregnancies in which GDM is absent.12 These macrosomic newborns are at increased risk of developing hypoglycemia, jaundice, polycythemia, hypocalcemia, hypomagnesemia, and respiratory distress syndrome.12 In addition, upon reaching adulthood, ospring from mothers with GDM are at increased risk of developing obesity, impaired glucose tolerance, T2D,14 and cardiovascular disease.12 Long-term follow-up of the ospring of Pima Indian mothers, the population with the worlds
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The likely importance of vitamin D during pregnancy is suggested by the presence of nuclear vitamin D receptors and the vitamin D-activating 1-a-hydroxylase enzyme in pregnancy-specic tissues such as the decidua and placenta.20 Serum 25-hydroxyvitamin D concentration is currently considered to be the best biomarker of vitamin D status, and it reects both dietary vitamin D intake and cutaneous vitamin D production. According to the most recent version of the dietary reference intakes for vitamin D from the Institute of Medicine of the National Academies, the role of vitamin D in pregnancy and fetal development is unclear.21 Moreover, pregnancy does not appear to increase the need for vitamin D. Based on analysis of available information, the current recommended dietary allowance (RDA) for vitamin D in pregnancy is 600 IU/day, the same as for nonpregnant women. This level of vitamin D intake is estimated to be capable of achieving a serum 25-hydroxyvitamin D concentration of approximately 50 nmol/L, which is deemed
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to be a sucient concentration to prevent vitamin D deciency (based on bone health) in 97.5% of the population.21 Serum vitamin D deciency is generally considered to reect a serum 25-hydroxyvitamin D concentration of <50 nmol/L (20 ng/mL). Prevalence estimates of vitamin D deciency in this paper are, therefore, based on this cut-o value. Surprisingly, pregnancy has no obvious eect on vitamin D status, and important pregnancy-associated changes in calcium economy appear to be independent of vitamin D status.21 The fetus requires a relatively large amount of calcium, about 30 g, during development, with the majority required in the third trimester,22 and total serum calcium concentrations are known to decline as pregnancy progresses.15 However, the change in serum calcium may reect a dilution eect due to pregnancyassociated changes in plasma volume. In addition, maternal serum 1,25-dihydroxyvitamin D, the active hormonal form of vitamin D, rises from early in the rst trimester and increases progressively during gestation, rising to twice as high in late pregnancy than in postpartum or in nonpregnant controls.22,23 The reason for this increase of 1,25-dihydroxyvitamin D remains unclear; some think it is linked to elevated 1a-hydroxylase activity in the maternal kidney,24 with possibly some additional input from the fetal kidney, placenta, and decidua by extrarenal 1-a hydroxylase enzyme activity.22,23 The changes in serum 1,25-dihydroxyvitamin D concentration during pregnancy could reect a rise in blood vitamin D-binding protein concentration. Free 1,25-dihydroxyvitamin D concentrations do not rise until the third trimester. On the other hand, these changes in 1,25-dihydroxyvitamin D do not appear to be linked to changes in intestinal calcium absorption. Animal studies have shown that maternal hormones such as prolactin and placental lactogen can stimulate intestinal calcium absorption independently of 1,25-dihydroxyvitamin D, indicating that these hormones could be responsible for the observation that intestinal calcium absorption doubles in humans and rodents early in pregnancy, well before free 1,25dihydroxyvitamin D concentrations increase late in pregnancy.24 Clearly, the role of vitamin D in pregnancy on maternal-fetal calcium transfer is open to further study. However, according to a recent evaluation of the evidence concerning dietary requirements for calcium and vitamin D made by the Institute of Medicine, the bulk of the evidence suggests that calcium is moved to the fetus without requiring calcitriol.21 There is no clear indication that pregnancy inuences vitamin D status or vitamin D requirements above those of nonpregnant women. However, some studies do report declines in vitamin D status throughout pregnancy and in the postpartum period. For example, Haliloglu et al.25 recently collected blood from 30 healthy Turkish
