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Vitamin D supplementation for women during pregnancy

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Referencias

References to studies included in this review

Asemi 2012 {published data only}

Asemi Z, Tabassi Z, Heidarzadeh Z, Khorammian H, Sabihi SS, Samimi M. Effect of calcium‐vitamin D supplementation on metabolic profiles in pregnant women at risk for pre‐eclampsia: a randomized placebo‐controlled trial. Pakistan Journal of Biological Sciences 2012;15(7):316‐24.

Asemi 2013a {published data only}

Asemi Z, Samimi M, Tabassi Z, Shakeri H, Esmaillzadeh A. Vitamin D supplementation affects serum high‐sensitivity C‐reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. Journal of Nutrition 2013;143(9):1432‐8.

Brooke 1980 {published data only}

Brooke OG, Brown IRF, Bone CDM, Carter ND, Cleeve HJW, Maxwell JD, et al. Vitamin D supplements in pregnant Asian women: effects on calcium status and fetal growth. British Medical Journal 1980;1:751‐4.
Brooke OG, Butters F, Wood C. Intrauterine vitamin D nutrition and postnatal growth in Asian infants. British Medical Journal 1981;283:1024.
Maxwell JD, Ang L, Brooke OG, Brown IRF. Vitamin D supplements enhance weight gain and nutritional status in pregnant Asians. British Journal of Obstetrics and Gynaecology 1981;88:987‐91.

Delvin 1986 {published data only}

Delvin EE, Salle BL, Glorieux FH, Adeleine P, David LS. Vitamin D supplementation during pregnancy: effect on neonatal calcium homeostasis. Journal of Pediatrics 1986;109:328‐34.

Diogenes 2013 {published data only}

Bezerra, F. Calcium plus vitamin d supplementation during pregnancy of adolescent mothers: effects on maternal and infant bone mass, calcium and bone metabolism and breast milk composition. ClinicalTrials.gov (http://clinicaltrials.gov/) [accessed 2012]2012.
Diogenes ME, Bezerra FF, Rezende EP, Taveira MF, Pinhal I, Donangelo CM. Effect of calcium plus vitamin D supplementation during pregnancy in Brazilian adolescent mothers: a randomized, placebo‐controlled trial. American Journal of Clinical Nutrition 2013;98(1):82‐91.

Grant 2013 {published data only}

Grant C. Randomised placebo controlled study of vitamin D during pregnancy and infancy. Australian New Zealand Clinical Trials Register [www.anzctr.org.au] (accessed 17 August 2010)2010.
Grant C, Stewart A, Scragg R, Milne T, Rowden J, Ekeroma A, et al. What dose of vitamin D supplementation is required in pregnancy and infancy to increase infants' serum 25‐hydroxyvitamin D concentration > 20ng/ml?. Pediatric Academic Societies Annual Meeting; 2013 May 4‐7; Washington DC, USA. 2013.
Grant CC, Stewart AW, Scragg R, Milne T, Rowden J, Ekeroma A, et al. Vitamin D during pregnancy and infancy and infant serum 25‐hydroxyvitamin D concentration. Pediatrics 2014;133(1):e143‐53.

Li 2000a {published data only}

Li X, Gou W. Study on prevention of pregnancy induced hypertension and effect of platelet intracellular free ca˜(2+) by calcium supplementation [补钙预防妊高征及对血小板细胞内游离钙浓度的影响]. Journal of Xi'an Medical University 2000;21(1):46‐8.

Mallet 1986 {published data only}

Mallet E, Gugi B, Brunelle P, Henocq A, Basuyau JP, Lemeur H. Vitamin D supplementation in pregnancy: a controlled trial of two methods. Obstetrics & Gynecology 1986;68:300‐4.

Marya 1987 {published data only}

Marya RK, Rathee S, Manrow M. Effect of calcium and vitamin D supplementation on toxaemia of pregnancy. Gynecologic and Obstetric Investigation 1987;24(1):38‐42.

Marya 1988 {published data only}

Marya RK, Rathee S, Dua V, Sangwan K. Effect of vitamin D supplementation during pregnancy on foetal growth. Indian Journal of Medical Research 1988;88:488‐92.

Mazurkevich 2013 {published data only}

Mazurkevich M, Doronin G, Firsova T. State of placental complex during physiological pregnancy during correction of mineral insufficiency. Journal of Perinatal Medicine 2013;41(Suppl 1):Abstract no:1213.

Roth 2010 {published data only}

Harrington J, Perumal N, Al Mahmud A, Baqui A, Roth DE. Vitamin D and fetal‐neonatal calcium homeostasis: findings from a randomized controlled trial of high‐dose antenatal vitamin D supplementation. Pediatric Research 2014;76(3):302‐9.
Perumal N, Al Mahmud A, Baqui A, Raqib R, Roth D. Effect of high‐dose vitamin D supplementation on blood pressure during the third trimester of pregnancy: A randomized controlled trial in Bangladesh. American Journal of Epidemiology 2012;176(1):80, Abstract no: 2.
Raqib R, Ly A, Akhtar E, Mily A, Perumal N, Al‐Mahmud A, et al. Prenatal vitamin D3 supplementation suppresses LL‐37 peptide expression in ex vivo activated neonatal macrophages but not their killing capacity. British Journal of Nutrition 2014;112(6):908‐15.
Roth D. Antenatal vitamin D3 supplementation in Bangladesh: randomized controlled trial (AViDD‐2). ClinicalTrials.gov (http://clinicaltrials.gov) [accessed 6 April 2011]2010.
Roth DE, Al Mahmud A, Perumal N, Pezzack B, Raqib R, Baqui AH. Effect of prenatal third‐trimester vitamin D3 supplementation (35,000 IU/week) on fetal and infant linear growth in Bangladesh: the AViDD trial. Pediatric Academic Societies Annual Meeting; 2013 May 4‐7; Washington DC, USA. 2013.
Roth DE, Al Mahmud A, Raqib R, Akhtar E, Perumal N, Pezzack B, et al. Randomized placebo‐controlled trial of high‐dose prenatal third‐trimester vitamin D3 supplementation in Bangladesh: the AViDD trial. Nutrition Journal 2013;12:47.
Roth DE, Al Mahmud A, Raqib R, Baqui AH. Effects of high‐dose antenatal 3rd‐trimester vitamin D supplementation (35,000 IU/week) on maternal and newborn vitamin D status: A randomized placebo‐controlled trial in Dhaka, Bangladesh. FASEB Journal 2012;26:[Abstract no. 392.3].
Roth DE, Al‐Mahmud A, El Arifeen S, Raqib R, Black RE, Baqui AH. Randomized pilot trial of two oral vitamin d3 supplementation regimens during the third trimester of pregnancy in Bangladeshi women: effects on neonatal vitamin d status and safety. Pediatric Academic Societies and Asian Society for Pediatric Research Joint Meeting; 2011 April 30‐May 3; Denver, Colorado, USA. 2011:1411.154.
Roth DE, Perumal N, Al A, Baqui AH. Maternal vitamin D3 supplementation during the third trimester of pregnancy: Effects on infant growth in a longitudinal follow‐up study in Bangladesh. Journal of Pediatrics 2013;163(6):1605‐11.

Sablok 2015 {published data only}

Sablok A, Batra A, Thariani K, Batra A, Bharti R, Aggarwal AR, et al. Supplementation of vitamin D in pregnancy and its correlation with feto‐maternal outcome. Clinical Endocrinology 2015 Feb 14 [Epub ahead of print].

Taherian 2002 {published data only}

Taherian AA, Taherian A, Shirmani A. Prevention of preeclampsia with low‐dose aspirin or calcium supplementation. Archives of Iranian Medicine 2002;5(3):151‐6.

Yu 2008 {published data only}

Yu C, Newton L, Robinson S, Teoh TG, Sethi M. Vitamin D deficiency and supplementation in pregnant women of four ethnic groups. Archives of Disease in Childhood. Fetal and Neonatal Edition 2008;93(Suppl 1):Fa68.
Yu CK, Sykes L, Sethi M, Teoh TG, Robinson S. Vitamin D deficiency and supplementation during pregnancy. Clinical Endocrinology 2009;70(5):685‐90.

References to studies excluded from this review

Ala‐Houhala 1986 {published data only}

Ala‐Houhala M, Koskinen T, Terho A, Koivula T, Visakorpi J. Maternal compared with infant vitamin D supplementation. Archives of Disease in Childhood 1986;61:1159‐63.

Asemi 2013b {published data only}

Asemi Z, Hashemi T, Karamali M, Samimi M, Esmaillzadeh A. Effects of vitamin D supplementation on glucose metabolism, lipid concentrations, inflammation, and oxidative stress in gestational diabetes: a double‐blind randomized controlled clinical trial. American Journal of Clinical Nutrition 2013;98(6):1425‐32.
Asemi Z, Karamali M, Esmaillzadeh A. Favorable effects of vitamin d supplementation on pregnancy outcomes in gestational diabetes: a double blind randomized controlled clinical trial. Hormone and Metabolic Research 2015;47(8):565‐70.

Asemi 2014 {published data only}

Asemi Z, Karamali M, Esmaillzadeh A. Effects of calcium‐vitamin D co‐supplementation on glycaemic control, inflammation and oxidative stress in gestational diabetes: a randomised placebo‐controlled trial. Diabetologia 2014;57(9):1798‐806.

Bhatia 2012a {published data only}

Bhatia V, Katam K, Agarwal A, Das V, Ramesh V. Vitamin D supplementation in pregnancy and its effect on cord blood 25 hydroxycholecalciferol and anthropometry of the newborn. Hormone Research in Paediatrics 2013;80(Suppl 1):220.
Das V. Vitamin D and calcium nutrition in pregnancy‐evaluation of optimal supplementation dose of vitamin D during antenatal period. Clinical Trials Registry ‐ India (http://www.ctri.nic.in/) [accessed 2010]2010.
Kalra P, Das V, Agarwal A, Kumar M, Ramesh V, Bhatia E, et al. Effect of vitamin D supplementation during pregnancy on neonatal mineral homeostasis and anthropometry of the newborn and infant. British Journal of Nutrition 2012;108(6):1052‐8.

Cockburn 1980 {published data only}

Cockburn F, Belton NR, Purvis RJ, Giles MM, Brown JK, Turner TL, et al. Maternal vitamin D intake and mineral metabolism in mothers and their newborn infants. British Medical Journal 1980;281(6232):11‐4.

Czech‐Kowalska 2013 {published data only}

Czech‐Kowalska J, Latka‐Grot J, Bulsiewicz D, Jaworski M, Pludowski P, Chazan B, et al. Influence of vitamin D supplementation on vitamin D status and bone mass during lactation ‐ double blinded randomized control trial. Annals of Nutrition & Metabolism 2013;63(Suppl 1):796, Abstract no: PO1128.

Das 2009 {published data only}

Bhatia V. A study of the effect of vitamin D supplementation in pregnant women, on the growth and biochemical features of the newborn baby and infant. Clinical Trials Registry ‐ India (http://ctri.nic.in) [accessed 2010]2010.
Das V, Agarwal A, Bhatia V, Pandey A, Agarwal S, Saxena P, et al. Evaluation of vitamin d status and need for supplementation in pregnant women of a rural area of North India. International Journal of Gynecology & Obstetrics 2009;107(Suppl 2):S151.
Sahu M, Das V, Aggarwal A, Rawat V, Saxena P, Bhatia V. Vitamin D replacement in pregnant women in rural north India: a pilot study. European Journal of Clinical Nutrition 2009;63(9):1157‐9.

Dawodu 2013 {published data only}

Dawodu A, Saadi HF, Bekdache G, Javed Y, Altaye M, Hollis BW. Randomized controlled trial (RCT) of vitamin D supplementation in pregnancy in a population with endemic vitamin D deficiency. Journal of Clinical Endocrinology & Metabolism 2013;98(6):2337‐46.

Etemadifar 2015 {published data only}

Etemadifar M, Janghorbani M. Efficacy of high‐dose vitamin D3 supplementation in vitamin D deficient pregnant women with multiple sclerosis: Preliminary findings of a randomized‐controlled trial. Iranian Journal of Neurology 2015;14(2):67‐73.

Hashemipour 2013 {published data only}

Hashemipour S. Effect of treatment of vitamin D deficiency during pregnancy on hypocalcemia. ClinicalTrials.gov (http://clinicaltrials.gov/) [accessed 5 February 2014]2013.
Hashemipour S, Ziaee A, Javadi A, Movahed F, Elmizadeh K, Javadi EH, et al. Effect of treatment of vitamin D deficiency and insufficiency during pregnancy on fetal growth indices and maternal weight gain: a randomized clinical trial. European Journal of Obstetrics & Gynecology and Reproductive Biology 2014;172:15‐9.

Hossain 2012 {published data only}

Hossain N, Kanani F, Khanani R, Ayaz S, Pal L. Effect of maternal supplementation with vitamin D during pregnancy on neonatal serum vitamin D levels and anthropometric measurements. International Journal of Gynecology and Obstetrics 2012;119(Suppl 3):S372.
Hossain N, Kanani FH, Ramzan S, Kausar R, Ayaz S, Khanani R, et al. Obstetric and neonatal outcomes of maternal vitamin D supplementation: results of an open‐label, randomised controlled trial of antenatal vitamin D supplementation in Pakistani women. Journal of Clinical Endocrinology and Metabolism 2013;99(7):2448‐55.

Hosseinzadeh 2012 {published data only}

Hosseinzadeh‐Shamsi‐Anar M, Mozaffari‐Khosravi H, Salami MA, Hadinedoushan H, Mozayan MR. The efficacy and safety of a high dose of vitamin d in mothers with gestational diabetes mellitus: A randomized controlled clinical trial. Iranian Journal of Medical Sciences 2012;37(3):159‐65.
Mozaffari‐Khosravi H, Hosseinzadeh‐Shamsi‐Anar M, Salami MA, Hadinedoushan H, Mozayan MR. Effects of a single post‐partum injection of a high dose of vitaminD on glucose tolerance and insulin resistance in mothers with first‐time gestational diabetes mellitus. Diabetic Medicine 2012;29(1):36‐42.

Ito 1994 {published data only}

Ito M, Koyama H, Ohshige A, Maeda T, Yoshimura T, Okamura H. Prevention of preeclampsia with calcium supplementation and vitamin D3 in an antenatal protocol. International Journal of Gynecology & Obstetrics 1994;47(2):115‐20.

