Hostname: page-component-586b7cd67f-g8jcs Total loading time: 0 Render date: 2024-11-27T22:09:26.838Z Has data issue: false hasContentIssue false

Calcium plus vitamin D supplementation affects pregnancy outcomes in gestational diabetes: randomized, double-blind, placebo-controlled trial

Published online by Cambridge University Press:  20 March 2015

Maryam Karamali
Affiliation:
Department of Gynecology and Obstetrics, School of Medicine, Arak University of Medical Sciences, Arak, Islamic Republic of Iran
Zatollah Asemi*
Affiliation:
Department of Nutrition, Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
Maedeh Ahmadi-Dastjerdi
Affiliation:
Department of Gynecology and Obstetrics, School of Medicine, Arak University of Medical Sciences, Arak, Islamic Republic of Iran
Ahmad Esmaillzadeh
Affiliation:
Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Islamic Republic of Iran Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Islamic Republic of Iran
*
* Corresponding author: Email [email protected]
Rights & Permissions [Opens in a new window]

Abstract

Objective

The present study was designed to assess the effects of Ca+vitamin D supplementation on pregnancy outcomes in women with gestational diabetes mellitus (GDM).

Design

A randomized, double-blind, placebo-controlled trial was conducted among sixty women with GDM. Participants were divided into two groups to receive Ca+vitamin D supplements or placebo. Individuals in the Ca+vitamin D group (n 30) received 1000 mg Ca/d and two pearls containing 1250 µg (50 000 IU) of cholecalciferol (vitamin D3) during the intervention (one at study baseline and another at day 21 of the intervention); those in the placebo group (n 30) received two placebos of vitamin D at the mentioned times and placebos of Ca every day for 6 weeks. Pregnancy outcomes were determined.

Setting

A urban community setting in Arak, Iran.

Subjects

Sixty women with GDM and their newborns, living in Arak, Iran were enrolled.

Results

Women treated with Ca+vitamin D had a significant decrease in caesarean section rate (23·3 % v. 63·3 %, P=0·002) and maternal hospitalization (0 v. 13·3 %, P=0·03) compared with those receiving placebo. In addition, newborns of GDM women randomized to Ca+vitamin D had no case of macrosomia, while the prevalence of macrosomia among those randomized to placebo was 13·3 % (P=0·03). Lower rates of hyperbilirubinaemia (20·0 % v. 56·7 %, P=0·03) and hospitalization (20·0 % v. 56·7 %, P=0·03) were also seen in the supplemented group of newborns than in the placebo group.

Conclusions

Ca+vitamin D supplementation for 6 weeks among pregnant women with GDM led to decreased caesarean section rate and maternal hospitalization, and decreased macrosomia, hyperbilirubinaemia and hospitalization in newborns.

Type
Research Papers
Copyright
Copyright © The Authors 2015 

Gestational diabetes mellitus (GDM) is defined as any degree of hyperglycaemia or glucose intolerance with first recognition during pregnancy( Reference Prutsky, Domecq and Sundaresh 1 ). The worldwide prevalence of GDM varies considerably; some reports indicated that it occurs in up to 14 % of all pregnancies( Reference Karcaaltincaba, Kandemir and Yalvac 2 ). GDM and maternal obesity are independently associated with several adverse complications( Reference Owens, O’Sullivan and Kirwan 3 ). The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study demonstrated a positive linear relationship between fasting and post-load glucose concentrations and adverse perinatal outcomes including fetal size, adiposity and hyperinsulinism( 4 ). In addition, GDM is associated with increased risk of adverse maternal and fetal outcomes( Reference Coustan 5 ).

Medical nutrition therapy, including use of a low-glycaemic-index diet and the Dietary Approaches to Stop Hypertension (DASH) eating plan( Reference Asemi, Samimi and Tabassi 6 ), have been suggested for prevention and management of GDM( Reference Reader 7 ). Beyond lifestyle interventions, Ca or vitamin D supplementation has also been proposed as an approach that could improve pregnancy outcomes in GDM patients( Reference Asemi, Hashemi and Karamali 8 , Reference Park, Lee and Kim 9 ). Previous studies have shown that circulating Ca and vitamin D levels are strongly associated with fasting insulin and post-challenge glucose concentrations, GDM and pregnancy outcomes( Reference Whitelaw, Scally and Tuffnell 10 , Reference Bener, Al-Hamaq and Saleh 11 ). In a systematic review, Ca supplementation (≥1 g/d) was associated with a significant reduction in the risk of pre-eclampsia, preterm birth and occurrence of the composite outcome ‘maternal death or serious morbidity’( Reference Hofmeyr, Lawrie and Atallah 12 ). Furthermore, vitamin D deficiency during pregnancy was associated with increased primary caesarean section rate( Reference Merewood, Mehta and Chen 13 ). However, some reports have shown that Ca and vitamin D supplementation did not affect pregnancy outcomes in mothers without GDM( Reference Thorne-Lyman and Fawzi 14 , Reference Trumbo and Ellwood 15 ).