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pregnant women in each trimester and during the postpartum period (6 weeks after delivery); they reported that serum 25-hydroxyvitamin D concentration decreased signicantly as follows: rst trimester, 48 18 nmol/L; second trimester, 39 18 nmol/L; third trimester, 28 22 nmol/L; and further decreases in the postpartum period (17 11 nmol/L). However, the authors did not address the contribution of any potential confounders, including possible seasonal eects, on vitamin D status. LOW VITAMIN D STATUS IS COMMON IN PREGNANT WOMEN In the absence of vitamin D supplementation, vitamin D status during pregnancy is likely to be a reection of a womans usual vitamin D status. Moreover, to a very large extent, fetal vitamin D status is a reection of maternal vitamin D status.Vitamin D deciency is common among pregnant women.19 Vitamin D deciency during pregnancy is geographically widespread and can occur in up to 95% of pregnant women, depending on country of residence and other factors.26 Residence in more northern or southern latitudes is associated with lower UVB radiation exposure and reduced cutaneous synthesis of vitamin D, leading to an increased risk of developing vitamin D deciency. In Belfast, Northern Ireland (latitude 55N), Holmes et al.26 found that the prevalence of vitamin D deciency was approximately 95% among both pregnant and nonpregnant women. Yu et al.27 compared serum 25-hydroxyvitamin D at gestational week 27 among 180 pregnant women of four ethnic groups living in London (latitude 51N). They found that Asian (47%), Middle Eastern (64%), and black women (58%) each had a higher prevalence of very poor vitamin D status, with serum 25-hydroxyvitamin D concentrations of <25 nmol/L, compared with Caucasian women (13%). The prevalence of secondary hyperparathyroidism in these women followed a similar ethnic/racial pattern. In addition, using multiple regression analysis, they found that ethnic group, age, parity, and daily sun exposure were signicant predictors of vitamin D levels. Similarly, Johnson et al.28 recently investigated the prevalence of vitamin D deciency during early pregnancy (<14 weeks) in 494 women from a southern city of the United States (Charleston, South Carolina; latitude 32N) and found that, despite plenty of sunshine, 41% of the women were vitamin D decient. As expected, race/ethnicity was an important determinant of vitamin D deciency, which was found in approximately 75% of African-Americans, 30% of Hispanics, and 10% of Caucasian women. In Shepparton, Victoria, in Australia (latitude 32S), Teale and Cunningham29 assessed vitamin D status in 330 pregnant women at approximately week 28 of gestation and found that vitamin D deciency was present among 26% of the
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pregnant women; this was despite abundant sunshine and a latitude that provided adequate ultraviolet light for vitamin D synthesis throughout the year. Studies from other parts of Australia, The Netherlands, and New Zealand also identied a high prevalence of vitamin D deciency in pregnant women; in particular, those with darker skin or limited skin sun exposure were found to be severely vitamin D decient.29 Such data led to the call for pregnant women, especially those who are dark-skinned or veiled, to be screened and treated for vitamin D deciency. However, in many countries, this is not a routine practice. In a 1984 study from Saudi Arabia, a region with plenty of sunlight (latitude 25N) but where cutaneous sun exposure is often limited, especially in women, it was revealed that 25% of mothers and 68% of their neonates had undetectable to low serum 25-hydroxyvitamin D levels (025 nmol/L) at delivery, which predisposes the mothers and infants to bone diseases such as osteomalacia and rickets, respectively.30 Similarly, a recent study reported in 2011 continued to show a high prevalence (72%) of vitamin D deciency among Saudi women of childbearing age.31 ADVERSE HEALTH EFFECTS