Litonjua 2014 {published data only}

Litonjua AA, Lange NE, Carey VJ, Brown S, Laranjo N, O'Connor GT, et al. The Vitamin D Antenatal Asthma Reduction Trial (VDAART): Rationale, design, and methods of a randomized, controlled trial of vitamin D supplementation in pregnancy for the primary prevention of asthma and allergies in children. Contemporary Clinical Trials 2014;38:37‐50.

MacDonald 1986 {published data only}

MacDonald HN. Fetal and maternal benefits from calcium and vitamin D supplementation of pregnant Asians. Personal communication1986.

Marya 1981 {published data only}

Marya RK, Rathee S, Lata V, Mudgil S. Effects of vitamin D supplementation in pregnancy. Gynecologic and Obstetric Investigation 1981;12:155‐61.

Mutlu 2013 {published data only}

Mutlu GY, Ozsu E, Kalaca S, Yuksel A, Cizmecioglu FM, Hatun S. The evaluation of vitamin D supplementation dose during pregnancy in a high‐risk population. Hormone Research in Paediatrics 2013;80(Suppl 1):92.
Mutlu GY, Ozsu E, Kalaca S, Yuksel A, Pehlevan Y, Cizmecioglu F, et al. Evaluation of vitamin D supplementation doses during pregnancy in a population at high risk for deficiency. Hormone Research in Paediatrics 2014;81(6):402‐8.

Roth 2013a {published data only}

Roth DE, Al A, Raqib R, Akhtar E, Black RE, Baqui AH. Pharmacokinetics of high‐dose weekly oral vitamin D3 supplementation during the third trimester of pregnancy in Dhaka, Bangladesh. Nutrients 2013;5(3):788‐810.
Roth DE, Al‐Mahmud A, El S, Raqib R, Black RE, Baqui AH. Randomized open‐label trial of two weekly oral vitamin D3 supplementation regimens during the third trimester of pregnancy in Bangladeshi women: Effects on maternal vitamin D status and safety. FASEB Journal 2011;25(Suppl):236.6.

Shakiba 2013 {published data only}

Shakiba M, Iranmanesh MR. Vitamin D requirement in pregnancy to prevent deficiency in neonates: A randomised trial. Singapore Medical Journal2013; Vol. 54, issue 5:285‐8.

Soheilykhah 2011 {published data only}

Soheilykhah S. Effect of different doses of vitamin D on insulin resistance in pregnant women attending in Shahid Sadoughi and Mojibian prenatal clinics. Iranian Registry of Clinical Trials (http://www.irct.ir/) [accessed 2 August 2011]2011.
Soheilykhah S, Mojibian M, Moghadam MJ, Shojaoddiny‐Ardekani A. The effect of different doses of vitamin D supplementation on insulin resistance during pregnancy. Gynecological Endocrinology 2013;29(4):396‐9.

Stephensen 2011 {published data only}

Stephensen CB. Effects of vitamin D supplementation during pregnancy on clinical outcomes and immune function. ClinicalTrials.gov (http://clinicaltrials.gov/) [accessed 21 May 2013]2011.
Zerofsky M, Jacoby B, Stephensen C. A randomized controlled trial of vitamin D supplementation in pregnancy: Effects on vitamin D status and clinical outcomes. FASEB Journal 2014;28(1 Suppl 1):[Abstract no. 1041.5].

Taheri 2014 {published data only}

Taheri M, Baheiraei A, Rahimi A, Modarres M. Resolving vitamin d deficiency in the preconception period among high‐risk reproductive women: A randomized controlled trial. Iranian Red Crescent Medical Journal 2014;16(1):e11175.

von Hurst 2009 {published data only}

von Hurst PR. The role of vitamin D in metabolism and bone health. A thesis presented in partial fulfilment of the requirements for the Degree of Doctor of Philosophy in Nutritional Science. Vol. 1, Albany: Massey University, 2009.
von Hurst PR, Stonehouse W, Coad J. Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient ‐ a randomised, placebo‐controlled trial. British Journal of Nutrition 2010;103(4):549‐55.
von Hurst PR, Stonehouse W, Matthys C, Conlon C, Kruger MC, Coad J. Study protocol‐‐metabolic syndrome, vitamin D and bone status in South Asian women living in Auckland, New Zealand: a randomised, placebo‐controlled, double‐blind vitamin D intervention. BMC Public Health 2008;8:267.

Wagner 2010a {published data only}

Wagner CL, McNeil R, Hamilton SA, Davis DJ, Prudgen C, Winkler J, et al. Vitamin D (vitD) supplementation during pregnancy: Thrasher Research Fund RCT in SC community center networks. Pediatric Academic Societies 2010 Annual Meeting; 2010 May 1‐4; Vancouver, Canada. 2010.
Wagner CL, McNeil R, Hamilton SA, Winkler J, Rodriguez Cook C, Warner G, et al. A randomized trial of vitamin D supplementation in 2 community health center networks in South Carolina. American Journal of Obstetrics and Gynecology 2013;208(2):137.e1‐137.e13.

Wagner 2010b {published data only (unpublished sought but not used)}

Appelgren KE, Nietert PJ, Hulsey TC, Hollis BW, Wagner CL. Analyzing adherence to prenatal supplement: does pill count measure up?. International Journal of Endocrinology 2010;2010:1‐8.
Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supplementation during pregnancy: Double‐blind, randomized clinical trial of safety and effectiveness. Journal of Bone and Mineral Research 2011;26(10):2341‐57.
Wagner CL. Evaluation of vitamin D requirements during pregnancy (ongoing trial). ClinicalTrials.gov (http://clinicaltrials.gov/) [accessed 21 March 2006]2006.
Wagner CL, Johnson D, Hulsey TC, Ebeling M, Shary J,  Smith PG, et al. Vitamin D supplementation during pregnancy Part I NICHD/CTSA randomized clinical trial (RCT): safety consideration. Pediatric Academic Societies Annual Meeting; 2010 May 1‐4; Vancouver, Canada. 2010.

Wagner 2010c {published data only}

Wagner CL, Johnson D, Hulsey TC, Ebeling M, Shary J, Smith PG, et al. Vitamin D supplementation during pregnancy part 2 NICHD/CTSA randomized clinical trial (RCT): outcomes. Pediatric Academic Societies' 2010 Annual Meeting; 2010 May 1‐4; Vancouver, Canada. 2010.
Wagner CL, McNeil RB, Johnson DD, Hulsey TC, Ebeling M, Robinson C, et al. Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: A combined analysis. Journal of Steroid Biochemistry & Molecular Biology 2013;136:313‐20.

Yap 2014 {published data only}

Yap C, Cheung NW, Gunton JE, Athayde N, Munns CF, Duke A, et al. Vitamin D supplementation and the effects on glucose metabolism during pregnancy: a randomized controlled trial. Diabetes Care 2014;37(7):1837‐44.

Benson 2009 {published data only}

Benson J. A randomised controlled trial on the effects of antenatal vitamin D supplementation to improve vitamin D levels in the maternal and cord blood at birth in vitamin D deficient pregnant women. Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) [accessed 19 Jul 2014]2009.
Rodda CP, Benson JE, Vinvent AJ, Whitehead CL, Polyakov A, Vollenhoven B. Maternal vitamin D supplementation during pregnancy prevents vitamin D deficiency in the newborn: A randomised controlled trial. Osteoporosis International 2011;Suppl 4:S521‐S559.

Bhatia 2012b {published data only}

Bhatia V. Vitamin D supplementation in pregnancy: regimens and long term effects on offspring. Clinical Trials Registry ‐ India (http://ctri.nic.in) [accessed 29 Jun 2014]2012.

Bhutta 2011 {published data only}

Bhutta ZA. Study of vitamin D supplementation on improvement of gums health. ClinicalTrials.gov (http://clinicaltrials.gov) [accessed 5 August 2014]2011.

Bisgaard 2009 {published data only}

Bisgaard H. Vitamin D supplementation during pregnancy for prevention of asthma in childhood (ABCvitaminD). ClinicalTrials.gov (http://clinicaltrials.gov/) [accessed 31 July 2009].

Ghasemi 2014 {published data only}

Ghasemi H. Comparison of effectiveness of vitamin D supplementation in decreasing the development of the gestational diabetes mellitus in pregnant women. IRCT Iranian Registry of Clinical Trials (www.irct.ir) [accessed 19 Jul 2014]2014.

Goldring 2010 {published data only}

Goldring S. Effects of prenatal vitamin D supplementation on respiratory and allergic phenotypes and bone density in the first three years of life. UKCRN (http://public.ukcrn.org.uk) [accessed 6 April 2011]2010.

Habib 2010 {published data only}

Habib MA. Evaluation of the effectiveness of vitamin D supplementation to pregnant women and their infants in Pakistan. ClinicalTrials.gov (http://clinicaltrials.gov/) [accessed 15 February 2011]2010.

Hacker 2010 {published data only}

Hacker AN. Bone Health in Pregnancy (B‐Hip). ClinicalTrials.gov (http://clinicaltrials.gov) [accessed 2010]2010.

Harvey 2012 {published data only}

Cooper C. A randomised double‐blind placebo‐controlled trial of vitamin D supplements for pregnant women with low levels of vitamin D in early pregnancy. ISRCTN Registry (www.isrctn.com) [accessed 15 September 2015]2008.
Harvey NC, Javaid K, Bishop N, Kennedy S, Papageorghiou AT, Fraser R, et al. MAVIDOS Maternal Vitamin D Osteoporosis Study: Study protocol for a randomized controlled trial. The MAVIDOS Study Group. Trials 2012;13:13.

Jannati 2012 {published data only}

Jannati M. The effect of 50000 IU Vitamin D supplement administered two weekly on neonatal and pregnant women outcome ‐ GDM. IRCT Iranian Registry of Clinical Trials (www.irct.ir) [accessed 20 Jul 2014]2012.

Jelsma 2013 {published data only}

Jelsma JG, van Poppel MN, Galjaard S, Desoye G, Corcoy R, Devlieger R, et al. DALI: Vitamin D and lifestyle intervention for gestational diabetes mellitus (GDM) prevention: an European multicentre, randomised trial ‐ study protocol. BMC Pregnancy and Childbirth 2013;13:142.

Judkins 2011 {published data only}

Judkins A. A randomised double blinded interventional trial to determine the effect of 50,000 IU vitamin D supplementation monthly or twice monthly from 20 weeks gestation. Australian New Zealand Clinical Trials Register (www.anzctr.org.au) [accessed 11 February 2011]2011.

Kachhawa 2014 {published data only}

Kachhawa G. A randomized controlled trial to investigate the effects of vitamin D supplementation on maternal and new‐born baby's vitamin D status in Asian‐Indian subjects ‐ VIDIMAN. Clinical Trials Registry ‐ India (http://www.ctri.nic.in/) [accessed 19 Jul 2014]2014.

Lalooha 2012 {published data only}

Lalooha F. The effect of vitamin D supplementation during pregnancy on newborn's anthropometric index. IRCT Iranian Registry of Clinical Trials (www.irct.ir) [accessed 17 August 2015]2012.

Lindqvist 2010 {published data only}

Lindqvist P. Vitamin D supplementation for prevention of placenta mediated pregnancy complications. ‐ Prevention of pregnancy complications with vitamin D. EU Clinical Trials Register (https://www.clinicaltrialsregister.eu) [accessed 19 Jul 2014]2010.

McLean 2012 {published data only}

McLean M. Effect of high‐dose versus low‐dose vitamin D supplementation in pregnancy on maternal glucose metabolism and the risk of gestational diabetes. Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) [accessed 19 Jul 2014]2012.

Mirghafourvand 2013 {published data only}

Mirghafourvand M. The effect of vitamin D and calcium plus vitamin D for leg cramps in pregnant women: a randomised controlled trial. IRCT Iranian Registry of Clinical Trials (www.irct.ir) (Accessed 20 Jul 2014).

Mozzafari 2010 {published data only}

Mozaffari H. Effect of vitamin D supplementation on glucose status, lipid profiles and inflammatory factors in mothers with a history of gestational diabetes. IRCT Iranian Registry of Clinical Trials (www.irct.ir) [accessed 20 Jul 2014]2010.

Nausheen 2014 {published data only}

Nausheen S. Assessment of dose effectiveness of vitamin D supplementation during pregnancy. ClinicalTrials.gov (http://clinicaltrials.gov/) [accessed 2 September 2014]2014.

Rasmussen 2009 {published data only}

Rasmussen G. Additional information on registered trial. Effects of vitamin D supplement before, during and after pregnancy on complications, birth weight and bone mineral density during lactation (gravita). Personal communication2011.
Rasmussen GB. Effects of vitamin D supplement before and during pregnancy on birth weight (gravita). ClinicalTrials.gov (http://clinicaltrials.gov/) [accessed 17 August 2010]2009.

Roth 2013b {published data only}

Roth D. Maternal vitamin D for infant growth (MDIG) trial. ClinicalTrials.gov (http://clinicaltrials.gov/) [accessed 5 February 2014]2013.

Simsek 2011 {published data only}

Simsek S. Vitamin D supplementation in gestational diabetes mellitus. Netherlands Clinical Trials Registry [accessed 31 May 2013]2011.

Wagner 2013 {published data only}

Wagner CL. Preventing health disparities during pregnancy through vitamin D supplementation. ClinicalTrials.gov (http://clinicaltrials.gov/) [accessed 5 February 2014]2013.

Aghajafari 2013

Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O'Beirne M, Rabi DM. 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.

Akcakus 2006

Akcakus M, Koklu E, Budak N, Kula M, Kurtoglu S, Koklu S. The relationship between birthweight, 25‐hydroxyvitamin D concentrations and bone mineral status in neonates. Annals of Tropical Paediatrics 2006;26(4):267‐75.

Ariyuki 1987

Ariyuki F. Growth retardation induced in rat fetuses by maternal fasting and massive doses of ergocalciferol. Journal of Nutrition 1987;117(2):342‐8.

Armas 2004

Armas LA, Hollis BW, Heaney RP. Vitamin D2 is much less effective than vitamin D3 in humans. Journal of Clinical Endocrinology and Metabolism 2004;89(11):5387‐91.

Arunabh 2003

Arunabh S, Pollack S, Yeh J, Aloia JF. Body fat content and 25‐hydroxyvitamin D levels in healthy women. Journal of Clinical Endocrinology and Metabolism 2003;88(1):157‐61.