Vitamin D and Ca might affect pregnancy outcomes through influencing skeletal composition and smooth muscle strength( Reference Merewood, Mehta and Chen 13 ) as well as metabolic profiles( Reference Asemi, Karamali and Esmaillzadeh 16 ). Ca and vitamin D have been suggested to act jointly rather than independently. Previous reports have shown that joint supplementation is much more efficient in influencing metabolic profiles than single Ca or vitamin D supplementation( Reference Asemi, Foroozanfard and Hashemi 17 , Reference Tabesh, Azadbakht and Faghihimani 18 ). Considering the high prevalence of vitamin D deficiency and insufficient dietary intakes of Ca among Iranian pregnant women( Reference Asemi, Taghizadeh and Sarahroodi 19 , Reference Tabrizi and Pakdel 20 ), along with the beneficial effects of joint supplementation on metabolic profiles in GDM patients, we hypothesized that combined Ca and vitamin D supplementation might influence pregnancy outcomes in GDM patients. The current study was therefore conducted to investigate the effects of Ca+vitamin D supplementation on pregnancy outcomes among women with GDM.

Methods

Participants

We conducted a randomized, double-blind, placebo-controlled study in Arak, Iran, during March–July 2014 which was registered on the Iranian registry of clinical trials website (IRCT201407115623N23). For estimating sample size, we used a randomized clinical study sample size formula where type one (α) and type two errors (β) were 0·05 and 0·20 (power=80 %), respectively. Based on a previous study( Reference Roth, Perumal and Al Mahmud 21 ) and considering newborn weight at birth as a key variable, we considered 0·4 kg as standard deviation and 0·3 kg as the difference in the mean (d). According to this, we needed twenty-six subjects in each group to have 80 % study power. We included pregnant women aged 18–40 years who had been diagnosed with GDM by a ‘one-step’, 2 h oral glucose tolerance test with 75 g glucose load at 24–28 weeks’ gestation. Exclusion criteria were multiple gestation, major fetal anomalies, current illicit drug use, continuous daily Ca and/or vitamin D intake since last menstrual period, insulin-dependent diabetes, smoking and history of kidney stones. Pregnant women without a previous diagnosis of glucose intolerance were screened. Diagnosis of GDM was done based on the criteria of the American Diabetes Association( 22 ); those whose plasma glucose concentration met one of the following criteria were considered as having GDM: fasting ≥5·1 mmol/l, 1 h post-load ≥10 mmol/l or 2 h post-load ≥8·5 mmol/l. The present study was conducted according to the guidelines laid down in the Declaration of Helsinki and all procedures involving human subjects were approved by the ethics committee of Arak University of Medical Sciences. Written informed consent was obtained from all participants.

Study design

At study baseline and after stratification for pre-intervention BMI and weeks of gestation, GDM women were randomized to one of two treatment arms using computer-generated random numbers in a ratio of 1:1. A trained midwife at the maternity clinic, who was not blinded to the intervention, did the randomized allocation sequence, enrolled participants and assigned participants to interventions. The supplementation was started when the participants were between weeks 24 and 28 of their pregnancy. Although all participants were at this point of gestational age, participants were stratified based on their gestational age (<26 weeks, >26 weeks) before randomization. The women allocated to the Ca+vitamin D arm were advised to take calcium carbonate 1000 mg/d for 6 weeks plus a pearl containing 1250 µg (50 000 IU) of cholecalciferol (vitamin D3) twice during the study: at study baseline and day 21 of the intervention. The women allocated to the placebo arm were advised to take separate placebos for Ca (daily for 6 weeks) and for vitamin D (twice during the study: at study baseline and day 21 of the intervention), which were identical to the Ca tablets and vitamin D pearls in shape, colour and size. Ca supplement and its placebo were manufactured by Tehran Shimi Pharmaceutical Company (Tehran, Iran). Vitamin D and its placebo were manufactured by Dana Pharmaceutical Company (Tabriz, Iran) and Barij Essence Pharmaceutical Company (Kashan, Iran). Although the duration of the intervention was 6 weeks, all women were followed up until delivery. We did not continue the supplementation until delivery because we wanted to determine the effects of co-supplementation on pregnancy outcomes and were concerned that a large number of women would drop out if they were asked to provide blood near the end of their pregnancies. Participants were asked not to consume any supplements other than the one provided to them by the investigators. All participants were also consuming folic acid 400 µg/d from the beginning of pregnancy and ferrous sulfate 60 mg/d from the second trimester. Compliance to the Ca+vitamin D supplementation was assessed through quantification of serum Ca and vitamin D levels. The use of Ca+vitamin D supplements and placebos throughout the study was also checked by asking participants to bring the medication containers. Dietary information was assessed by a trained dietitian using a 3 d diet record (two weekdays and one weekend day) that was completed at week 1, 3 and 5 of the intervention. The dietary records were based on estimated values in household measurements. To obtain nutrient intakes of participants based on these 3 d food diaries, we used Nutritionist IV software (First Databank, San Bruno, CA, USA) modified for Iranian foods.