OF LOW VITAMIN D STATUS ON MOTHER AND INFANT There is considerable evidence that low maternal serum 25-hydroxyvitamin D is associated with adverse outcomes for both mother and fetus in pregnancy, as well as for the neonate and child after pregnancy.22 These adverse eects can include alterations in calcium homeostasis, which causes hypocalcemia and abnormal softening or thinning of the skull (craniotabes) and high bone turnover in the neonate as well as osteomalacia and hypovitaminosis D myopathy in the mother.27 Aside from the adverse skeletal eects, vitamin D deciency during pregnancy has been linked with a number of maternal problems, including infertility, preeclampsia, gestational diabetes, and an increased rate of caesarean section.22,23,32 Stores of vitamin D in newborns are dependent on maternal vitamin D status.26 Maternal serum and cord blood 25-hydroxyvitamin D are highly correlated,33 and both maternal serum and cord blood 25-hydroxyvitamin D increase after maternal vitamin D supplementation.20 It has been suggested that low serum 25-hydroxyvitamin D in the mother might cause reduced transfer of 25-hydroxyvitamin D to the fetus, leading to impaired growth, low infant birth weight, delayed bone ossication and congenital rickets, abnormal tooth enamel formation, and lower bone mineral content.25 Case reports show that neonatal complications from extreme maternal vitamin D deciency can be life threatening, e.g., severe hypocalcemic ts with high risks of resultant brain damage and neonatal heart failure.20 Long-term complications of poor
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vitamin D status for the ospring are not well understood, but may relate to changes in fetal programming that could lead to increased risk of osteopenia,16 type 1 diabetes,22 asthma, and schizophrenia in later life.23 VITAMIN D AND GLUCOSE HOMEOSTASIS A connection between vitamin D status and insulin and glucose metabolism in animals has been appreciated for approximately 30 years.34,35 Early animal studies suggested that vitamin D deciency causes impaired insulin release from the rat pancreas. With increasing concern about the obesity epidemic and concomitant comorbidities, such as type 2 diabetes, as well as growing widespread concern about possible nonskeletal adverse eects of low vitamin D status, there has been renewed research interest in the possible role of vitamin D status in glucose metabolism. However, the evidence for a possible role of vitamin D in glucose homeostasis in humans is still controversial. The relationship was recently reviewed by Pittas and Dawson-Hughes,36 who summarized several mechanisms based on ndings in both animal and human studies. In brief, as pointed out by these authors, the eect of vitamin D on regulation of pancreatic b-cell function and insulin secretion could be by a direct or indirect eect of the binding of the circulating active hormonal vitamin D form, 1,25-dihydroxyvitamin D, to the b-cell vitamin D receptor, which could regulate the balance between the extracellular and intracellular b-cell calcium pools.36 Vitamin D action may also be needed to ensure a normal rate of calcium inux across cell membranes and maintenance of an adequate intracellular cytosolic calcium pool, which is important for insulinmediated intracellular processes in insulin-responsive tissues.19 In addition, vitamin D action could enhance insulin sensitivity by stimulating insulin receptor expression, thereby enhancing insulin-mediated glucose transport.36 Clinical evidence from a few small, and nonrandomized, studies suggested that vitamin D supplementation can increase insulin secretion.16 During pregnancy, observational studies have found that maternal vitamin D deciency is associated with an increased risk of several adverse pregnancy events, including gestational diabetes.22 To date, however, only a limited number of studies have investigated the association of vitamin D with glucose homeostasis during pregnancy and in the development of GDM. These studies are discussed below. Do women with gestational diabetes have poorer vitamin D status? Several cross-sectional studies have reported an association between low maternal vitamin D status and GDM (summarized in Table 1).