August 1992

August P, Marcaccio B, Gertner JM, Druzin ML, Resnick LM, Laragh JH. Abnormal 1,25‐dihydroxyvitamin D metabolism in preeclampsia. American Journal of Obstetrics and Gynecology 1992;166(4):1295‐9.

Balshem 2010

Balshem H, Helfanda M, Schunemann HJ, Oxmand AD, Kunze R, Brozek J, et al. GRADE guidelines: rating the quality of evidence: introduction. Journal of Clinical Epidemiology 2010;64(4):401‐6.

Bandeira 2006

Bandeira F, Griz L, Dreyer P, Eufrazino C, Bandeira C, Freese E. Vitamin D deficiency: a global perspective [Deficiência de vitamina D: uma perspectiva global]. Arquivos Brasileiros de Endocrinologia e Metabologia 2006;50(4):640‐6.

Bener 2009

Bener A, Alsaied A, Al‐Ali M, Al‐Kubaisi A, Basha B, Abraham A, et al. High prevalence of vitamin D deficiency in type 1 diabetes mellitus and healthy children. Acta Diabetologica 2009;4(2):183‐9.

Bodnar 2007

Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM. Maternal vitamin D deficiency increases the risk of preeclampsia. Journal of Clinical Endocrinology and Metabolism 2007;92(9):3517‐22.

Bodnar 2010

Bodnar LM,  Catov JM,  Zmuda JM,  Cooper ME,  Parrott MS,  Roberts JM,  et al. Maternal serum 25‐hydroxyvitamin D concentrations are associated with small‐for‐gestational age births in white women. Journal of Nutrition 2010;140(9):999‐1006.

Butte 2002

Butte NF, Lopez‐Alarcon MG, Garza C. Nutrient adequacy of exclusive breastfeeding of the term infant during the first six months of life. Geneva: World Health Organization, 2002.

Canadian Paediatric Society 2007

Canadian Paediatric Society, First Nations, Inuit and Métis Health Committee. Vitamin D supplementation: recommendations for Canadian mothers and infants. Paediatrics & Child Health 2007;12(7):583‐98.

Cantorna 2008

Cantorna MT, Yu S, Bruce D. The paradoxical effects of vitamin D on type 1 mediated immunity. Molecular Aspects of Medicine 2008;29:369‐75.

Cardus 2006

Cardus A, Parisi E, Gallego C, Aldea M, Fernandez E, Valdivielso JM. 1,25‐Dihydroxyvitamin D3 stimulates vascular smooth muscle cell proliferation through a VEGF‐mediated pathway. Kidney International 2006;69:1377‐84.

Chan 1979

Chan GM, Buchino JJ, Mehlhorn D, Bove KE, Steichen JJ, Tsang RC. Effect of vitamin D on pregnant rabbits and their offspring. Pediatric Research 1979;13(2):121‐6.

Chocano‐Bedoya 2009

Chocano‐Bedoya P, Ronnenberg AG. Vitamin D and tuberculosis. Nutrition Reviews 2009;67(5):289‐93.

Christian 2003

Christian P, Khatry SK, Katz J, Pradhan EK, LeClerq SC, Shrestha SR, et al. Effects of alternative maternal micronutrient supplements on low birth weight in rural Nepal: double blind randomised community trial. BMJ 2003;326(7389):571.

Clemens 1982

Clemens TL, Adams JS, Henderson SL, Holick MF. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet 1982;319:74‐6.

Clifton‐Bligh 2008

Clifton‐Bligh RJ, McElduff P, McElduff A. Maternal vitamin D deficiency, ethnicity and gestational diabetes. Diabetic Medicine 2008;25(6):678‐84.

Dawodu 2005

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Asemi 2012

Methods

Randomised single‐blinded controlled trial with 2 arms: vitamin D plus calcium and placebo.

Participants

54 pregnant women at risk for pre‐eclampsia, primigravida, aged 18‐35 years old carrying singleton pregnancy at their third trimester attending maternity clinics affiliated to Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran (latitude: 33.9889° N, 51.4772° E).

Exclusion criteria: maternal severe pre‐eclampsia, IUFD, placenta abortion, preterm delivery and GDM.

Interventions

Participants were randomly allocated to 1 of 2 groups: group 1 (n = 27): women received 500 mg of carbonate calcium plus 200 IU of vitamin D (cholecalciferol‐D3) daily for 9 weeks; group 2 (n = 27): women received placebo. The intervention lasted 9 weeks overall, starting at 25 weeks of pregnancy until week 34. Participants were asked not to alter their routine physical activity or usual diets and not to consume any supplement other than the one provided to them by the investigators.

Health worker cadre: the trial was carried out in maternity clinics affiliated to Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran and the investigators provided the supplements to the participants.

Outcomes

Maternal: body weight and height, BMI, fasting plasma glucose levels, serum total cholesterol, triglycerol concentrations, serum HDL‐cholesterol, serum LDL‐cholesterol levels, dietary intakes, total HDL: cholesterol ratio, gestational diabetes, severe pre‐eclampsia, preterm delivery.

Laboratory method used for assessment of vitamin D concentrations: serum 25‐hydroxyvitamin D [25(OH)D] concentrations were measured using a commercial ELISA kit (Immuno Diagnostic Systems). The inter‐ and intra‐assay coefficient of variation for serum 25(OH)D assays ranged from 5% to 7.5%.

Notes

  • Total dose of supplementary vitamin D during pregnancy: 56,000 IU vitamin D or less;

  • start of supplementation: 20 weeks of pregnancy or more;

  • pre‐gestational BMI (kg/m2): overweight;

  • supplementation scheme/regimen: daily;

  • skin pigmentation based on Fitzpatrick skin tone chart (Fitzpatrick 1988): mixed/unknown;

  • latitude: north of the Tropic of Cancer;

  • season at the start of pregnancy: mixed/unknown.

Source of funding: grant from the Vice‐Chancellor for research, KUMS, and Iran.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Trial reported randomisation performed by the use of computer‐generated random numbers.

Allocation concealment (selection bias)

Low risk

Trial reported that the appearance of the placebo capsules, such as colour, shape, size, and packaging, was identical to the vitamin D3 capsules.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants and investigators were blind to the interventions.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Trial is reported as blinded, although it is not specifically described if all were blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Lost to follow‐up of 3 women in the vitamin D group due to preterm delivery (n = 1), IUFD (n = 1), and placental abruption (n = 1). 3 women in the placebo group were also excluded for the following reasons: GDM (n = 1), preterm delivery (n = 1), and severe pre‐eclampsia (n = 1).

Selective reporting (reporting bias)

Unclear risk

There is insufficient information to permit judgement.

Other bias

Low risk

The study appears to be free of other sources of bias.

Asemi 2013a

Methods

Randomised, double‐blind, placebo‐controlled clinical trial with 2 arms: vitamin D and placebo, during March 2012 to September 2012.

Participants

48 pregnant women, primigravida, aged 18–40 years old at 25 weeks of gestation and a singleton pregnancy attending maternity clinics affiliated with Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran. Women with pre‐eclampsia, hypertension, GDM, IUFD, or those with a history of rheumatoid arthritis, hepatic or renal failure, metabolic bone disease and malabsorption, or thyroid, parathyroid, or adrenal diseases were excluded from the analysis. Also, smokers and those taking medications including nonsteroidal antiinflammatory drugs and aspirin were excluded.

Interventions

Participants were randomly assigned to receive 1 of 2 groups: group 1 (n = 24) received 400 IU vitamin D (cholecalciferol‐D3) supplements daily; and group 2 (n = 24) received placebo for 9 weeks. Additionally, all participants also consumed 400 μg (0.4 mg) folic acid daily from the beginning of pregnancy and 60 mg elemental iron (as ferrous sulphate) daily from the second trimester.

Health worker cadre: the trial was carried out in maternity clinics affiliated to Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran and the investigators provided the supplements to the participants. A trained midwife at the maternity clinic performed anthropometric measurements at study baseline and at 6 weeks after the intervention.

Outcomes

Maternal: weight, height, BMI, systolic blood pressure and diastolic blood pressure, serum calcium concentrations, serum 25‐hydroxyvitamin D [25(OH)D], serum hs‐C‐reactive protein, fasting plasma glucose, serum cholesterol, LDL‐cholesterol, HDL‐cholesterol concentrations, serum insulin, quantitative Insulin sensitivity check index (QUICKI) score, plasma total antioxidant capacity, plasma total glutathione, GDM, preterm delivery, IUFD, placental abruption, severe pre‐eclampsia.

Laboratory method used for assessment of vitamin D concentrations: serum 25‐hydroxyvitamin D [25(OH)D] concentrations were measured using a commercial ELISA kit (Immuno Diagnostic Systems).

Notes

  • Total dose of supplementary vitamin D during pregnancy: 56,000 IU vitamin D or less;

  • start of supplementation: 20 weeks of pregnancy or more;

  • pre‐gestational BMI (kg/m2): overweight (25 or higher);

  • supplementation scheme/regimen: daily in a 9‐week period;

  • skin pigmentation based on Fitzpatrick skin tone chart (Fitzpatrick 1988): mixed/unknown;

  • latitude: north of the Tropic of Cancer;

  • season at the start of pregnancy: spring‐summer period.

Source of funding: the Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random assignment was performed by the use of computer‐generated random numbers.

Allocation concealment (selection bias)

Low risk

A trained midwife at the maternity clinic performed the randomised allocation sequence and assigned participants to the groups. Placebo pills contained microcrystalline cellulose and were packed in identical tablets and coded by the producer to guarantee blinding.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants and investigators were blind to the interventions.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Measurements of laboratory were performed in a blinded fashion, in duplicate, in pairs (before/after intervention) at the same time, in the same analytical run, and in random order to reduce systematic error and inter assay variability.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

3 in each group were lost to follow‐up but the outcomes are accounted for as they are clinical outcomes of interest for this review.

Selective reporting (reporting bias)

Unclear risk

There is insufficient information to permit judgement.

Other bias

Low risk

The study appears to be free of other sources of bias.

Brooke 1980

Methods

Randomised double‐blind controlled trial; 2‐arm design with individual randomisation.

Participants

126 Asian pregnant women 28‐32 weeks of gestation attending the antenatal clinic at St George's Hospital, London, United Kingdom (latitude: 51°30'N, north of tropic of Cancer). All pregnant women were first‐generation immigrants mostly from India, Pakistan, Bangladesh, Sri Lanka, Mauritius and east Africa.

Exclusion and elimination criteria: preterm deliveries, congenital malformations and maternal illnesses likely to affect fetal growth (such as diabetes) although these data are not presented.

Interventions

Participants were randomly allocated to 1 of 2 groups: group 1 (n = 59 at the end of the trial): women received daily 1000 IU vitamin D (ergocalciferol‐D2) daily (estimated total dose: 56000‐84000 IU); group 2 (n = 67 at the end of the trial) received a placebo until term.

Start of supplementation: weeks 28‐32 gestation.

Length of the intervention/follow‐up: 8‐12 weeks from supplementation to term.

Health worker cadre: St George's Hospital Medical School, London, United Kingdom. Medical doctors that were part of the team conducted the measurements and provided the supplements.

Outcomes

Maternal: maternal weight gain, dietary vitamin D intake, 25‐hydroxyvitamin D (25‐OHD) concentrations in cord blood and at term. Plasma calcium (adjusted for albumin concentration), inorganic phosphate, bilirubin, albumin concentrations and total alkaline phosphatase activity, alanine transaminase and ʏ‐glutamyl transferase activities, vitamin D binding globulin concentration, compliance.

Infant: weight, crown‐heel length, crown‐rump length, rump‐heel length, occipitofrontal head circumference, forearm length, lower leg length, triceps and subscapular skinfold thickness, fontanelle area, plasma cholecalciferol at day 3 and day 6. weight, length and head circumference at 3, 6, 9 and 12 months.

Laboratory method used for assessment of vitamin D concentrations: Serum 25‐OHD concentration was measured by competitive protein binding assay after chromatographic purification of lipid extracts of serum.

Notes

  • Total dose of supplementary vitamin D during pregnancy: 5 more than 56,000 to 200,000 IU;

  • start of supplementation: 20 weeks of pregnancy or more;

  • pre‐gestational BMI (kg/m2): unknown/mixed;

  • supplementation scheme/regimen: daily;

  • skin pigmentation based on Fitzpatrick skin tone chart (Fitzpatrick 1988): mixed/unknown;

  • latitude: north of the Tropic of Cancer;

  • season at the start of pregnancy: authors report that to avoid distortion of the results due to seasonal variation in sunlight hours the trial was carried out during autumn and winter 1977, the whole of 1978 and spring and summer 1979.

Source of funding: The pathological research fund, St George's Hospital Medical School, and the South‐west Thames Regional Health Authority.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Trial reported random allocation to the groups, although the method of sequence generation was not described.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants received either vitamin D or placebo.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

There is insufficient information to permit judgement.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Unclear number of randomised participants. Preterm deliveries, congenital malformations, and maternal illnesses likely to affect fetal growth (such as diabetes) were eliminated from the trial. There is not complete documentation of the exclusions.

Selective reporting (reporting bias)

Unclear risk

There is insufficient information to permit judgement.

Other bias

Low risk

The study appears to be free of other sources of bias. There were no significant baseline differences between the groups in maternal age, parity, height, vegetarian: non‐vegetarian ratio or the distribution of the various countries of origin.

Delvin 1986

Methods

Randomised trial; 2‐arm design with individual randomisation.

Participants

40 pregnant women attending their compulsory visit during the third month of pregnancy at the Obstetrical Unit of the Hopital Edouard Herriot, Lyon, France (latitude: 45° 45' 0" N north of tropic of Cancer). Inclusion criterion: singleton pregnancy at term and uneventful vaginal deliveries. Pre‐gestational BMI and skin pigmentation not reported.

Interventions

Participants  were randomly assigned to 1 of 2 groups at the time of the compulsory visit: group 1 (n = 20): women received daily 1000 IU vitamin D (cholecalciferol‐D3) (estimated total dose: 55,000 IU); group 2 (n = 20): women received no supplement during the last trimester of pregnancy for 12 weeks from start of supplementation to term.

Health worker cadre: compliance was verified by a weekly visit by a midwife.