Assessment of anthropometric measures

Anthropometric measurements were conducted at baseline and after 6 weeks of intervention. Maternal height was measured using a daily calibrated stadiometer (Seca, Hamburg, Germany) to the nearest 0·1 cm and weight was measured to the nearest 0·1 kg using digital scales (Seca). Maternal BMI was calculated as weight in kilograms divided by the square of height in metres. Weight and length of all babies were measured in the labour ward following birth by a trained midwife using standard methods (Seca 155 scale). Infants’ head circumference was measured to the nearest 1 mm with a Seca girth-measuring tape. We also determined infants’ 1- and 5-min Apgar scores as another measure of pregnancy outcome. Preterm delivery was defined when delivery occurred at <37 weeks of pregnancy and newborn macrosomia was defined as birth weight >4000 g( Reference Boulet, Alexander and Salihu 23 ).

Biochemical and polyhydramnios assessment

Ten millilitres of fasting blood were obtained from each participant after a 10–12 h overnight fast at study entry and at the end of the research at Arak reference laboratory. The blood samples were centrifuged and serum was stored at −70°C until further assays. Commercial kits were used to measure fasting plasma glucose and serum Ca concentrations (Pars Azmun, Tehran, Iran). Participants underwent a 2 h oral glucose tolerance test and blood samples were collected at time 60 and 120 min to measure plasma glucose levels. Serum 25-hydroxyvitamin D concentrations were measured using a commercial ELISA kit (IDS, Boldon, UK). The inter- and intra-assay CV for serum 25-hydroxyvitamin D assays ranged from 4·5 to 7·0 %. Hyperbilirubinaemia was considered when the total serum bilirubin level was at or above 15 mg/dl (257 mol/l) in infants 25 to 48 h old, 18 mg/dl (308 mol/l) in infants 49 to 72 h old, and 20 mg/dl (342 mol/l) in infants older than 72 h( Reference Porter and Dennis 24 ). Polyhydramnios was diagnosed with a sonographic method after second vitamin D or placebo administration. On the basis of this measurement, polyhydramnios was defined as an amniotic fluid index in excess of 25 cm( Reference Nobile de, Radaelli and Taricco 25 ).

Statistical analysis

To ensure the normal distribution of variables, histograms and the Kolmogorov–Smirnov test were applied. We used independent-samples Student’s t test to detect differences in baseline measures as well as in dietary intakes between the two groups. Pearson’s χ 2 test was used for comparison of categorical variables. To assess if the magnitude of change in dependent variables depended on the baseline maternal age, BMI and fasting plasma glucose, we controlled all analyses for baseline values of age, BMI and fasting plasma glucose to avoid potential bias. These analyses were done using two-factor repeated-measures ANOVA. P<0·05 was considered as statistically significant. All statistical analyses were done using the statistical software package SPSS 17.

Results

Nine hundred pregnant women attending maternity clinics affiliated to Arak University of Medical Sciences, Arak, Iran were screened for GDM and sixty patients were included in the clinical trial. Sixty GDM women in two groups were randomized to receive Ca+vitamin D or placebo. Finally, sixty participants (Ca+vitamin D (n 30) and placebo (n 30)) completed the trial (Fig. 1). On average, the compliance rate in the present study was high, such that 100 % of pearls and tablets were taken during the course of the study in both groups.

Fig. 1 Summary of patient flow in the present randomized, double-blind, placebo-controlled trial (GDM, gestational diabetes mellitus)

Mean age, pre-pregnancy weight and BMI was not statistically different between the two groups (Table 1). Baseline weight and BMI as well as post-intervention means of these variables were not significantly different between Ca+vitamin D and placebo groups. Participants who received Ca+vitamin D supplements had a significant rise in serum vitamin D level (19·0 v. 0·5 ng/ml, P<0·001) and a trend towards a significant increase in serum Ca level (0·6 v. −0·1 mg/dl, P=0·09) compared with the placebo group.

Table 1 General characteristics, serum calcium and vitamin D levels of the study participants: women with gestational diabetes mellitus and their newborns, Arak, Iran, March–July 2014

* Received placebo for Ca (daily for 6 weeks) and placebo for vitamin D twice during the study: at study baseline and day 21 of the intervention.

Received calcium carbonate 1000 mg/d for 6 weeks plus a pearl containing 1250 µg (50 000 IU) of cholecalciferol (vitamin D3) twice during the study: at study baseline and day 21 of the intervention.