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Table 1 Observational studies investigating an association between vitamin D status and glucose metabolism in pregnant women. Reference Participants Major Adjustments Main study ndings measures 741 pregnant women in Iran Insulin Age Serum 25(OH)D lower in GDM (16.5 nmol/L) and IGT group Maghbooli at week 2428 of gestation Glucose Parity (18.9 nmol/L) versus normal group (23 nmol/L) et al. HOMA BMI Prevalence of insulin insensitivity (HOMA 3) higher in VDD (2008)11 OGTT (43%) versus NVD Serum 25(OH)D inversely correlated with HOMA and ISOGTT Clifton-Bligh 307 pregnant women in Insulin Seasonality Serum 25(OH)D inversely correlated with fasting plasma glucose, et al. Australia at week 29 of Glucose Ethnicity fasting insulin, and insulin resistance (2008)16 gestation HOMA Age Serum 25(OH)D lower in women with GDM (48 nmol/L) versus BMI normal group (55 nmol/L) Odds ratio for risk of having GDM if VDD not signicant (OR = 1.92; 95% CI: 0.894.17) 147 pregnant Australian HbA1C Age Serum 25(OH)D inversely correlated with HbA1C, fasting glucose Lau et al. women with GDM at week and 2h-OGTT blood glucose Glucose Ethnicity (2011)8 35 of gestation Insulin Occupational status OGTT Season BMI 204 pregnant women in Iran OGTT None Serum 25(OH)D lower in GDM (24 nmol/L) and IGT group Soheilykhah at week 2428 of gestation (16.5 nmol/L) versus normal group (32 nmol/L) et al. Women with GDM had 2.66-fold increased risk of being VDD (2010)18 versus normal group No association between serum 25(OH)D and fasting glucose, age, parity or BMI 559 pregnant women in South GDM Age Negative association between serum 25(OH)D and 30-min blood Farrant et al. India at week 30 of Insulin Fat mass glucose, and positive association with split proinsulin, after (2009)37 gestation Glucose control for age, fat mass and GDM Proinsulin 3233 Split Proinsulin HOMA Nested case-control study GDM (at week Serum 25(OH)D lower in GDM cases (60.5 nmol/L) versus controls Zhang et al. of 57 GDM cases versus 114 2428) (75.3 nmol/L), after controlling for established risk factors for (2008)19 non-GDM controls from 953 GDM, including BMI mostly non-Hispanic white Risk of developing GDM 2.66-fold higher in VDD women pregnant women studied in Tacoma, Washington Blood drawn at week 16 of gestation for vitamin D status assessment

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Soheilykhah et al.18 investigated serum 25hydroxyvitamin D at weeks 2428 of gestation among 204 consecutively enrolled pregnant Iranian women. Exclusion criteria included women with pregestational diabetes, multiple pregnancies, fetal abnormality, chronic disease, hypertension, and history of consumption of anticonvulsant drugs. GDM was dened as at least two of four abnormally elevated blood glucose concentrations in a 100 g oral glucose tolerance test (OGTT). A person with only one abnormal value on the OGTT was considered as having impaired glucose tolerance. Based on the oral glucose tolerance test, 26% of this group had GDM and 19% had IGT. Vitamin D deciency was found in 78% of the cohort. The study participants were then divided into three groupings: 54 women with GDM, 39 women with impaired glucose tolerance (IGT), and 111 women with a normal glucose tolerance test. Women with GDM and IGT had a signicantly lower median serum 25hydroxyvitamin D concentration than normal control subjects (24 and 17 nmol/L versus 32 nmol/L, respectively). Women with GDM had a twofold higher (nonsignicant) risk of having vitamin D deciency, and a signicant 2.7-fold (95% CI, 1.265.6) increased risk of having more severe vitamin D deciency (serum 25-hydroxyvitamin D < 37.7 nmol/L) compared with the control group. Serum 25-hydroxyvitamin D had no signicant correlation with age, parity, BMI, or fasting blood glucose level in these subjects. Maghbooli et al.11 investigated in 741 pregnant Iranian women the relationship at weeks 2428 of gestation between serum 25-hydroxyvitamin D concentrations and insulin resistance, using the homeostasis model assessment index (HOMA) equation to obtain estimates. They found that in this pregnancy cohort there was a 71% prevalence of vitamin D deciency (dened in this study as a serum 25-hydroxyvitamin D level <25 nmol/L), and the prevalence of severe vitamin D deciency (<12.5 nmol/L) was 29% in the entire cohort. GDM developed in 7% of all pregnancies. Participants were classied into three groups according to their glucose homeostasis: GDM, IGT, and normal. There was a signicant dierence in serum 25-hydroxyvitamin D concentration between the GDM and normal groups (16 10 versus 23 18 nmol/L) and between the IGT and normal groups (19 12 nmol/L versus 23 18 nmol/L). Also, severe vitamin D deciency was more common in the GDM group than in the IGT and normal groups (44%, 33%, and 23%, respectively.) These observations would be consistent with the notion that poorer vitamin D status might increase the risk of GDM. Likewise, in regard to the question of vitamin D deciency and insulin resistance in this study, the prevalence of a HOMA index 3 (indicative of insulin resistance) in those with vitamin D deciency was higher than in those with normal vitamin D