Outcomes

Maternal: serum (during last trimester of pregnancy) and cord blood immunoreactive parathyroid hormone (iPTH), 25‐hydroxyvitamin D (25‐OHD), 1‐alfa,25‐dihydroxyvitamin D (1,25(OH)2D), total calcium, ionised calcium, magnesium, inorganic phosphate.

Infant: immunoreactive parathyroid hormone (iPTH), 25‐hydroxyvitamin D (25‐OHD), 1‐alfa,25‐dihydroxyvitamin D (1,25(OH)2D), total calcium, ionised calcium, magnesium, inorganic phosphate at 4 days of age.

Laboratory method used for assessment of vitamin D concentrations: Serum 25‐OHD and 1,25(OH) D levels were measured by radioligand assays with slight modifications. With sample volumes of 0.75 to 1.5 mL, the inter assay variation coefficient for the 2 assays were 8% and 10%, respectively.

Notes

  • Total dose of supplementary vitamin D during pregnancy: 56,000 IU vitamin D or less;

  • start of supplementation: 20 weeks of pregnancy, or more;

  • pre‐gestational BMI (kg/m2): unknown/mixed;

  • supplementation scheme/regimen: daily;

  • skin pigmentation based on Fitzpatrick skin tone chart (Fitzpatrick 1988): mixed/unknown;

  • latitude: north of the Tropic of Cancer;

  • season at the start of pregnancy: winter‐spring. All selections were performed in December, and all deliveries occurred in June.

Source of funding: Shriners of North America, the France‐Quebec Exchange Program, and INSERM Grant 121023.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Trial reported as randomised but the method of sequence generation was not described.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

1 group received supplements while the other received no treatment.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Compliance was verified by the midwife. As 1 group received supplements and the other received no intervention it is clear that the midwife knew which women were in each group.

Incomplete outcome data (attrition bias)
All outcomes

High risk

1 participant from the control group (5%) and 5 (25%) from the vitamin D supplemented group. Laboratory methods reported for 25 to 30 participants (depending on the outcome) out of 40 originally randomised.

Selective reporting (reporting bias)

Unclear risk

There is insufficient information to permit judgement.

Other bias

Low risk

The study appears to be free of other sources of bias.

Diogenes 2013

Methods

Randomised, placebo‐controlled trial; 2‐arm design with individual randomisation.

Participants

84 pregnant adolescents (13‐19 years of age) primigravidae (pregnant for the first time) with singleton pregnancies and 23‐29 weeks of gestation attending prenatal care at the Maternidade Escola, Universidade Federal do Rio de Janeiro, Brazil (latitude: 22.9083° S, 43.1964° W) from September 2009 to June 2011 and intending to exclusively or predominantly breast feed.

Women with chronic health problems, pregnancy complications, smokers, users of nutritional supplements besides iron plus folate supplements provided during standard prenatal care, and mothers who decided not to breast feed were excluded from the study.

Interventions

Participants were randomly assigned to: 1 of 2 groups: group 1 (n = 43) received a commercially available supplement (Rexall Sundown®) containing 600 mg calcium (as calcium carbonate) plus 200 IU vitamin D (cholecalciferol‐D3) daily; group 2 (n = 41) received placebo (capsules of microcrystalline cellulose and corn starch; Quintessencia) daily.

Health worker cadre: capsules of calcium plus vitamin D or placebo were provided monthly to participants by a member of the research team during prenatal visits. Compliance was controlled by counting the remaining capsules at each visit and by telephone reminders. Calcium and vitamin D dietary intake was assessed by at least 3 24‐hour dietary recall questionnaires applied by a trained nutritionist. Standing height and body weight were measured by using a stadiometer (Seca) and a calibrated electronic scale (Filizola), respectively. The same operator performed all scanning and calibration.

Outcomes

Maternal: 1 measurement at 5 and 20 weeks postpartum, serum 25(OH)D, parathyroid hormone, insulin‐like growth factor (IGF‐I), lumbar spine PA, bone mineral content, serum prolactin and estradiol.

Laboratory method used for assessment of vitamin D concentrations: Serum 25(OH)D, intact parathyroid hormone (PTH), and IGF‐I were analysed by using a chemiluminescent enzyme‐labelled immunometric assay.

Notes

  • Total dose of supplementary vitamin D during pregnancy: 56,000 IU vitamin D or less;

  • start of supplementation: 20 weeks of pregnancy or more. The supplementation started from 26 weeks of pregnancy (baseline) until parturition;

  • pre‐gestational BMI (kg/m2): normal weight;

  • supplementation scheme/regimen: daily;

  • skin pigmentation based on Fitzpatrick skin tone chart (Fitzpatrick 1988): mixed/unknown;

  • latitude: the city lies on the Tropic of Capricorn;

  • season at the start of pregnancy: all year round.

Source of funding: Conselho Nacional de Desenvolvimento Cientıfico e Tecnologico [grant 471872/2008‐3 (to CMD) and a doctoral fellowship (to MELD)] and the Fundacao Carlos Chagas Filho de Amparo a` Pesquisa do Estado do Rio de Janeiro (grant E‐26/102.759/2008; to CMD), Brazil.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random assignment was done by a member of the research team in a 1:1 ratio within permuted blocks of size 10.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants were randomly and single‐blinded assigned to 1 of the 2 groups.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgment.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Out of 43 patients in the intervention group: decided not to breast feed (n = 1), lost to follow‐up (n = 2), pregnancy complications (n = 1), time constrains (n = 3), no reason given (n = 4), moved out of area (n = 2). Analysed at 5 weeks postpartum (n = 30).

Out of 41 patients in the placebo group: decided not to breast feed (n = 1), other health issues (n = 1), lost to follow‐up (n = 2), pregnancy complications (n = 2), time constrains (n = 3), no reason given (n = 5), moved out of area (n = 1). Analysed at 5 week postpartum (n = 26).

9 mothers were lost for the 20‐week measurement, which reduced the effective sample size for the bone change over the postpartum time assessment. Nevertheless, the magnitude of significant differences between groups in bone measures at the lumbar spine at 20 weeks postpartum, after adjustment for confounding factors, probably reduced the potential bias because of uncontrolled factors, such as the unknown bone status before pregnancy.

Selective reporting (reporting bias)

Low risk

The trial was approved by the Ethical Committee of Maternidade Escola, Universidade Federal do Rio de Janeiro (www.clinicaltrials.gov; NCT01732328).

Other bias

Unclear risk

The study appears to be free of other sources of bias.

Grant 2013

Methods

Randomised, double‐blind, placebo‐controlled multi‐arm parallel study.

Participants

260 pregnant women 26‐30 weeks' gestation, with a singleton pregnancy attending community based primary care maternity clinic in Auckland, New Zealand (latitude 36°S) from April 2010 to July 2011 and then their infants, from birth to age 6 months.

Women already taking vitamin D supplementation 200 IU per day, a history of renal stones or hypercalcaemia, or any serious pregnancy complication at enrolment were excluded from the study.

Interventions

Participants were randomly assigned to 1 of 3 mother/infant groups: group 1 (n = 87) women received placebo from 26‐30 weeks of pregnancy until parturition and their infants also received placebo from 0‐6 months of age; group 2 (n = 87) women received 1000 IU vitamin D (cholecalciferol‐D3) from 26‐30 weeks of pregnancy until parturition and their infants received 400 IU vitamin D from 0‐6 moths of age; group 3 (n = 86) women received 2000 IU vitamin D (cholecalciferol‐D3) from 26‐30 weeks of pregnancy until parturition and their infants received 800 IU from birth to 6 months of age.

Health worker cadre: the study was conducted by the research team but it is not reported who provided the supplements or measured the outcomes.

Outcomes

Maternal: serum 25(OH)D concentration.

Infant: serum 25(OH)D concentration.

Laboratory method used for assessment of vitamin D concentrations: serum 25(OH)D concentration was measured using isotope‐dilution liquid chromatography–tandem mass spectrometry in a Vitamin D External Quality Assurance Scheme–certified laboratory.

Notes

  • Total dose of supplementary vitamin D during pregnancy: 56,000 IU vitamin D or less;

  • start of supplementation: 20 weeks of pregnancy or more;

  • pre‐gestational BMI (kg/m2): unknown/mixed;

  • supplementation scheme/regimen: daily;

  • skin pigmentation based on Fitzpatrick skin tone chart (Fitzpatrick 1988): mixed/unknown;

  • latitude:between Tropics of Cancer and Capricorn;

  • season at the start of pregnancy: all year round.

Source of funding: Health Research Council of New Zealand, grant number 09/215R. Dr Mitchell is supported by Cure Kids. Study medicine was prepared by the Ddrops Company (Woodbridge, Ontario, Canada).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Trial reported computer‐generated randomisation list.

Allocation concealment (selection bias)

Low risk

The allocation sequence was concealed from research staff involved in recruitment. Trial reported randomly allocated treatment to each participant and labelled identical study medicine bottles such that study staff and participants were unaware of the treatment status.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

The study statistician randomly allocated a treatment to each participant and labelled identical study medicine bottles such that study staff and participants were unaware of the treatment status.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

The study staff and participants were unaware of the treatment status.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Reported compliance did not differ between groups. Placebo group: discontinued intervention during pregnancy (n = 3), withdrew at 30 & 32 weeks of gestation (n = 2), late fetal death at 37 weeks of gestation (n = 1). Lower dose vitamin D group: discontinued intervention during pregnancy (n = 3), withdrew @ 32 weeks of gestation (n = 2), moved from region @ 36 weeks of gestation (n = 1). Higher dose vitamin D group: discontinued intervention during pregnancy (n = 3), withdrew @ 29 & 38 weeks of gestation (n = 2), moved from region @ 36 weeks of gestation (n = 1).

Selective reporting (reporting bias)

Low risk

Registration was with the Australian NZ Clinical Trials Registry (ACTRN12610000483055).

Other bias

Low risk

The study appears to be free of other sources of bias.

Li 2000a

Methods

Clinical controlled trial with 3 arms.

Participants

88 pregnant women with a predisposition to pregnancy‐induced hypertension, at 20‐24 weeks' gestation, a BMI index of lower than 24, and an arterial pressure of < 11.3 kPa attending an outpatient clinic and labour ward of the First Afifliated Hospital of Xi’an Medical University, Xi’an, China.

Interventions

Participants were divided into 3 groups: group 1 (n = 29) received a daily dose of a tablet containing 600 mg of calcium and 200 IU of vitamin D (Caltrate‐D) daily from 20‐24 weeks until deliver; group 2 (n = 29) received 1200 mg of calcium and 400 IU vitamin D (Caltrate‐D) daily from 20‐24 weeks until deliver; group 3 (n = 30) received no intervention from 20‐24 weeks until delivery.

Health worker cadre: not reported.

Outcomes

Blood pressure, ionised calcium and platelet intracellular calcium, incidence rates of pregnancy‐induced hypertension.

Notes

  • Total dose of supplementary vitamin D during pregnancy: 56,000 IU vitamin D or less;

  • start of supplementation: 20 weeks of pregnancy or more;

  • pre‐gestational BMI (kg/m2): unknown/mixed;

  • supplementation scheme/regimen: daily;

  • skin pigmentation based on Fitzpatrick skin tone chart (Fitzpatrick 1988): mixed/unknown;

  • latitude:north of Tropic of Cancer;

  • season at the start of pregnancy: all year round.

Source of funding: not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The assignment of the groups method is not reported.

Allocation concealment (selection bias)

Unclear risk

It is unclear if there was allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

2 groups received an intervention while women from group 3 received no intervention. There is no report on blinding.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

2 groups received an intervention while women from group 3 received no intervention. There is no report on blinding.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Loss to follow‐up not reported.

Selective reporting (reporting bias)

Unclear risk

There is insufficient information to make a judgement.

Other bias

High risk

The details of the methods are not available. The report is rather short.

Mallet 1986

Methods

Randomised controlled trial; 3‐arm design with individual randomisation.

Participants

77 white pregnant women 18‐36 years of age in the last trimester of pregnancy living in Northwest of France (latitude: 49° 26' 0" N north of tropic of Cancer). Pre‐gestational BMI not reported.

Interventions

Participants were randomly assigned to 1 of 3 groups: group 1 (n = 21) women received daily 1000 IU of vitamin D (ergocalciferol‐D2) for the last 3 months of pregnancy (estimated total dose throughout pregnancy: 90,000 IU); group 2 (n = 27) women received a single dose of 200,000 IU (5 mg) vitamin D at the 7th month of pregnancy; group 3 (n = 29) women received no supplement and served as controls.

Length of the intervention/follow‐up: 12 weeks from start of supplementation to term.

Health worker cadre: the study was conducted by the research team at the maternity of Balvedere, Rouen, Frances but the roles are not described. It is unclear who provided the supplements and measured the outcomes.

Outcomes

Maternal: 24‐hour urinary calcium excretion after 6 weeks supplementation, calcium, 25‐hydroxyvitamin D (25‐OHD) and1‐alfa,25‐dihydroxyvitamin D (1,25(OH)2D) metabolites of vitamin D from serum and cord during labour and delivery.

Infant: serum calcium levels at days 2 and 6 of life, birthweight.

Laboratory method used for assessment of vitamin D concentrations: for 25 OHD and 1,25 (OH)2 D determinations the following techniques were used: extraction with chloroform‐methanol‐water according to Preece, double step purification, first on a Sephadex LH 20 column with chloroform hexan 45‐55 vol/vol as solvent, then on a high‐pressure liquid pression system according to Shepard. Plasma metabolites were measured by competitive assay using rat protein for 25 OHD and chicken intestine cytosol for 1,25 (OH)2 D according to Jongen. Assay sensitivity for 1,25 (OH)2 D was 5 pmol/tube and for 25 OHD was 25 pmol/tube.

Notes

  • Total dose of supplementary vitamin D during pregnancy: more than 56,000 to 200,000 IU;

  • start of supplementation: 20 weeks of pregnancy or more;

  • pre‐gestational BMI (kg/m2): unknown/mixed;

  • supplementation scheme/regimen: single/daily;

  • skin pigmentation based on Fitzpatrick skin tone chart (Fitzpatrick 1988): mixed/unknown;

  • latitude: north of the Tropic of Cancer;

  • season at the start of pregnancy: winter pregnancy. Infants born during February and March.

Source of funding: not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation by random numbers table.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Different interventions were used: daily dose or single dose or no supplement.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

There is insufficient information to permit judgement.