Obtained from an independent-samples Student’s t test.

Based on the 3 d dietary records obtained throughout the intervention, no statistically significant difference was seen between the two groups in terms of dietary intakes of energy, fat, protein, carbohydrate, SFA, PUFA, MUFA, cholesterol, total dietary fibre, Ca and vitamin D (Table 2).

Table 2 Dietary intakes of study participants throughout the study: women with gestational diabetes mellitus, Arak, Iran, March–July 2014

* Received placebo for Ca (daily for 6 weeks) and placebo for vitamin D twice during the study: at study baseline and day 21 of the intervention.

Received calcium carbonate 1000 mg/d for 6 weeks plus a pearl containing 1250 µg (50 000 IU) of cholecalciferol (vitamin D3) twice during the study: at study baseline and day 21 of the intervention.

Obtained from an independent-samples Student’s t test.

Women treated with Ca+vitamin D had a significant decrease in caesarean section rate (23·3 % v. 63·3 %, P=0·002) and maternal hospitalization (0 v. 13·3 %, P=0·03) compared with the placebo group (Table 3). In addition, newborns of GDM women randomized to Ca+vitamin D had no case of macrosomia, while the prevalence of macrosomia among those randomized to placebo was 13·3 % (P=0·03). Lower rates of hyperbilirubinaemia (20·0 % v. 56·7 %, P=0·03) and hospitalization (20·0 % v. 56·7 %, P=0·03) were also seen in the supplemented group of newborns than in the placebo group. We did not find a significant difference in pre-eclampsia, maternal polyhydramnios, needing to progress to insulin therapy after the intervention, newborns’ birth size and Apgar scores when comparing the two groups. Adjustment for baseline maternal age, BMI and fasting plasma glucose did not alter the findings.

Table 3 Effect of calcium plus vitamin D supplementation on pregnancy outcomes: women with gestational diabetes mellitus and their newborns, Arak, Iran, March–July 2014

* Received placebo for Ca (daily for 6 weeks) and placebo for vitamin D twice during the study: at study baseline and day 21 of the intervention.

Received calcium carbonate 1000 mg/d for 6 weeks plus a pearl containing 1250 µg (50 000 IU) of cholecalciferol (vitamin D3) twice during the study: at study baseline and day 21 of the intervention.

Obtained from Pearson’s χ 2 test.

§ Obtained from an independent-samples Student’s t test.

|| Obtained from two-way repeated-measures ANOVA adjusted for baseline maternal BMI.

Obtained from two-way repeated-measures ANOVA adjusted for baseline maternal age, BMI and fasting plasma glucose.

Discussion

Our study demonstrated that Ca+vitamin D supplementation for 6 weeks among pregnant women with GDM at 24–28 weeks of gestation led to decreased caesarean section and maternal hospitalization rates, and decreased macrosomia, hyperbilirubinaemia and hospitalization in newborns compared with placebo; however, we did not find any significant effect on other indicators of pregnancy outcome. To our knowledge, the present study is the first one reporting the effect of Ca and vitamin D supplementation on pregnancy outcomes of women with GDM.

Women with GDM are a high-risk group for several complications including development of type 2 diabetes mellitus, metabolic syndrome and CVD( Reference Noctor, Crowe and Carmody 26 ).

The findings of the present study showed that Ca+vitamin D supplementation among pregnant women with GDM resulted in decreased caesarean section rate and maternal hospitalization, but did not influence other pregnancy complications including pre-eclampsia, maternal polyhydramnios and needing to progress to insulin therapy after the intervention. In line with our study, vitamin D supplementation did not affect preterm delivery( Reference Thorne-Lyman and Fawzi 14 ) and pre-eclampsia among healthy nulliparous women( Reference Haugen, Brantsaeter and Trogstad 27 ). Furthermore, in another study, vitamin D deficiency during pregnancy was associated with almost four times greater odds of primary caesarean section( Reference Merewood, Mehta and Chen 13 ). Higher serum Ca levels were also reported in pregnant women at the time of vaginal delivery compared with term women not in labour or women who did not go into labour but delivered by scheduled caesarean( Reference Papandreou, Chasiotis and Seferiadis 28 ). Nevertheless, data on the effect of combined Ca and vitamin D supplementation on maternal, perinatal or infant health outcomes in GDM patients are rare. In a study by Zhou et al.( Reference Zhou, Su and Liu 29 ), no significant differences were found in terms of polyhydramnios, oligohydramnios, pre-eclampsia and caesarean section among pregnant women with different levels of vitamin D at 16–20-weeks’ gestation. Reduced intracellular Ca signals and expression of Ca entry channels in uteruses from diabetic patients may result in a reduction in muscle content( Reference Al-Qahtani, Heath and Quenby 30 ), which in turn could reduce force and increase the caesarean section rate. In addition, macrosomia has also been reported as a risk factor for caesarean section in women with diabetes( Reference Ehrenberg, Durnwald and Catalano 31 ). Furthermore, pure vitamin D deficiency, depending upon its chronicity, may induce hyperparathyroidism and consequent leaching of total bone Ca in order to maintain normocalcaemia, which might explain the initiation of early labour( Reference Merewood, Mehta and Chen 13 ).