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status (43% versus 31%). Serum 25-hydroxyvitamin D was signicantly correlated with the HOMA index, but no correlation with serum 25-hydroxyvitamin D was observed with age, parity, and BMI. In all subjects combined, there was a signicant positive correlation found between the HOMA index and BMI and parity, but there was no correlation with age. However, the association between insulin resistance and serum 25-hydroxyvitamin D remained the same, even after adjustment for age and BMI. Clifton-Bligh et al.16 studied the association during the second or third trimester of gestation between serum 25-hydroxyvitamin D and glucose metabolism, and the eect of ethnicity on this relationship, in a convenience cohort of 307 pregnant women attending a prenatal clinic in metropolitan Sydney, Australia. Ethnic groups were Europeans, Southeast Asians,Asians, and Middle Easterners. In this cohort, 48% of the women were vitamin D decient, while GDM was evident in 32% of the cohort. In the entire group, serum 25-hydroxyvitamin D was negatively correlated with fasting plasma glucose, fasting insulin, and insulin resistance (calculated by HOMA-IR). The association between serum 25-hydroxyvitamin D and fasting glucose remained signicant after accounting for ethnicity, age, and BMI in multivariate analyses. However, the associations between 25-hydroxyvitamin D and fasting insulin and HOMA-IR were no longer signicant after accounting for the previous confounders. A possible problem in interpretation of these ndings is that the role of the confounding factors, such as ethnicity and obesity, in this relationship is unclear. Multivariate analysis, with its assumption of a linear relationship between the confounders, may also not be sucient to answer this question; moreover, it should be noted that certain ethnic groups may be predisposed to both vitamin D deciency and fasting hyperglycemia through independent mechanisms. The high proportion of GDM in this group (32%) was likely due to a bias toward women with a greater risk of having GDM because it included all women who had a blood test at this obstetrical clinic, which also included women specically referred for a follow-up OGTT. Although mean serum 25-hydroxyvitamin D was lower in those with GDM, the odds ratio (OR) for GDM risk in those with vitamin D deciency (OR: 1.92) did not reach statistical signicance. Nevertheless, the overall ndings in this study are consistent with the hypothesis that poor vitamin D status is a risk factor for poor glucose control in pregnant women. Lau et al.8 investigated during the third trimester (mean gestational age of 35 2 weeks) the association between serum 25-hydroxyvitamin D and glycated hemoglobin (HbA1c), an integrated measure of blood glucose control, in 147 pregnant Australian women with GDM. Interestingly, despite the fact that all women were
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advised to take daily prenatal multivitamins that contained either 400 IU or 500 IU vitamin D (cholecalciferol), 41% of the participants had vitamin D deciency. Ethnicity, occupational status, and season signicantly inuenced serum 25-hydroxyvitamin D, but BMI did not. Indian subcontinent and Middle Eastern groups had similar levels of serum 25-hydroxyvitamin D (median levels: 49 and 38 nmol/L, respectively), which were signicantly lower than those for the East or Southeast Asian and Caucasian groups (median levels: 63 and 62 nmol/L, respectively). Other confounders that may aect vitamin D status, such as sunlight exposure, physical activity, dietary vitamin D, and calcium intake, were not examined. Serum 25-hydroxyvitamin D was inversely associated with fasting and 2-h blood glucose concentration during an oral glucose tolerance test, as well as with log[HbA1c]. The latter relationship also remained signicant after removal of HbA1c outliers that were >7%, as