Incomplete outcome data (attrition bias)
All outcomes

High risk

It is unclear if there was attrition, but given the uneven number of participants reported it is likely that there were losses to follow‐up.

Selective reporting (reporting bias)

Unclear risk

There is insufficient information to permit judgement.

Other bias

High risk

Groups are reported with notorious different sample size. It is unclear whether the numbers reflect the participants who finished the trial (unclear and uneven losses to follow‐up); a non randomised process; or a selection bias in which randomised participants did not receive the intervention.

Marya 1987

Methods

Randomised controlled trial; 2‐arm design with randomisation at individual level.

Participants

400 pregnant women 20‐35 years of age, attending the antenatal clinic of Medical College Hospital in Rohtak, India (latitude: 76° 34' 0' north of Tropic of Cancer). Pre‐gestational BMI and skin pigmentation not reported.

Interventions

Participants were allocated to 1 of 2 groups: group 1 (n = 200) received a daily supplement containing 1200 IU vitamin D and 375 mg calcium (estimated total dose from week 20‐24 of gestation to term:134,400‐168,000 IU); group 2 (n = 200) received no supplement from 20‐24 weeks of pregnancy until delivery.

Length of the intervention/follow‐up: 20‐24 weeks from start of supplementation to term.

Health worker cadre: not specified.

Outcomes

Maternal: pre‐eclampsia (defined as blood pressure of 140 mmHg or higher systolic and/or 90 mmHg diastolic along with proteinuria higher than 300 mg/24 hours); systolic and diastolic blood pressure at 24, 28, 32 and 36 weeks of gestation. Serum calcium and creatinine.

Laboratory method used for assessment of vitamin D concentrations: not assessed.

Notes

Biochemical analyses were made for those who developed pre‐eclampsia (n = 12) and also in a group of women with no pre‐eclampsia (n = 25) and a control group of non pregnant women. The results of the stratified analysis are not reported in this review.

  • Total dose of supplementary vitamin D during pregnancy: more than 56,000 to 200,000 IU;

  • start of supplementation: 20 weeks of pregnancy, or more;

  • pre‐gestational BMI (kg/m2): unknown/mixed;

  • supplementation scheme/regimen: daily;

  • skin pigmentation based on Fitzpatrick skin tone chart (Fitzpatrick 1988): mixed/unknown;

  • latitude: north of the Tropic of Cancer;

  • season at the start of pregnancy: mixed/unknown.

Source of funding: not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

400 pregnant women, of these 200 were randomly selected and put on a daily supplement of calcium and vitamin D.

Method of sequence generation not described.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

There is insufficient information to permit judgement.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

There is insufficient information to permit judgement.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Only data on biochemical were reported for those who developed pre‐eclampsia and some of those with no pre‐eclampsia and a group of non pregnant controls.

Selective reporting (reporting bias)

High risk

Outcomes reported for some subgroups only.

Other bias

Low risk

The study appears to be free of other sources of bias.

Marya 1988

Methods

Randomised clinical trial; 2‐arm design with individual randomisation.

Participants

200 pregnant women, aged 22‐35 years old, attending the antenatal clinic of the Medical College Hospital, Rohtak, India (latitude: 76° 34' 0' north of Tropic of Cancer). Inclusion criterion: uncomplicated single pregnancy. Exclusion criteria: pre‐eclampsia, antepartum haemorrhage, premature delivery. Pre‐gestational BMI and skin pigmentation not reported.

Interventions

Participants were allocated to 1 of the following groups: group 1 (n = 100) women received 2 doses of 600,000 IU (each dose at 7th and 8th month of pregnancy (estimated total dose: 1,200,000 IU); group 2 (n = 100): women received no intervention.

Length of the intervention/follow‐up: 12 weeks from start of supplementation to term.

Health worker cadre: not specified.

Outcomes

Maternal: venous and cord serum calcium, serum proteins, inorganic phosphate, alkaline phosphatase, weight. Radiological examination on women with abnormal biochemistry or osteomalacia symptomatology. Side effects: back age, leg‐pains, general weakness, cramps.

Infant: birthweight, low birthweight, crown‐heel length, head circumference, mid‐arm circumference within 24 hours after birth. Skinfold thickness (triceps and infrascapular).

Laboratory method used for assessment of vitamin D concentrations: not assessed.

Notes

  • Total dose of supplementary vitamin D during pregnancy: more than 200,000 IU of vitamin D;

  • start of supplementation: 20 weeks of pregnancy or more;

  • pre‐gestational BMI (kg/m2): unknown/mixed;

  • supplementation scheme/regimen: 2 single doses were provided at 7th and 8th month of pregnancy;

  • skin pigmentation based on Fitzpatrick skin tone chart (Fitzpatrick 1988): mixed/unknown;

  • latitude: north of the Tropic of Cancer;

  • season at the start of pregnancy: mixed/unknown.

Source of funding: not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

'200 pregnant women, of these 100 were randomly selected (supplemented group) had been administered two doses of vitamin D.'

Method of sequence generation not described.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

There is insufficient information to permit judgement.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

There is insufficient information to permit judgement.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Losses to follow‐up are not documented although exclusions included pregnancy complications. Result tables mention that each arm was comprised of 100 women, a number that corresponds to that described for the treatment allocation.

Selective reporting (reporting bias)

Unclear risk

There is insufficient information to permit judgement.

Other bias

Low risk

The study appears to be free of other sources of bias.

Mazurkevich 2013

Methods

Randomised control trial.

Participants

72 pregnant women with physiological pregnancy aged 18‐35 with low alimentary consumption of calcium (< 600 mg/day) who attended to Moscow State University of medicine and dentistry, department of obstetrics and gynaecology. (Latitude: 55.7500° N, 37.6167° E).

Interventions

Participants were randomly assigned to 1 of 2 groups: group 1 (n = 43): 1250 mg of calcium carbonate and 200 IU of vitamin D (cholecalciferol‐D3) from the second pregnancy trimester until term, in 2 takes a day; group 2 (n = 29): did not undergo the intended preventive measures.

Health worker cadre: not reported.

Outcomes

Maternal: resistance of uterine arteries, resistance of umbilical arteries, uterine‐placental circulation.

Infant: fetal‐placental circulation, intrauterine growth retardation, assessed by dopplerometry.

Laboratory method used for assessment of vitamin D concentrations: not assessed.

Notes

  • Total dose of supplementary vitamin D during pregnancy: 56,000 IU or less IU;

  • start of supplementation: 20 weeks of pregnancy, or more;

  • pre‐gestational BMI (kg/m2): unknown/mixed;

  • supplementation scheme/regimen: daily;

  • skin pigmentation based on Fitzpatrick skin tone chart (Fitzpatrick 1988): mixed/unknown;

  • latitude: north of the Tropic of Cancer;

  • season at the start of pregnancy: mixed/unknown.

Source of funding: not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"72 pregnant women with physiological pregnancy aged 18‐35 with low alimentary consumption of calcium (<600 mg/day) were randomised into two groups."

Method of sequence generation not described.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

It is not reported whether the trial was blinded to participants, outcome assessor or care providers.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

There is insufficient information to permit judgement.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

There is insufficient information to permit judgement.

Selective reporting (reporting bias)

Unclear risk

There is insufficient information to permit judgement.

Other bias

Low risk

The study appears to be free of other sources of bias.

Roth 2010

Methods

Randomised placebo‐controlled trial.

Participants

160 pregnant women aged 18 < 35 years old, attending to the International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh (latitude: 23.7000° N, 90.3750° E, north of the Tropic of Cancer). Inclusion criteria: patients with residence in Dhaka, with plans to have the delivery performed at the Shimantik maternity centre, and to stay in Dhaka throughout the pregnancy and 1 month past the delivery, with gestational age of 26th to 29th (inclusive), estimated based on the first day of the last menstrual period. Exclusion criteria: Use of any dietary supplement containing more than 400 IU/day (10 mcg/day) of vitamin D within the month prior to enrolment, or refusal to stop taking supplemental vitamin D at any dose after enrolment, current use of anti‐convulsant or anti‐mycobacterial (tuberculosis) medications, severe anaemia (haemoglobin concentration < 70 g/L), complicated medical or obstetric history: cardiovascular disease, uterine haemorrhage, placenta praevia, threatened abortion, hypertension, pre‐eclampsia, preterm labour, or multiple gestation), prior history of delivery of an infant with a major congenital anomaly, birth asphyxia, or perinatal death (stillbirth or death within first week of life).

Interventions

Participants were randomly assigned to 1 of 2 groups: group 1 (n = 80): women received vitamin D (cholecalciferol‐D3) 35,000 IU per week, started at 26‐29 weeks' gestation, until delivery; group 2 (n = 80): women received placebo control administered weekly from 26‐29 weeks' gestation until delivery.

Health worker cadre: supplement doses were measured in disposable plastic syringes and orally administered by study personnel.

Outcomes

Maternal: serum 25‐hydroxyvitamin D concentration, serum calcium concentration, urine Ca:Cr ratio.

Infant: immune function, infant growth, postnatal vitamin D status, serum calcium.

Laboratory method used for assessment of vitamin D concentrations: Serum 25(OH)D was quantified by high‐performance liquid chromatography tandem mass spectroscopy (LCMS/MS) in the Department of Pathology and Laboratory Medicine at the Hospital for Sick Children.

Notes

  • Total dose of supplementary vitamin D during pregnancy: more than 200,000 IU;

  • start of supplementation: 20 weeks of pregnancy or more;

  • pre‐gestational BMI (kg/m2): unknown/mixed;

  • supplementation scheme/regimen: daily;

  • skin pigmentation based on Fitzpatrick skin tone chart (Fitzpatrick 1988): mixed/unknown;

  • latitude: north of the Tropic of Cancer;

  • season at the start of pregnancy: summer.

Source of funding: The Thrasher Research Fund, Salt Lake City, USA.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Trial reported computer‐generated randomisation list.

Allocation concealment (selection bias)

Low risk

The allocation sequence was prepared by International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh personnel not otherwise involved in the study, and was concealed from investigators.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Trial reported that participants and research staff (including lab personnel) were blinded to allocation.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Trial reported that participants and research staff (including lab personnel) were blinded to allocation.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Of the 160 participants recruited and randomly assigned to either vitamin D (35,000 IU/week) or placebo, 13 were lost to follow‐up prior to delivery (6 in the placebo group and 7 in the vitamin D group), all because of having left the Dhaka area.

Selective reporting (reporting bias)

Low risk

This trial was registered at ClinicalTrials.gov (NCT01126528) and all outcomes were reported as per registration.

Other bias

Unclear risk

The study appears to be free of other sources of bias.

Sablok 2015

Methods

Randomised controlled trial with 2 arms, with randomisation at the individual level from years 2010 to 2012.

Participants

180 primigravidae women with singleton pregnancy at 14–20 weeks in the Department of Obstetrics and Gynaecology in Safdarjung Hospital, New Delhi, India (28°38′08″ N, 77°13′28″ E north of Tropic of Cancer).
Pregnant women with pre‐existing osteomalacia, known hyperparathyroidism, renal, liver dysfunction, tuberculosis, sarcoidosis and women not willing to comply to the study protocol were excluded.

Interventions

Participants were randomly assigned to 1 of 2 groups: group 1 (n = 60) women did not receive any supplementation of vitamin D; group 2 (n = 120) women received vitamin D (cholecalciferol‐D3) supplementation in dosages depending upon the level of serum 25(OH)‐D levels estimated at entry into the study. Participants from this second group with sufficient levels of vitamin D (serum 25(OH)‐D levels > 50 nmol/L), received only 1 dose of 60,000 IU vitamin D (cholecalciferol‐D3) at 20 weeks; participants with insufficient levels of vitamin D (serum 25(OH)‐D levels 25–50 nmol/L) received 2 doses of 120,000 IU vitamin D (cholecalciferol‐D3) at 20 weeks and 24 weeks; and participants with deficient levels of vitamin D status (serum 25(OH)‐D levels < 25 nmol/L) received 4 doses of 120,000 IU vitamin D cholecalciferol‐D3) at 20, 24, 28 and 32 weeks.

Health worker cadre: unclear what the roles of the researchers and other workers in the health worker cadre.

Outcomes

Maternal: preterm labour, pre‐eclampsia, GDM, serum 25(OH)‐D concentration, serum calcium, phosphorus and serum ALP levels.
Infants: Apgar score, birthweight, low birthweight, 25(OH)‐D concentration in cord blood, small‐for‐gestational age; appropriate for gestational age.

Laboratory method used for assessment of vitamin D concentrations: Serum 25(OH)D was quantified by sandwich ELISA.

Notes

  • By total dose of supplementary vitamin D during pregnancy: more than 56,000 to 200,000 IU to more than 200,000 IU of vitamin D;

  • by start of supplementation: 20 weeks of pregnancy, or more;

  • by pre‐gestational BMI (kg/m2): healthy weight;

  • by supplementation scheme/regimen: single given at different weeks of gestation in the supplemented group;

  • by skin pigmentation based on Fitzpatrick skin tone chart (Fitzpatrick 1988): mixed/unknown;

  • by latitude: north of the Tropic of Cancer;

  • by season at the start of pregnancy: all year round. Authors report that sufficient levels of vitamin D were seen in 93.3% patients who had more than 4 hours of sun exposure every day as compared to 18.5% in those with less than 1 hour of daily sun exposure.

Source of funding: self‐funded.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was performed using computer‐generated random number tables.

Allocation concealment (selection bias)

High risk

As participants were assigned to either no intervention or intervention and the intervention dosage depended on the vitamin D status, there was a selection bias based on status of vitamin D at baseline.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

1 group received no intervention at all and the other different doses of vitamin D at different times.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

1 group received no intervention at all and the other different doses of vitamin D at different times.

Incomplete outcome data (attrition bias)
All outcomes

High risk

The level of attrition was different in groups 1 and 2: 3/60 (5%) participants in group 1 and 12/120 (10%) participants in group 2 were lost to follow‐up.

Selective reporting (reporting bias)

Unclear risk

There is insufficient information to permit judgement.

Other bias

Low risk

The study appears to be free of other evident sources of bias.

Taherian 2002

Methods

Randomised controlled study with 3 arms.

Participants

990 nulliparous women attending antenatal outpatient clinics of Isfahan Health Centers (32.6333° N, 51.6500° E north of Tropic of Cancer) between April 1998 and March 2001, with singleton pregnancies, first prenatal visit before 20 weeks of gestation, systolic/diastolic blood pressure lower than 130/80 mmHg, and no proteinuria detectable by a dipstick.