The current study showed that taking Ca+vitamin D supplementation in GDM women led to decreased hyperbilirubinaemia and hospitalization in newborns. In agreement with our study, oral Ca supplementation resulted in a significant decrease in serum bilirubin in patients with Crigler–Najjar type I( Reference Van der Veere, Jansen and Sinaasappel 32 ). Furthermore, Miroliaee et al.( Reference Miroliaee, Nasiri-Toosi and Khalilzadeh 33 ) found that lower serum levels of vitamin D were associated with hyperbilirubinaemia in patients with non-cholestatic chronic liver disease. Fisher and Fisher( Reference Fisher and Fisher 34 ) have also shown that serum vitamin D levels of less than 25 nmol/l could be a reliable predictor of higher serum bilirubin. In addition, improved liver enzyme levels were seen in the cord blood of infants whose mothers received one 1500 µg dose of cholecalciferol in the second trimester or two 3000 µg doses of cholecalciferol each in the second and third trimesters( Reference Kalra, Das and Agarwal 35 ). However, some investigators observed no evidence of vitamin D insufficiency in cirrhosis( Reference Floreani, Zappala and Fries 36 ), non-cirrhotic viral liver disease( Reference Duarte, Farias and Coelho 37 ) and haemochromatosis( Reference Guggenbuhl, Deugnier and Boisdet 38 ). Several mechanisms can explain the effects of Ca and vitamin D supplementation on reducing newborns’ hyperbilirubinaemia. Ca may act as a trapping agent for bilirubin in the intestine, thereby preventing back-diffusion across the intestinal wall( Reference Van Der Veere, Schoemaker and Bakker 39 ). Furthermore, the strong relationship between both the prevalence and degree of vitamin D insufficiency and the severity of chronic liver disease may indicate specific impairments of vitamin D metabolism in the liver. Impaired 25-hydroxylation of vitamin D in liver related to the degree of hepatic dysfunction has been reported in patients with alcoholic cirrhosis( Reference Hepner, Roginsky and Moo 40 ). In rats, bile duct ligation led to a 64 % decrease in hepatic 25-hydroxylation of vitamin D( Reference Bolt, Sitrin and Favus 41 ). In addition, the active form of vitamin D induces vitamin D receptors which in turn act as receptors for secondary bile acids, such as lithocholic acid and 3-ketocholanic acid, and result in their catabolism via induction of cytochrome 3A enzymes( Reference Makishima, Lu and Xie 42 , Reference Xie, Radominska-Pandya and Shi 43 ).

We did not find any significant effect of combined Ca+vitamin D supplementation on birth size. Our results are in agreement with previous studies showing that taking 1500 mg Ca from week 20 of gestation among women with low Ca intake did not affect fetal and infant growth during the first year of life( Reference Abdel-Aleem, Merialdi and Elsnosy 44 ). In addition, others did not observe any significant effect of vitamin D supplementation during pregnancy on birth size( Reference Roth, Perumal and Al Mahmud 21 , Reference Hossain, Kanani and Ramzan 45 ). In contrast, some studies have indicated that either one oral dose of 1500 μg cholecalciferol or two doses of 3000 μg cholecalciferol in the second and third trimesters resulted in increased birth weight, length and head circumference( Reference Kalra, Das and Agarwal 35 ). Some studies that have been performed to determine the effect of maternal Ca status on birth size have generally reported larger birth weights with supplementation( Reference Villar and Repke 46 , Reference Lopez-Jaramillo, Delgado and Jacome 47 ). Discrepancies between our study and others might be explained by the different doses of Ca and vitamin D, different stages of gestation as well as the different durations of supplementation.

Limitations of the study

Our study has some limitations. First is the duration of this trial. We were unable to continue the Ca+vitamin D supplementation up to delivery time. Second, we did not assess the effects of Ca+vitamin D supplementation on other pregnancy outcomes including neonatal respiratory distress syndrome and Ca and vitamin D concentrations in amniotic fluid. Furthermore, in the current study, we did not assess cord blood levels of Ca and vitamin D. Further studies are suggested to determine the effect of Ca+vitamin D supplementation on cord blood levels of Ca and vitamin D. In the current study, we did not quantify serum vitamin D levels at the study baseline to see the percentage of women who were vitamin D deficient. Serum vitamin D levels were measured at the end of the trial to assess compliance to vitamin D supplements. When we found that some patients were vitamin D deficient (at the end of the study), we suggested they take vitamin D supplements. We calculated the sample size based on the primary outcome variable (newborn weight). Therefore, the study had enough power to detect differences for this parameter. However, we did not consider secondary outcome variables such as infant growth parameters or other pregnancy outcomes in the sample size calculation. As the study is not powered to detect differences in these outcome measures, one cannot make any conclusions about them. Therefore, further large-scale studies are needed to examine the effect of Ca+vitamin D supplementation on these pregnancy outcomes. Participants’ dietary intakes were examined through the use of 3 d dietary records to find differences in dietary intakes between the two groups. We did not observe any significant difference in dietary intakes between the two groups. However, it must be kept in mind that all dietary assessment methods, including dietary records, are subject to bias particularly when the dietary information is collected from household information. This limitation should also be taken into account in interpretation of our findings.