well as after removal of HbA1c values that were >6%, even though this excluded 38% (n = 56) of the study sample. Moreover, excluding both low (<5%) and high (>7%) HbA1c outliers also did not negate the observed inverse relationship between serum 25-hydroxyvitamin D and HbA1c. Multivariable analysis identied serum 25-hydroxyvitamin D and blood glucose concentration during the oral glucose tolerance test as independent predictors of fasting HbA1c levels. These ndings suggest that, even within a patient group with established GDM, poorer vitamin D status is associated with poorer blood glucose control. However, the multiple ethnic groups in this cohort make a clear interpretation of these ndings uncertain. In a cross-sectional study of 559 nondiabetic pregnant women living in South India, Farrant et al.37 investigated the associations between maternal vitamin D status and risk of having gestational diabetes at 30 weeks gestation; as well as associations with newborn size at delivery, and cord blood insulin concentration at delivery. Vitamin D deciency was present in 66% of the women in this study, and 31% were found to have more severe vitamin D deciency (serum 25-hydroxyvitamin D <28 nmol/L). GDM was found in 7% of the cohort. Median serum 25-hydroxyvitamin D concentrations were similar in women with and without GDM (~38 nmol/L). In this study, there was no association found between maternal vitamin D status and risk of gestational diabetes. Observations from this study do not support the idea that GDM is associated with a lower vitamin D status, or that vitamin D deciency increases the risk of having GDM. The only signicant association found was that, within the group of mothers with vitamin D deciency, there was an inverse association between serum 25-hydroxyvitamin D and 30-min glucose concentrations after an oral glucose load and a positive associa164

tion between serum 25-hydroxyvitamin D and fasting proinsulin concentrations, including after adjustment for maternal age, fat mass, and GDM status. This observation would be consistent with the idea that low vitamin D status may aect blood glucose metabolism by inuencing the early phase of glucose-induced insulin secretion following an oral glucose load. Overall, these ve cross-sectional studies are generally supportive of the hypothesis that women with gestational diabetes have poorer vitamin D status than pregnant women with normal glucose metabolism. However, caution should be exercised in concluding that this intriguing association is causal, rather than merely associative. As cross-sectional studies, it is not possible to predict causality and the associations observed may be inuenced by ambiguous or incomplete control of important confounding variables such as ethnicity, seasonality, physical activity, parity, prepregnancy BMI, or other risk factors for GDM and/or vitamin D deciency. Factors leading to a greater risk of developing vitamin D deciency in some women may also be independently associated with an increased risk of glucose abnormalities during pregnancy. Also, in each of the studies examined above, measurement of serum 25-hydroxyvitamin D was in late pregnancy when GDM had already developed. It would be important to know the extent to which vitamin D status early in pregnancy might inuence the risk of developing GDM. To our knowledge, this question has been addressed in only one prospective cohort study by Zhang et al.19 Does vitamin D deciency increase the risk of developing gestational diabetes? Zhang et al.19 conducted a prospective cohort study among 953 mostly non-Hispanic white pregnant women in Tacoma, Washington in the United States, examining the association between maternal plasma 25hydroxyvitamin D in early pregnancy (~16 week) and the risk of developing GDM. These researchers found that among the 953 pregnant women enrolled in their study, 57 women (~6%) developed GDM. Using a nested casecontrol design, women with GDM were matched (by season of conception) with 114 control women from the cohort who did not develop GDM. Mean maternal plasma 25-hydroxyvitamin D, measured at approximately 16 weeks of gestation, was signicantly lower, by 20%, in the group that developed GDM than in the control group (60.5 versus 75.3 nmol/L), and this dierence between groups remained after controlling for established risk factors of GDM, including maternal age, family history of T2D, race/ethnicity, and prepregnancy BMI. Vitamin D deciency was evident in 33% of the women who developed GDM compared to 14% in controls, which is conNutrition Reviews Vol. 71(3):158167