Women with history of cardiovascular, renal or endocrinologic problems, medical or obstetric complications and those with known hazardous condition (multifetal gestation, hydatidi‐form mole) were excluded.

Interventions

Participants were randomly assigned to 1 of 3 groups: group 1 (n = 330) received 75 mg aspirin each day from 20th week of gestation until delivery; group 2 (n = 330) received a tablet containing 500 mg calcium carbonate + 200 IU vitamin D (cholecalciferol‐D3) daily from 20th week of gestation until delivery; and group 3 (n = 330) received no intervention. All cases received standard prenatal care.

Health worker cadre: the women were examined by trained staff every 4 weeks through the 28 weeks of gestation, and every 2 weeks through the 36th week and weekly thereafter. Blood pressure was measured by a certified examiner.

Outcomes

Maternal: blood pressure, bodyweight, BMI, maternal height, urine protein measurements, maternal weight gain, duration of gestation.

Infant: neonatal weight at birth, the presence of respiratory distress syndrome, sepsis, jaundice and intrauterine growth retardation, fetal or neonatal death.

Notes

  • Total dose of supplementary vitamin D during pregnancy: less than 56,000 IU;

  • start of supplementation: 20 weeks of pregnancy or more;

  • pre‐gestational BMI (kg/m2): normal weight (18.5 to 24.9);

  • supplementation scheme/regimen: daily;

  • skin pigmentation based on Fitzpatrick skin tone chart (Fitzpatrick 1988): mixed/unknown;

  • latitude: north of the Tropic of Cancer;

  • season at the start of pregnancy: April 1998 to March 2001.

Source of funding: Research Deputy of Isfahan University of Medical Sciences grant (No: 76085).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

By table of random numbers.

Allocation concealment (selection bias)

Unclear risk

There is no mention of any allocation. It is unclear whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

There is no mention of the study being blinded to participants of health care providers.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

There is no mention of the study being blinded to participants of health care providers.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No attrition reported.

Selective reporting (reporting bias)

Low risk

It appears unlikely. This study was conducted to evaluate the effect of low‐dose aspirin or calcium supplements, taken during pregnancy, on the incidence of pre‐eclampsia in nulliparous healthy women.

Other bias

Low risk

The study appears to be free of other evident sources of bias.

Yu 2008

Methods

Randomised controlled trial; 4 x 3 block design with randomisation at individual level.

Participants

180 pregnant women (45 Indian Asians, 45 Middle Eastern, 45 Black and 45 Caucasian) women at 27 weeks' gestation attending the routine antenatal clinic at St Mary’s Hospital, London, United Kingdom (latitude: 51°30'N north of tropic of Cancer). Exclusion criteria: pre‐existing sarcoidosis, osteomalacia, renal dysfunction and tuberculosis. Pre‐gestational BMI and skin pigmentation (in addition to ethnicity) not reported. The study took place between April 2007 and November 2007.

Interventions

Participants were randomised in blocks of 15 within each of the 4 ethnic groups to 3 groups; group 1 (n = 60) women received a daily dose of vitamin D (ergocalciferol D2) at 800 IU (estimated total dose 72,800 IU); group 2 (n = 60): women received a stat dose of 200,000 IU of calciferol; group 3 (n = 60): women received no treatment.

Length of the intervention/follow‐up: 13 weeks from start of supplementation to term.

Health worker cadre: each woman collected her tablets directly from the hospital pharmacy department or her local pharmacy.

Outcomes

Maternal: maternal and cord 25‐hydroxyvitamin D levels at delivery, maternal PTH and corrected calcium levels at delivery, adverse events.

Infant: small‐for‐gestational age was defined as birthweight less than the 10th percentile after adjustments for gestation at delivery, infant sex, maternal ethnicity, parity, height and weight.

Laboratory method used for assessment of vitamin D concentrations: not specified.

Notes

Women who did not speak English were only included if a health advocate was able to interpret and a leaflet was provided in their language.

  • Total dose of supplementary vitamin D during pregnancy: more than 56,000 to 200,000 IU;

  • start of supplementation: 20 weeks of pregnancy or more;

  • pre‐gestational BMI (kg/m2): unknown/mixed;

  • supplementation scheme/regimen: single and daily;

  • skin pigmentation based on Fitzpatrick skin tone chart (Fitzpatrick 1988): mixed/unknown;

  • latitude: north of the Tropic of Cancer;

  • season at the start of pregnancy: summer. April to November 2007; summer.

Source of funding: Institute of Obstetrics and Gynaecology Trust, Wolfson and Weston Research Centre for Family Health, Imperial College, Du Cane Road, Hammersmith Hospital, London W12 0NN, UK.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random number lists were drawn up by an independent researcher, with randomisation in blocks of 15.

Allocation concealment (selection bias)

Low risk

The person seeing the pregnant women allocated the next available number on entry to the trial, and each woman collected her tablets directly from the hospital pharmacy department or her local pharmacy.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

All study personnel and participants were not blinded to treatment assignment.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

There is insufficient information to permit judgement.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only 1 loss to follow‐up on group 3.

Selective reporting (reporting bias)

Low risk

The study was approved by St Mary’s Hospital Ethics Committee (Ref: 06/Q0702/172) and the Medicines and Healthcare products Regulatory Agency.

Other bias

Unclear risk

Women were randomised within each ethnic group. It is not clear if the ethnicity can be clearly established as it was self reported. Women who did not speak English were included only if a health advocate was able to interpret and a leaflet was provided in their language (English, Arabic, Bengali and Farsi) although the ability to read was not clearly established.

BMI: body mass index
GDM: gestational diabetes mellitus
HDL: high‐density lipoprotein
IGF‐I: insulin‐like growth factor
IU: international units
IUFD: intrauterine fetal death
LDL: low‐density lipoprotein
PA: physical activity
PTH: parathyroid hormone

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Ala‐Houhala 1986

49 healthy, well‐nourished mothers delivering in January 1984 in the maternity wards and outpatient clinic of the Department of Paediatrics of the University Central Hospital of Tampere, Finland (latitude 61°N) and exclusively breastfeeding their infants, were divided in succession into 3 groups: group 1 (n = 17): mothers were given 2000 IU vitamin D3 a day, infants not supplemented; group 2 (n = 16): mothers were given 1000 IU vitamin D3 a day, infants not supplemented; group 3 (n = 16): mothers were not supplemented, and their breast fed infants were given 400 IU of vitamin D2 a day. During pregnancy, 33 mothers had no vitamin D supplementation, 8 mothers received 500 IU a day of vitamin D during the second trimester of pregnancy, and 8 mothers received 500 IU a day throughout the pregnancy. The mothers from these 3 groups supplemented in pregnancy were distributed in the postpartum maternal vitamin D supplementation and infant vitamin D supplementation interventions.

This is not a randomised trial and the intervention includes mothers at postpartum and their infants.

Asemi 2013b

54 pregnant women aged 18–40 years diagnosed with GDM by a 100‐g oral glucose‐tolerance test at 24–28 weeks' gestation attending maternity clinics affiliated with Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran (latitude: 33.9889° N, 51.4772° E), during March 2012 to September 2012 and further analysis during January 2013 to April 2013. Participants were randomly assigned to 1 of 2 groups: group 1 (n = 27), women received capsules containing 50,000 IU vitamin D (cholecalciferol‐D3) (D‐Vitin 50000; Zahravi Pharm Co) 2 times during the study (at baseline and at day 21 of the intervention): group 2 (n = 27), women received 2 placebos (Barij Essence Co) at the same times. The duration of the study was 6 weeks; however, vitamin D was given only 2 times during the 6 weeks. Additionally, all participants also consumed 400 μg (0.4 mg) folic acid daily from the beginning of pregnancy and 60 mg elemental iron (as ferrous sulphate) daily from the second trimester. The trial was carried out in maternity clinics affiliated to Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran and the investigators provided the supplements to the participants. A trained midwife at the maternity clinic performed anthropometric measurements at study baseline and at 6 weeks after the intervention. All pregnant women in the study had a diagnosis of gestational diabetes. The type of participant is outside the scope of this review.

Asemi 2014

56 pregnant women 18‐40 years of age with gestational diabetes and 24‐28 weeks' gestation attending prenatal care at maternity clinics affiliated to Kashan University of Medical Sciences, Kashan, Iran were randomly assigned to 1 of 2 groups: group 1 (n = 28) received 1000 mg calcium per day and a 50,000 U vitamin D (cholecalciferol‐D3) pearl twice during the study (at study baseline and on day 21 of the intervention); group 2 (n = 28) received 2 placebos at the same times. Participants with premature preterm rupture of the membrane, placenta abruption, pre‐eclampsia, eclampsia, chronic hypertension, hypothyroidism, urinary tract infection, kidney or liver diseases, stressful life conditions, smokers or using oestrogen therapy or women requiring insulin therapy during the intervention (FPG > 5.8 mmol/L and 2 hours postprandial blood sugar > 6.7mmol/L).were excluded. All participants were also consuming 400 μg (0.4 mg) folic acid daily from the beginning of pregnancy and 60 mg elemental iron (as ferrous sulphate) from the second trimester. The calcium 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). The trial was carried out in maternity clinics affiliated to Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran and the investigators provided the supplements to the participants. A trained midwife at the maternity clinic performed anthropometric measurements at study baseline and at 6 weeks after the intervention. Outcomes measured included serum 25‐hydroxyvitamin D [25(OH)D] concentrations, FPG, serum calcium, cholesterol, triacylglycerol, LDL‐cholesterol and HDL‐cholesterol, serum insulin, serum high‐sensitivity C‐reactive protein, plasma total antioxidant capacity, plasma total glutathione, plasma malondialdehyde. Participants were pregnant women with diagnosis of gestational diabetes. The type of participant is outside the scope of this review.

Bhatia 2012a

299 pregnant women with 12 and 24 weeks of gestation of lower‐middle and middle socio‐economic groups attending the antenatal clinic in Queen Mary Hospital, Chhatrapati Sahuji Maharaj, India, were randomly assigned to 1 of 2 groups, group 1: received 1500 mcg cholecalciferol at induction into the study, or group 2 3000 mcg cholecalciferol at induction as well as at 28 weeks of gestation. All were prescribed 1 g of elemental calcium daily as calcium carbonate without vitamin D. Patients excluded from the study if they were already on calcium or vitamin D supplementation, anticonvulsants, antitubercular treatment or had any medical condition that affected calcium and vitamin D metabolism (including renal and hepatic disease). Only 97 women were followed up.

Both groups received vitamin D and calcium. This type of intervention is outside the scope of our review.

Cockburn 1980

1139 pregnant women were assigned to 1 of 2 wards: group 1 (n = 506) Caucasian pregnant women assigned to 1 ward of the Simpson Memorial Maternity Pavilion, Edinburgh, United Kingdom during the 9 months from September to May, were given a daily dietary supplement of 400 IU of vitamin D2 from about the 12th week of pregnancy until delivery; group 2 women (n = 633) were assigned to another ward over the same period and were given a placebo containing no vitamin D. Outcomes included plasma concentrations of calcium, phosphorus, magnesium, total proteins, and 25‐hydroxycholecalciferol at 24th and 34th weeks of pregnancy and at delivery. Infant plasma concentrations of calcium, phosphorus, magnesium, total proteins, and 25‐hydroxycholecalciferol were measured from umbilical venous blood taken from the infants at birth and on capillary blood on the 6th day.

This is not a randomised trial.

Czech‐Kowalska 2013

174 healthy postpartum women who had delivered babies at term in Poland, were randomised to 1 of 2 groups: group 1 (n = 70) received 1200 IU/d vitamin D (cholecalciferol‐D3 as 800 IU/d alone + 400 IU/d from a multiple micronutrient supplements; group 2 (n = 67) received 400 IU/d vitamin D (cholecalciferol‐D3 as placebo + 400 IU/d from multiple micronutrient supplements) during 6 months of lactation. Outcomes measured included serum 25‐hydroxyvitamin D (S‐25‐OHD), PTH and densitometry after delivery, at 3 and 6 months postpartum. Serum and urinary calcium were assessed at 3 and 6 months postpartum. Participants from both groups received vitamin D supplements. The participants were postpartum women. The type of participant and the type of interventions are outside the scope of this review.

Das 2009

150 consecutive pregnant women pregnant women during their second trimester from 6 villages of a poor socio‐economic region in district Barabanki (latitude 26.8 ºN), Uttar Pradesh, north India.  The participants were initially randomised to receive either no dose or 1 dose of 60,000 IU cholecalciferol under observation in the 5th gestational month. However, the first few results showed rampant vitamin D deficiency and no improvement at delivery despite good exposure to sun and calcium supplementation. Therefore, this randomisation was abandoned subsequently and 2 comparison groups were followed up, alternate women receiving either 60,000 IU in the 5th month or 120,000 IU, each in the 5th and 7th months of pregnancy.

This is not a randomised trial and the comparisons are outside the scope of this review.

Dawodu 2013

192 Arab women between 12–16 weeks of gestation after their last menstrual period or by ultrasound assessment who had a singleton pregnancy; and planned to receive prenatal and delivery care in primary health care clinics affiliated with Tawam Hospital, Al Ain, United Arab Emirates. Exclusion criteria were pre‐existing calcium and parathyroid conditions, active thyroid disease, liver or kidney disease, or type 1 diabetes, which are likely to affect vitamin D and calcium status. All participants received vitamin D supplementation in different regimens.

The type of intervention is outside the scope of this review.

Etemadifar 2015

45 pregnant women with confirmed multiple sclerosis who attended an outpatient clinic in Isfahan University of Medical Sciences, Iran aged 20‐40 years with low serum 25‐hydroxyvitamin D (25(OH)D) levels were randomly allocated to 2 groups in an open‐label randomised, controlled clinical Phase I/II pilot study. 1 group received 50,000 IU/week vitamin D3 (n = 21) or routine care (n = 22) from 12 to 16 weeks of gestation till delivery. Inclusion criteria were women with a magnetic resonance imaging, clinical or laboratory‐supported diagnosis of definite multiple sclerosis, stable neurological functioning for at least 1‐month prior to study entry, and an expanded disability status scale (EDSS) score ≤ 6, serum 25(OH)D level < 20 ng/mL and a willingness to continue current medications for the duration of the study. The main outcome measures were mean change in serum 25(OH)D levels, EDSS score, and number of relapse events during pregnancy and within 6 months after delivery. Participants had a confirmed diagnosis of multiple sclerosis.