Conclusion

In conclusion, Ca+vitamin D supplementation for 6 weeks among pregnant women with GDM led to decreased caesarean section rate and maternal hospitalization, and decreased macrosomia, hyperbilirubinaemia and hospitalization in newborns compared with placebo; however, we did not find any significant effect on pre-eclampsia, maternal polyhydramnios, needing to progress to insulin therapy after the intervention, newborns’ birth size and Apgar scores.

Acknowledgements

Acknowledgements: The authors would like to thank the staff of Kossar Clinic (Arak, Iran) for their assistance in this project. Financial support: The present study was supported by the Vice-Chancellor for Research, Arak University of Medical Sciences, Arak, Iran (grant number 92–158). The funder had no role in the design, analysis or writing of this article. Conflict of interest: None. Authorship: M.K. and M.A-D. contributed in data collection and manuscript drafting. Z.A. and A.E. contributed in conception, design, statistical analysis and drafting of the manuscript. All authors read and approved the final version of the paper. Z.A. is the guarantor of this work; as such, he had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This study is registered at the Iranian registry of clinical trials website (registration number IRCT201407115623N23; www.irct.ir). Ethics of human subject participation: The present study was conducted according to the guidelines laid down in the Declaration of Helsinki and all procedures involving human subjects were approved by the ethics committee of Arak University of Medical Sciences. Written informed consent was obtained from all participants.