sistent with most of the other cross-sectional studies discussed above11,16,18 in which GDM patients were more likely to be vitamin D decient or to have lower serum 25-hydroxyvitamin D. In the Tacoma study, the risk of developing GDM, assessed at week 2428 of gestation, was 2.66-fold (95% CI: 1.017.02) higher in women who were vitamin D decient at week 16 of gestation compared to the nondecient women, when controlled for established risk factors of GDM. Moreover, after restricting the analysis to non-Hispanic whites only, who comprised the majority of study participants, vitamin D deciency at week 16 of gestation was associated with a 3.77-fold increased risk of developing GDM after covariance adjustments. Moreover, these researchers found that each 12.5 nmol/L decrease in serum 25-hydroxyvitamin D was related to a 1.29-fold (95% CI: 1.051.60) increase in GDM risk. Additional adjustment for season and physical activity did not substantially change these ndings. Overweight, vitamin D-decient women were at vefold greater risk of developing GDM compared to lean women with adequate vitamin D status. Importantly, the ndings in this study demonstrate that maternal vitamin D deciency in early pregnancy (~16 weeks) is signicantly associated with an elevated risk of having GDM assessed at week 2428 of gestation. The researchers cautioned, however, about possible overinterpretation of their ndings because women in the study had only a single measurement of serum 25-hydroxyvitamin D, which may not reect their vitamin D status throughout their pregnancy. In addition, since GDM was not assessed until 23 months later, there is the possibility that some of the GDM cases identied at week 2428 of gestation may have already had undiagnosed glucose intolerance at 16 weeks when blood was drawn for vitamin D measurement. On the other hand, the fact that the study population was mainly non-Hispanic whites suggests that ethnicity was an unlikely potential confounder in their study, as could be claimed in some of the other studies in this research area. Moreover, although there seems to be increasing evidence of an association between poor vitamin D status and GDM risk, it still is not clear how vitamin D is involved with the pathogenesis of GDM and whether increasing vitamin D status in early pregnancy can reduce the risk of developing GDM. These important questions will require more basic research and the ndings of vitamin D supplementation trials in pregnant women. Intervention studies linking vitamin D status to GDM risk 1-a-hydroxyvitamin D treatment. Rudnicki and Pedersen17 were the rst to conduct a clinical trial to study the eect of administration of the active vitamin D hormone,
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1,25-dihydroxyvitamin D3, on glucose metabolism in pregnant women with GDM. In that study, 12 GDM patients at approximately 27 weeks of gestation were given the vitamin D analogue 1a-hydroxyvitamin D, which is activated in vivo by hepatic C-25 hydroxylation of the compound to the 1,25-dihydroxyvitamin D hormone. The participants received a single intravenous dose of 1a-hydroxyvitamin D3 (Etalpha, 2 mg/m2, LEO Pharma, Inc.) and were instructed to take 0.25 mg 1a-hydroxyvitamin D3 orally for the following two weeks and also follow a calcium-restricted diet. An OGTT was conducted three times in each patient: at baseline, 2 h after the intravenous 1a-hydroxyvitamin D3 dose, and then at 14 days after the oral 1a-hydroxyvitamin D3 dosing period. Interestingly, the fasting serum glucose level immediately decreased signicantly from 5.6 to 4.8 mmol/L (100.9 to 86.5 mg/dL) after intravenous treatment with 1a-hydroxyvitamin D, but was 5.3 mmol/L (95.5 mg/dL) after 2 weeks of oral 1a-hydroxyvitamin D. This study found that the serum glucose concentration was not different, but the serum insulin levels tended to be lower after both intravenous and oral 1a-hydroxyvitamin D supplementation, suggesting a possible increase in insulin sensitivity. In a multiple regression model analysis, including serum 1,25-dihydroxyvitamin D, serum insulin, body weight and height as predictors of serum glucose, only serum 1,25-dihydroxyvitamin D and serum insulin remained in the nal regression model. Although the study shows that intravenous 1a-hydroxyvitamin D can signicantly decrease fasting glucose in GDM, this eect may have been short-lived because the daily oral supplementation of 1a-hydroxyvitamin D did not sustain the initially observed eect on fasting glucose. This might be due to a number