This type of participant is outside the scope of this review.

Hashemipour 2013

160 pregnant women (24–26 weeks of gestation) who attended an obstetric clinic in Qazvin, Iran, from December 2011 to March 2012 were randomised, and included in 2 arms. Inclusion criteria were: gestational age of 24–26 weeks, singleton pregnancy and BMI of 19–26 kg/m2. Exclusion criteria at study enrolment were: diabetes before pregnancy, chronic hypertension, history of repeated abortion, rheumatoid arthritis, parathyroid disorders, hepatic or renal diseases, and use of aspirin, anticonvulsive and immunosuppressive drugs. Women in the control group received a multivitamin containing 400 IU vitamin D3 plus 200 mg elemental calcium each day until delivery. Women in the intervention group received a weekly dose of 50,000 IU oral vitamin D3 for 8 weeks (from 26 to 28 weeks of pregnancy) as well as the drug regimen (multivitamin and elemental calcium) given to the control group.

Both groups received vitamin D and calcium. This type of intervention is outside the scope of our review.

Hossain 2012

200 pregnant women who attended the Department of Obstetrics & Gynaecology unit 3, Dow University and Civil Hospital Karachi, Pakistan aged between 18 and 40 years were randomised, and included in 2 arms. Participants were allocated to 1 of 2 groups: group 1 (n = 100) received along with ferrous sulphate, 4000 IU of vitamin D3; group 2 (n = 100) received routine antenatal care (ferrous sulphate and calcium). Both groups received above medications from 20 weeks of pregnancy until delivery. Maternal serum levels of 25(OH)D levels were done at the time of recruitment, and at the time of delivery. Neonatal levels were done within 48 hours of delivery.

This type of intervention is outside the scope of our review.

Hosseinzadeh 2012

48 pregnant women with GDM (diagnosed by performing oral glucose tolerance test at 24‐28th week of gestation) in Yazd, Iran were randomly assigned to 1 of 2 groups group 1 (n = 24) were assigned to received an intramuscular dose 300,000 IU of vitamin D and group 2 (n = 24) were assigned to receive no intervention. The participants were asked to refer to Yazd Diabetes Research Center 3‐10 days after delivery for outcome assessments that included plasma glycosylated haemoglobin A1C (HbA1C), serum 25(OH) vitamin D3, PTH, serum calcium and phosphorus. Vitamin D was provided by intramuscular injection and not orally.

The type of intervention is outside the scope of this review.

Ito 1994

876 singleton pregnant women with blood pressure lower than 140/90 mmHg at 20 weeks’ gestation, and no evidence of proteinuria, who were attending the obstetric clinic of Kumamoto University Hospital, Japan were divided into 2 groups: group 1 (n = 666) women received conventional antenatal care; group 2 (n = 210 women) were managed under a protocol for the prediction of pre‐eclampsia with an angiotensin sensitivity test and prevention of the condition by calcium supplementation. Participants from group 2 were further assigned to 1 of 4 groups according to their risk of developing pre‐eclampsia, based on the angiotensin sensitivity test and the effective pressor dose: group A received 156 mg/day of oral elemental calcium (as calcium L‐aspartate, Aspara‐Ca from 22 weeks’ gestation, followed by 312 mg/day oral elemental calcium  and vitamin D3 (0.5 μg for 3 days) from 30 weeks’ gestation to term. Participants in group B received 156 mg/day oral elemental calcium from 22 weeks’ gestation and 312 mg/day oral elemental calcium from 30 weeks’ gestation to term; group C received 312 mg/day oral elemental calcium from 30 weeks’ gestation to term and group D received no supplementation.

This is not a randomised trial and the type of intervention is outside the scope of this review.

Litonjua 2014

881 pregnant women with either a personal history of asthma or allergies or a similar history in the spouse or partner, between 18 and 40 years of age and at an estimated gestational age between 10 and 18 weeks, were recruited at a scheduled obstetrical prenatal visit at 3 clinical centres: Boston Medical Center (Boston, MA), Washington University at Saint Louis (St. Louis, MO), and Kaiser Permanente Southern California Region (San Diego, CA). Participants were randomised to either vitamin D (cholecalciferol, 4000 IU/ day; equivalent to 100 μg/day) or placebo. All pregnant mother participants received prenatal vitamins containing 400 IU (10 μg/day) of cholecalciferol; thus, the vitamin D arm received a total of 4400 IU/day (110 μg/day) and the placebo arm received 400 IU/day (10 μg/day).

Both groups received vitamin D supplements. This type of intervention is outside the scope of our review.

MacDonald 1986

This trial was registered in 1986 on the Oxford Database of Perinatal Trials and reports the recruitment and follow‐up completed in 1979. The registration form reports a randomised controlled trial to assess the efficacy of calcium and vitamin D supplementation versus placebo in the prevention of maternal and fetal hypocalcaemia. The reports indicates that the sample size was 55 Asian women with morbidity and laboratory results as primary outcomes but no further information is available.

Marya 1981

45 Hindu pregnant women were randomly assigned to 1 of 2 groups: group 1 (n = 25) received tablets containing 1200 IU vitamin D and 375 mg calcium daily throughout the 3rd trimester; group 2 (n = 20) received oral single dose of 600,000 IU vitamin D2 once during 7th month and 8th month (total 2 doses). This group was compared with group 3 (n = 75) who had not received vitamin D supplements during pregnancy. The results were also compared with data from 25 non pregnant, non‐lactating healthy women. Patients with complications such as pre‐eclampsia, antepartum haemorrhage or twin pregnancies were excluded.

The randomised study compares 2 doses of vitamin D supplementation.

The type of study, type of participants and types of interventions are outside the scope of this review.

Mutlu 2013

91 pregnant women aged 16‐42 years were admitted to Kocaeli Maternity and Children Hospital between April 2011 and April 2012. The participants were randomly divided into 3 groups: 600 IU/d (control group; n = 31); 1,200 IU/d (n = 31), and 2,000 IU/d (n = 32) of vitamin D. All groups received vitamin D supplements. This type of comparison is outside the scope of our review.

Roth 2013a

28 pregnant women were enrolled at a maternal health clinic in inner‐city Dhaka, Bangladesh Aged 18 to 34 years; at 27 to 30 weeks of pregnancy with no pre‐existing medical conditions; current vitamin D supplement use; anti‐convulsant or anti‐mycobacterial medications; severe anaemia (haemoglobin concentration less than 70 g/L); hypertension at enrolment (systolic blood pressure 140 mmHg or higher or diastolic blood pressure 90 mmHg or higher on at least 2 measurements); major risk factors for preterm delivery or pregnancy complications; or previous delivery of an infant with a congenital anomaly or perinatal death. Participants were randomly assigned to 1 of 2 groups: group 1 (N = 14) were assigned to receive a single dose of vitamin D3 70,000 IU (1.75 mg, where 1 mg = 40,000 IU) on day 0 followed by vitamin D3 35,000 IU (0.875 mg) per week starting on day 7 and continuing until delivery); Group 2 (N = 14), were assigned to receive vitamin D3 14,000 IU (0.350 mg) per week starting on day 0 and continuing until delivery. A cohort of a non pregnant participants (N = 16) received the a single dose of vitamin D3 70,000 IU on day 0 followed by vitamin D3 35,000 IU per week starting on day 7 and continuing until the last dose on day 63 (total of 10 doses). This group was used as a comparison group. All participants received vitamin D supplementation in different regimens. The type of intervention is outside the scope of this review.

Shakiba 2013

51 healthy pregnant women from the beginning of their second trimester of pregnancy during the autumn and winter of 2009 in recruited from 2 primary care clinics in Yazd (31°53’50”N/54°22’04”E), Iran. Participants were distributed in 3 groups according to their serum 25(OH)D at the beginning of the second trimester of pregnancy. Participants with low concentrations (25(OH)D levels < 20 ng/mL) (n = 17) were treated with 200,000 IU (50,000 IU/week for 4 weeks) of vitamin D (as (cholecalciferol‐D3), followed by supplementation with 50,000 IU/month vitamin D (cholecalciferol‐D3). The other 34 participants were randomly assigned to 1 of 2 groups: group 1 received 50,000 IU/month vitamin D (cholecalciferol‐D3); group 2 received 100,000 IU/month vitamin D (50,000 IU every 2 weeks) of vitamin D (cholecalciferol‐D3) supplementation. All participants received vitamin D supplements. Only the participants with higher vitamin D status were randomised to different doses and regimens. The type of study design and the type of intervention are outside the scope of this review.

Soheilykhah 2011

120 pregnant women were recruited from 2 prenatal clinics (Mojibian Hospital and Shahid Sadoughi Hospital) in Yazd, Iran, from 2009 to 2011. Exclusion criteria consisted of women with diabetes or gestational diabetes treated with insulin, women with thyroid or parathyroid disorders, polycystic ovary disease before pregnancy, BMI before pregnancy of more than 30 kg/m2 and women who received vitamin D supplementation during the prior 6 months. Participants were randomly assigned to 1 of 3 groups: group 1 received the DRI of 200 IU vitamin D (calciferol) daily, group 2 received 50,000 IU monthly (2000 IU daily) and group 3 received 50,000 IU every 2 weeks (4000 IU daily). Supplementation started in the 12th week of pregnancy and continued until delivery.

All groups received vitamin D supplements. This type of comparison is outside the scope of our review.

Stephensen 2011

Pregnant women less than 20 weeks' gestation and over 18 years of age with no use of medications known to affect vitamin D metabolism, diagnosis of type 1 diabetes, history of thyroid, renal, or liver disease, problems with digestion or absorption participated in the study at USDA Western Human Nutrition Research Center and clinicians at UC Davis Medical Center. They were distributed into 2 groups, receiving: either 400 IU or 2000 IU of vitamin D per day for the duration of their pregnancy.

Both groups received vitamin D supplements. This type of intervention is outside the scope of our review.

Taheri 2014

229 women 18‐35 years old, who were confirmed to be vitamin D deficient (vitamin D < 75 nmol/L), were randomised into the intervention, and control groups and after 15 weeks consumption of the supplement (2000 IU/day oral vitamin D) and placebo. The study was conducted among reproductive women in a high‐risk population for vitamin D deficiency.

The participants of the study were not pregnant women. The type of participant is outside the scope of this review.

von Hurst 2009

235 South Asian women, aged 23‐68 years, living in Auckland, New Zealand were recruited for the study and those who were insulin resistant ‐ homeostasis model assessment 1 (HOMA1) > 1.93 and had serum 25‐hydroxyvitamin D concentration < 50 nmol/L were randomly assigned to 1 of 2 groups: group 1 (n = 42) received 100 μg (4000 IU) vitamin D(3); group 2 (n = 39) received a placebo daily for 6 months.

The study participants were non‐pregnant women. The type of participant is outside the scope of this review.

Wagner 2010a

257 pregnant women 12‐16 weeks’ gestation were enrolled at Eau Claire Cooperative Health Center (ECCHC) in Columbia, SC, and Northwoods Community Health Center (NCHC) in North Charleston, SC, USA and were randomly assigned to receive either 2000 IU/d vitamin D versus 4000 IU/d vitamin D (cholecalciferol‐D3), followed 1‐month run‐in at 2000 IU vitamin D daily. Participants were monitored for hypercalciuria, hypercalcaemia, and 25(OH)D status.

Both groups received vitamin D at different doses. The type of intervention is outside the scope of this review.

Wagner 2010b

494 apparently healthy pregnant women (16‐45 years of age) with 12‐16 weeks' gestation of singletons attending prenatal care in Medical University of South Carolina, Charleston, South Carolina in South Carolina, United States were randomised into 1 of 3 groups stratified by race: group 1 received 400 IU vitamin D (cholecalciferol‐D3)/day; group 2 received 2000 IU vitamin D (cholecalciferol‐D3)/day; and group 3 received 4000 IU vitamin D (cholecalciferol‐D3)/day until delivery. All women received daily multiple micronutrients supplements. 350 women continued until delivery. Outcomes included monthly 25‐hydroxyvitamin D; 1,25(OH)2D; intact PTH, serum calcium, creatinine, phosphorus, and urinary calcium/creatinine levels, gestational age at delivery, birthweight, mode of delivery, co‐morbidities of pregnancy, pre‐eclampsia, gestational diabetes, any infection, preterm labour and premature birth.

All women received vitamin D supplementation at different doses. The type of intervention is outside the scope of this review.

Wagner 2010c

This is an analysis of data from 2 randomised controlled trials by the same research group (Wagner 2010b; Wagner 2010a). In Wagner 2010b, women were randomised to 400, 2000, or 4000 IU vitamin D (cholecalciferol‐D3)/day, stratified by race. In Wagner 2010a, participants were randomised to 2000 or 4000 IU vitamin D (cholecalciferol‐D3)/day.

Yap 2014

179 pregnant women 18 years of age or older, with singleton pregnancy, with plasma 25‐hydroxivitamin D (25OHD) concentrations lower than 32 ng/mL, less than 20 weeks of gestation were randomly assigned to 1 of 2 groups: group 1 (n = 89) received 5000 IU/d of vitamin D (cholecalciferol‐D3) until delivery; group 2 (n = 90) received 400 IU/d of vitamin D (cholecalciferol‐D3) until delivery. Outcomes included glycaemia and glucose tolerance, gestational diabetes at 26‐28 weeks of gestation; neonatal 25OHD, maternal hypertension, mode of delivery, prematurity, birthweight, crown‐heel length, occipitofrontal head circumference. All participants received vitamin D supplements at different doses. The type of intervention is outside the scope of this review.

BMI: body mass index
DRI: dietary references intakes
FPG: fasting plasma glucose
GDM: gestational diabetes mellitus
IU: international units
mcg: microgram
PTH: parathyroid hormone
25OHD: 25‐hydroxycholecalciferol

Characteristics of ongoing studies [ordered by study ID]

Benson 2009

Trial name or title

A randomised controlled trial on the effects of antenatal vitamin D supplementation to improve vitamin D levels in the maternal and cord blood at birth in vitamin D deficient pregnant women.

Methods

Randomised controlled trial.

Participants

Pregnant women between 14‐18 weeks' gestation at risk, defined as: dark skinned, veiled; with vitamin D deficiency that has not commenced treatment prior to recruitment. Exclusion criteria: women taking barbiturates or anticonvulsants (decreased vitamin D absorption) and severe renal failure.