References

1. Prutsky, GJ, Domecq, JP, Sundaresh, V et al. (2013) Screening for gestational diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab 98, 43114318.CrossRefGoogle ScholarPubMed
2. Karcaaltincaba, D, Kandemir, O, Yalvac, S et al. (2009) Prevalence of gestational diabetes mellitus and gestational impaired glucose tolerance in pregnant women evaluated by National Diabetes Data Group and Carpenter and Coustan criteria. Int J Gynaecol Obstet 106, 246249.CrossRefGoogle Scholar
3. Owens, LA, O’Sullivan, EP, Kirwan, B et al. (2010) ATLANTIC DIP: the impact of obesity on pregnancy outcome in glucose-tolerant women. Diabetes Care 33, 577579.CrossRefGoogle ScholarPubMed
4. HAPO Study Cooperative Research Group (2010) Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study: associations with maternal body mass index. BJOG 117, 575584.CrossRefGoogle Scholar
5. Coustan, DR (2014) Diagnosis of gestational diabetes. Scand J Clin Lab Invest Suppl 74, 2733.CrossRefGoogle Scholar
6. Asemi, Z, Samimi, M, Tabassi, Z et al. (2013) A randomized controlled clinical trial investigating the effect of DASH diet on insulin resistance, inflammation, and oxidative stress in gestational diabetes. Nutrition 29, 619624.CrossRefGoogle ScholarPubMed
7. Reader, DM (2007) Medical nutrition therapy and lifestyle interventions. Diabetes Care 30, Suppl. 2, S188S193.CrossRefGoogle ScholarPubMed
8. Asemi, Z, Hashemi, T, Karamali, M et al. (2013) 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 98, 14251432.CrossRefGoogle ScholarPubMed
9. Park, HJ, Lee, J, Kim, JM et al. (2013) A study of snack consumption, night-eating habits, and nutrient intake in gestational diabetes mellitus. Clin Nutr Res 2, 4251.CrossRefGoogle ScholarPubMed
10. Whitelaw, DC, Scally, AJ, Tuffnell, DJ et al. (2014) 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 99, 938946.CrossRefGoogle ScholarPubMed
11. Bener, A, Al-Hamaq, AO & Saleh, NM (2013) Association between vitamin D insufficiency and adverse pregnancy outcome: global comparisons. Int J Womens Health 5, 523531.CrossRefGoogle ScholarPubMed
12. Hofmeyr, GJ, Lawrie, TA, Atallah, AN et al. (2014) Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 6, CD001059.Google Scholar
13. Merewood, A, Mehta, SD, Chen, TC et al. (2009) Association between vitamin D deficiency and primary cesarean section. J Clin Endocrinol Metab 94, 940945.CrossRefGoogle ScholarPubMed
14. Thorne-Lyman, A & Fawzi, WW (2012) Vitamin D during pregnancy and maternal, neonatal and infant health outcomes: a systematic review and meta-analysis. Paediatr Perinat Epidemiol 26, Suppl. 1, 7590.CrossRefGoogle ScholarPubMed
15. Trumbo, PR & Ellwood, KC (2007) Supplemental calcium and risk reduction of hypertension, pregnancy-induced hypertension, and preeclampsia: an evidence-based review by the US Food and Drug Administration. Nutr Rev 65, 7887.CrossRefGoogle ScholarPubMed
16. Asemi, Z, Karamali, M & Esmaillzadeh, A (2014) Effects of calcium–vitamin D co-supplementation on glycaemic control, inflammation and oxidative stress in gestational diabetes: a randomised placebo-controlled trial. Diabetologia 57, 17981806.CrossRefGoogle ScholarPubMed
17. Asemi, Z, Foroozanfard, F, Hashemi, T et al. (2014) Calcium plus vitamin D supplementation affects glucose metabolism and lipid concentrations in overweight and obese vitamin D deficient women with polycystic ovary syndrome. Clin Nutr (Epublication ahead of print version).Google ScholarPubMed
18. Tabesh, M, Azadbakht, L, Faghihimani, E et al. (2014) Calcium–vitamin D cosupplementation influences circulating inflammatory biomarkers and adipocytokines in vitamin D-insufficient diabetics: a randomized controlled clinical trial. J Clin Endocrinol Metab 99, E2485E2493.CrossRefGoogle ScholarPubMed
19. Asemi, Z, Taghizadeh, M, Sarahroodi, S et al. (2010) Assessment of the relationship of vitamin D with serum antioxidant vitamins E and A and their deficiencies in Iranian pregnant women. Saudi Med J 31, 11191123.Google Scholar
20. Tabrizi, FM & Pakdel, FG (2014) Serum level of some minerals during three trimesters of pregnancy in Iranian women and their newborns: a longitudinal study. Indian J Clin Biochem 29, 174180.CrossRefGoogle ScholarPubMed
21. Roth, DE, Perumal, N, Al Mahmud, A et al. (2013) Maternal vitamin D3 supplementation during the third trimester of pregnancy: effects on infant growth in a longitudinal follow-up study in Bangladesh. J Pediatr 163, 16051611.e3.CrossRefGoogle Scholar
22. American Diabetes Association (2014) Diagnosis and classification of diabetes mellitus. Diabetes Care 37, Suppl. 1, S81S90.CrossRefGoogle Scholar
23. Boulet, SL, Alexander, GR, Salihu, HM et al. (2003) Macrosomic births in the united states: determinants, outcomes, and proposed grades of risk. Am J Obstet Gynecol 188, 13721378.CrossRefGoogle ScholarPubMed
24. Porter, ML & Dennis, BL (2002) Hyperbilirubinemia in the term newborn. Am Fam Physician 65, 599606.Google ScholarPubMed
25. Nobile de, Santis MS, Radaelli, T, Taricco, E et al. (2004) Excess of amniotic fluid: pathophysiology, correlated diseases and clinical management. Acta Biomed 75, Suppl. 1, 5355.Google Scholar