of reasons, such as the following: the low prescribed oral 1a-hydroxyvitamin D dose regimen; or increased 1,25-dihydroxyvitamin D breakdown induced by continued daily dosing of 1a-hydroxyvitamin D. It should also be mentioned that the three glucose tolerance tests were done in sequential order with no independent control group, and the vitamin D status of the patients is unknown. Vitamin D treatment. Recently, a preliminary meeting report (Wagner et al., Pediatric Academic Societies Annual Meeting 2010, Abstract 1665.6, unpublished data) described the ndings of a vitamin D treatment trial in 350 pregnant women at week 1216 weeks gestation. Subjects were rst stratied by race (African-American, Hispanic, and Caucasian) and then randomized into one of three vitamin D treatment groups: 400, 2,000, or 4,000 IU vitamin D3/day as dietary supplementation until delivery. According to the report, vitamin D suciency was strongly associated with decreased risk of pregnancy
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comorbidities, including preeclampsia, GDM, infection, preterm labor [PTL]/preterm birth [PTB] <37 weeks gestation). The group with the greatest eect was the 4,000 IU vitamin D/day regimen, which proved to have no adverse eect and raised serum 25-hydroxyvitamin D level to 100 nmol/L. The complete published ndings from this study are keenly awaited. In summary, a critical review of the literature concerning vitamin D and GDM indicates consistent observations in several countries that women with GDM have lower vitamin D status (Table 1). However, there is a need for intervention trials to test the possible benecial eect of vitamin D supplementation in pregnant women with low vitamin D status to reduce the risk of developing GDM. CONCLUSION GDM imparts signicant and long-lasting health risks on mother and baby. Fetal programming in utero is believed to increase the risk of obesity and chronic diseases in ospring of mothers with GDM. Therefore, it is very important that GDM is promptly recognized and appropriately managed to reduce perinatal deaths and to improve the quality of life for both mother and child. Vitamin D deciency remains a common problem among certain pregnant women of various ethnicities and in many countries, and may have long-term negative consequences on both mother and child. Even some countries with abundant sunshine, such as Australia, have taken steps to screen and treat for vitamin D deciency among pregnant women, with an emphasis on those who are dark-skinned or veiled.24 This action was taken after a high prevalence of vitamin D deciency was detected among pregnant women living in Australia; however, not all countries have taken similar action or have agreed on the appropriate course of action. For example, a very recent ocial statement issued by the American College of Obstetricians and Gynecologists in July 2011 stated that most pregnant women do not need to be screened for vitamin D deciency, nor do they need to be given additional supplements.38 The authors also noted, When vitamin D deciency is identied during pregnancy, most experts agree that 1,0002,000 IU/day of vitamin D is safe. Recommendations concerning routine vitamin D supplementation during pregnancy beyond that contained in a prenatal vitamin should await the completion of ongoing randomized clinical trials.38 In light of the evidence available to date, there is an intriguing suggestion that vitamin D deciency in pregnant women increases the risk for GDM. However, this determination is based largely on only six published observational studies and one short-term intervention study with an active analog form of 1,25(OH)2vitamin D;
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these seven studies investigated the association between vitamin D status and gestational diabetes or measures of glucose metabolism. The eect of treating pre-existing vitamin D deciency on the subsequent development of GDM in pregnant women is unknown. This gap in knowledge is an important concern given the widespread occurrence of low vitamin D status in certain population groups and countries and the rising incidence of GDM and T2D in the world. Well-designed, randomized vitamin D supplementation trials are needed in pregnant women to determine optimal vitamin D status and dosing and to evaluate the potential eectiveness of vitamin D supplementation on the risk of developing GDM.

Acknowledgment Declaration of interest. The authors have no relevant interests to declare.

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