26. Noctor, E, Crowe, C, Carmody, LA et al. (2015) ATLANTIC-DIP: prevalence of metabolic syndrome and insulin resistance in women with previous gestational diabetes mellitus by International Association of Diabetes in Pregnancy Study Groups criteria. Acta Diabetol 52, 153160.CrossRefGoogle ScholarPubMed
27. Haugen, M, Brantsaeter, AL, Trogstad, L et al. (2009) Vitamin D supplementation and reduced risk of preeclampsia in nulliparous women. Epidemiology 20, 720726.CrossRefGoogle ScholarPubMed
28. Papandreou, L, Chasiotis, G, Seferiadis, K et al. (2004) Calcium levels during the initiation of labor. Eur J Obstet Gynecol Reprod Biol 115, 1722.CrossRefGoogle ScholarPubMed
29. Zhou, J, Su, L, Liu, M et al. (2014) Associations between 25-hydroxyvitamin D levels and pregnancy outcomes: a prospective observational study in southern China. Eur J Clin Nutr 68, 925930.CrossRefGoogle ScholarPubMed
30. Al-Qahtani, S, Heath, A, Quenby, S et al. (2012) Diabetes is associated with impairment of uterine contractility and high Caesarean section rate. Diabetologia 55, 489498.CrossRefGoogle ScholarPubMed
31. Ehrenberg, HM, Durnwald, CP, Catalano, P et al. (2004) The influence of obesity and diabetes on the risk of cesarean delivery. Am J Obstet Gynecol 191, 969974.CrossRefGoogle ScholarPubMed
32. Van der Veere, CN, Jansen, PL, Sinaasappel, M et al. (1997) Oral calcium phosphate: a new therapy for Crigler–Najjar disease? Gastroenterology 112, 455462.CrossRefGoogle ScholarPubMed
33. Miroliaee, A, Nasiri-Toosi, M, Khalilzadeh, O et al. (2010) Disturbances of parathyroid hormone–vitamin D axis in non-cholestatic chronic liver disease: a cross-sectional study. Hepatol Int 4, 634640.CrossRefGoogle ScholarPubMed
34. Fisher, L & Fisher, A (2007) Vitamin D and parathyroid hormone in outpatients with noncholestatic chronic liver disease. Clin Gastroenterol Hepatol 5, 513520.CrossRefGoogle ScholarPubMed
35. Kalra, P, Das, V, Agarwal, A et al. (2012) Effect of vitamin D supplementation during pregnancy on neonatal mineral homeostasis and anthropometry of the newborn and infant. Br J Nutr 108, 10521058.CrossRefGoogle ScholarPubMed
36. Floreani, A, Zappala, F, Fries, W et al. (1997) A 3-year pilot study with 1,25-dihydroxyvitamin D, calcium, and calcitonin for severe osteodystrophy in primary biliary cirrhosis. J Clin Gastroenterol 24, 239244.CrossRefGoogle ScholarPubMed
37. Duarte, MP, Farias, ML, Coelho, HS et al. (2001) Calcium–parathyroid hormone–vitamin D axis and metabolic bone disease in chronic viral liver disease. J Gastroenterol Hepatol 16, 10221027.CrossRefGoogle ScholarPubMed
38. Guggenbuhl, P, Deugnier, Y, Boisdet, JF et al. (2005) Bone mineral density in men with genetic hemochromatosis and HFE gene mutation. Osteoporos Int 16, 18091814.CrossRefGoogle ScholarPubMed
39. Van Der Veere, CN, Schoemaker, B, Bakker, C et al. (1996) Influence of dietary calcium phosphate on the disposition of bilirubin in rats with unconjugated hyperbilirubinemia. Hepatology 24, 620626.CrossRefGoogle ScholarPubMed
40. Hepner, GW, Roginsky, M & Moo, HF (1976) Abnormal vitamin D metabolism in patients with cirrhosis. Am J Dig Dis 21, 527532.CrossRefGoogle ScholarPubMed
41. Bolt, MJ, Sitrin, MD, Favus, MJ et al. (1981) Hepatic vitamin D 25-hydroxylase: inhibition by bile duct ligation or bile salts. Hepatology 1, 436440.CrossRefGoogle ScholarPubMed
42. Makishima, M, Lu, TT, Xie, W et al. (2002) Vitamin D receptor as an intestinal bile acid sensor. Science 296, 13131316.CrossRefGoogle ScholarPubMed
43. Xie, W, Radominska-Pandya, A, Shi, Y et al. (2001) An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Proc Natl Acad Sci U S A 98, 33753380.CrossRefGoogle ScholarPubMed
44. Abdel-Aleem, H, Merialdi, M, Elsnosy, ED et al. (2009) The effect of calcium supplementation during pregnancy on fetal and infant growth: a nested randomized controlled trial within WHO calcium supplementation trial. J Matern Fetal Neonatal Med 22, 94100.CrossRefGoogle ScholarPubMed
45. Hossain, N, Kanani, FH, Ramzan, S et al. (2014) Obstetric and neonatal outcomes of maternal vitamin D supplementation: results of an open-label, randomized controlled trial of antenatal vitamin D supplementation in Pakistani women. J Clin Endocrinol Metab 99, 24482455.CrossRefGoogle ScholarPubMed
46. Villar, J & Repke, JT (1990) Calcium supplementation during pregnancy may reduce preterm delivery in high-risk populations. Am J Obstet Gynecol 163, 11241131.CrossRefGoogle ScholarPubMed
47. Lopez-Jaramillo, P, Delgado, F, Jacome, P et al. (1997) Calcium supplementation and the risk of preeclampsia in Ecuadorian pregnant teenagers. Obstet Gynecol 90, 162167.CrossRefGoogle ScholarPubMed
Figure 0

Fig. 1 Summary of patient flow in the present randomized, double-blind, placebo-controlled trial (GDM, gestational diabetes mellitus)

Figure 1

Table 1 General characteristics, serum calcium and vitamin D levels of the study participants: women with gestational diabetes mellitus and their newborns, Arak, Iran, March–July 2014

Figure 2

Table 2 Dietary intakes of study participants throughout the study: women with gestational diabetes mellitus, Arak, Iran, March–July 2014

Figure 3

Table 3 Effect of calcium plus vitamin D supplementation on pregnancy outcomes: women with gestational diabetes mellitus and their newborns, Arak, Iran, March–July 2014