Interventions

Participants will be individually randomised to 1 of 2 groups: group 1: 2000 international units (IU) of cholecalciferol orally daily commencing between 14 and 18 weeks' gestation. If still deficient at 28 weeks the dose will be doubled to 4000 IU orally daily until birth; group 2: No treatment during pregnancy. The mother will receive 300,000 IU cholecalciferol orally immediately and the baby 150,000 IU cholecalciferol orally immediately after birth.

Outcomes

Maternal: vitamin D level.

Infant: vitamin D level.

Starting date

1/04/2008.

Contact information

Name: Jodie Benson
Address: co/ Monash Medical Centre Clayton Rd, Clayton Victoria 3168, Australia
Tel: +61 3 95946666
Email: [email protected]

Notes

Sponsor: Royal Australian and New Zealand College of Obstetrics and Gynaecology, Australia.

ACTRN12609000142235.

Bhatia 2012b

Trial name or title

Vitamin D supplementation in pregnancy: regimens and long term effects on offspring.

Methods

Randomised, parallel group, placebo‐controlled trial.

Participants

Pregnant women attending antenatal clinic in Chhatrapati Shahuji Medical University (CSMMU), Uttar Pradesh, India, and in 14 to 20 weeks of pregnancy.

Exclusion criteria: chronic liver disease, renal disease or treatment with antitubercular or antiepileptic drugs or vitamin D in the previous 3 months.

Interventions

Participants will be individually randomised to 1 of 3 groups: group 1: cholecalciferol: 400 units per day orally from recruitment till the end of pregnancy; group 2: cholecalciferol: 60,000 units orally every 4 weeks; group 3: cholecalciferol: 60,000 units orally every 8 weeks from recruitment till the end of pregnancy.

Outcomes

Maternal: serum 25OHD.

Infant: birthweight, length, head circumference and anterior fontanelle diameter, cord serum 25OHD, neonatal serum calcium.

Starting date

04‐11‐2011.

Contact information

Vijayalakshmi Bhatia
Address: Department of endocrinology, SGPGIMS, Raebareli Road, Lucknow 226014 Lucknow, UTTAR PRADESH India
Tel: +91‐522‐2494380
Email: [email protected]
Affiliation: Sanjay Gandhi Postgraduate
Institute of Medical Sciences

Notes

Sponsor: Department of Biotechnology, Goverment of India.

CTRI/2012/02/002395.

Bhutta 2011

Trial name or title

Study of vitamin D supplementation on improvement of gums health (vitamin D).

Methods

Randomised, parallel assignment, double blind.

Participants

Pregnant females from 12‐20 weeks of gestation who agree to participate in the study with presence of at least 20 natural teeth in mouth excluding third molars. For controls: non pregnant, healthy females matched with pregnant women with respect to age and education. Exclusion criteria: pregnant females with high vitamin D levels, women with metabolic diseases such as diabetes (type 1 or 2), presence of acute dental or periodontal disease, presence of systemic disease and/or medication affecting the periodontium; receipt of systemic antibiotic treatment or dental prophylaxis in the previous 3 months and those who do not provide informed consent.

Interventions

Participants will be individually randomised to 1 of 2 groups: group 1: vitamin D3 4000 mg per day, 1 tablespoon syrup per day; group 2: placebo, 1 table spoon syrup per day.

Outcomes

Maternal: Periodontal Probing Depth, Interleukin 6 (IL‐6), IL‐2, IL‐4, IL‐10, TNF, IFN‐ɣ and IL‐17 levels.

Starting date

June 2010.

Contact information

Farhan Raza Khan, Consultant, Dentistry, Aga Khan University.

Notes

Sponsor: Aga Khan University, Pakistan.

(www.clinicaltrials.gov; NCT01422122

Bisgaard 2009

Trial name or title

Vitamin D supplementation during pregnancy for prevention of asthma in childhood: an interventional trial in the ABC (Asthma Begins in Childhood) cohort.

Methods

Randomised double‐blind, placebo‐controlled trial with 2 arms.

Participants

Danish‐fluent pregnant women 18 years of age or older, with 22‐26 week of gestation living in Sealand, Denmark participating in the ABC‐cohort. The mothers in ABC also participate in an interventional trial with fish oil supplementation, and the vitamin D randomisation is stratified by fish oil treatment group.

Women with intake of more than 400 IU of vitamin D during the previous 6 months, endocrinological disease such as calcium metabolic disorder, parathyroid disorder, thyroid disorder or diabetes type 1, tuberculosis, sarcoidosis or in need of diuretics or heart medication including calcium channel blockers are excluded.

Interventions

Participants will be individually randomised to 1 of 2 groups: group 1: receives a daily supplement with 2400 IU of vitamin D3 from week 24 of gestation to 1 week after delivery; group 2: receives placebo from week 24 of gestation to 1 week after delivery.

Outcomes

Maternal: 25‐OH‐vitamin D, PTH, calcium, alkaline phosphatase concentrations 1 week postpartum.

Infant: upper and lower respiratory infections, allergy, eczema from 0‐3 years of age.

Starting date

Date of start: 03/2009.

Status: recruiting participants.

Contact information

Hans Bisgaard, MD, DMSc

Copenhagen Studies on Asthma in Childhood

Copenhagen University Hospital of Copenhagen

Gentofte, Denmark, 2820

Tel: +45 39777360

E‐mail: [email protected]

Notes

Sponsor: Copenhagen Studies on Asthma in Childhood.

Ghasemi 2014

Trial name or title

Comparison of effectiveness of vitamin D supplementation in decreasing the development of the gestational diabetes mellitus in pregnant women.

Methods

Single‐arm study, not blinded.

Participants

75 pregnant women referring to obstetric clinic of Shahid Beheshti and Alzahra hospital in Esfahan city in 2012 (overall 225 persons). Inclusion criteria: patient satisfaction; normal BMI; gestational age below 16 weeks; no history of diabetes mellitus type 2 or GDM; no family history of diabetes mellitus type 1 in first degree relatives. Exclusion criteria: patient dissatisfaction; incorrect consumption of vitamin D supplementation; Follow‐up discontinuation.

Interventions

Participants will be individually randomised to 1 of 2 groups: group 1: vitamin D supplementation with dose of 50,000 unit every 2 weeks for 10 weeks; group 2: are not treated with vitamin D supplementation.

Persons with level of above 25 nmol/L, were selected as normal healthy control group.

Outcomes

Maternal: gestational blood sugar level, serum vitamin D level.

Starting date

2012‐03‐20.

Contact information

Name: Dr. Hatav Ghasemi Tehrani
Address: Isfahan‐ Alzahra Hospital‐Gynecology Department Isfahan
Tel: 00983116249032
Email: [email protected]
Affiliation: Isfahan University Of Medical
Iran, Islamic Republic Of Sciences

Notes

Sponsor: Isfahan University Of Medical Sciences.

Goldring 2010

Trial name or title

Effects of prenatal vitamin D supplementation on respiratory and allergic phenotypes and bone density in the first 3 years of life.

Methods

Randomised interventional prevention trial.

Participants

180 mothers attending antenatal clinic at St Marys Hospital, London, United Kingdom. This is a follow‐up trial of the infants of these trial participants. All of the offspring of the 180 mothers recruited in this trial are eligible and are invited to participate in this follow‐up study when their children are 3 years of age.

Interventions

Participants will be individually randomised to 1 of 2 groups: group 1 (n = 60): received no vitamin D; group 2 (n = 60): received 800 IU of vitamin D daily for the remainder of pregnancy; group 3 (n = 60) received a single oral dose of 200,000 IU vitamin D at 27 weeks' gestation.

Outcomes

Infant: wheezing episode in the first 3 years of life, measured at 36‐48 months, use of inhaled bronchodilators in the last 12 months, doctor‐diagnosed rhinitis, any wheezing episode in the preceding 12 months, doctor‐diagnosed asthma, doctor‐diagnosed eczema, doctor‐diagnosed food allergy, positive skin prick test responses, 25‐hydroxyvitamin D levels, bronchodilator responsiveness, exhaled nitric oxide level (in parts per billion), nasal secretions for inflammatory mediators, pulmonary airflow resistance and reactance at a range of frequencies using impulse oscillometry, total number of all wheezing episodes since birth and total number of upper and lower respiratory tract infections since birth, at 36‐48 months.

Starting date

Date of start: 01/03/2010.

Status: ongoing. Anticipated end date: 31/05/2011.

Contact information

Dr Stephen Goldring

Department of Paediatrics

Wright‐Fleming Institute, Norfolk Place, London W2 1PG , United Kingdom

E‐mail: [email protected]

Notes

Sponsor: Imperial College London (UK).

Habib 2010

Trial name or title

Evaluation of the effectiveness of vitamin D supplementation to pregnant women and their infants in Pakistan.

Methods

Randomised controlled trial.

Participants

550 apparently healthy pregnant women 15‐49 years of age from 20‐22 weeks of gestation and their infants in Pakistan.

Pregnant women with pre‐existing type 1 or type II diabetes, multiple fetuses, babies (twins, triplets), with high levels of vitamin D will be excluded. Infants with multiple congenital anomalies, serious birth injury, birth asphyxia, serious infections, very low birthweight, will be excluded.

Interventions

Participants will be individually randomised to 1 of 2 groups: group 1 will receive a daily dose of 4000 IU of vitamin D from 20‐22 weeks of pregnancy till the time of delivery; group 2 will receive placebo.

The infants will be stratified in 2 groups: group 1 will receive 400 IU of vitamin D for 6 months as intervention (if mothers are from group 1); group 2 will receive placebo (if mothers are from group 2).

Outcomes

Maternal: pre‐eclampsia, gestational hypertension, poor weight gain during pregnancy, stillbirth rates, prevalence and risk factors for maternal vitamin D deficiency.

Infant: low birthweight, prematurity, neonatal seizures, infants with growth failure, signs and symptoms of vitamin D deficiency, infections: pneumonia, diarrhoea and receptor polymorphism, prevalence and risk factors for neonatal vitamin D deficiency.

Starting date

Date of start: February 2010.

Status: recruiting participants. Estimated study completion date: June 2011.

Contact information

Muhammad Atif Habib, MBBS, MPH

Project Office Aga Khan University

Tel: +92 21 3 4864798

Email: [email protected]

Principal investigator: Zulfiqar A Bhutta, FRCPCH, PhD

Aga Khan University, Pakistan.

Notes

Sponsors: Aga Khan University and John Snow, Inc.

Hacker 2010

Trial name or title

Testing the calcium DRI during pregnancy: a study of bone health in black and white women.

Methods

Randomised controlled trial.

Participants

120 African American or Caucasian primigravidae women 19‐40 years of age in their first trimester of pregnancy in Children's Hospital & Research Center Oakland, California, USA.

Women who are smokers, have a pre‐pregnancy BMI higher than 30, have a medical condition that affects bone or taking a medication that affects bone will be excluded.

Interventions

Participants will be randomly assigned to 1 of 3 groups: group 1: will receive 1000 mg of calcium; group 2: will receive 2000 IU vitamin D; group 3: will receive a placebo.

The intervention will be provided from week 16 of pregnancy until delivery.

Outcomes

Primary:

Maternal: change in peripheral cortical and trabecular bone loss and gain during a reproductive cycle in black and white women.

Infant: none.

Secondary: change in bone markers of bone formation and resorption during pregnancy and postpartum, differences in calcium absorption in late pregnancy among black and white women, differences in adaptive immune function tests and markers of inflammation during pregnancy.

Infant: none.

Starting date

Date of start: 05/2010.

Status: currently recruiting participants.

Expected study completion date: May 2013.

Contact information

Andrea N Hacker, MS, RD

Children's Hospital & ResearchCenter Oakland, CA, USA

Tel: +1 510 428‐3885

Email: [email protected]

Principal Investigators: Ellen Fung, PhD, RD and Janet King, PhD, RD

Notes

Sponsors: Children's Hospital & Research Center Oakland and USDA, Western Human Nutrition Research Center, USA.

Harvey 2012

Trial name or title

MAVIDOS Maternal vitamin D osteoporosis study: study protocol for a randomised controlled trial. The MAVIDOS Study Group.

Methods

Randomised, double‐blind, placebo‐controlled trial.

Participants

Pregnant women over 18 years old, with a singleton pregnancy with less than 17 weeks' gestation at first assessment (based on last menstrual period (LMP) and dating scan), aiming to give birth at local maternity hospital, and with serum 25(OH)‐vitamin D concentration is 25‐100 nmol/L at nuchal fold/dating scan (10 to 17 weeks' gestation)

Interventions

Participants will be randomly assigned to 1 of 2 groups: group 1: will receive 1000 IU cholecalciferol orally daily; group 2: will receive placebo.

Starting from 14 weeks' gestation until delivery.

Outcomes

Infant: whole body bone mineral content of the neonate adjusted for gestational age and age at neonatal DXA scan, whole body bone area, bone mineral density, and size corrected bone mineral density (BMC adjusted for BA, length and weight), body composition adjusted for gestational age and age at DXA scan.

Starting date

2008 Apr 11.

Contact information

Nicholas C Harvey

MRC Lifecourse Epidemiology Unit, (University of Southampton), Southampton General Hospital, Southampton, United Kingdom.

Email: [email protected]

Notes

Sponsor: Southampton University Hospitals NHS Trust (UK).

ISRCTN82927713

Jannati 2012

Trial name or title

The effect of 50,000 IU vitamin D supplement administered 2 weekly on neonatal and pregnant women outcome ‐ GDM.

Methods

Randomised controlled trial.

Participants

Pregnant women, aged between 15 and 48, who came to prenatal clinic of Shahid Sadoughi and Mojibian Hospitals during first trimester with no history of corticosteroids or anticonvulsants use during the last 3 months were included. Exclusion criteria: history of thyroid or parathyroid diseases; receiving vitamin D more than maintenance dose during the last 6 months; treatment with corticosteroids or anticonvulsants and history of diabetes mellitus before pregnancy.

Interventions

Participants will be randomly assigned to 1 of 2 groups:group 1: vitamin D supplement, 50,000 IU tablet, every 2 weeks; group 2: vitamin D supplement, calcium‐D tablet, 200 IU daily.

Outcomes

Maternal: vitamin D values and GDM.

Starting date

July 2011.

Contact information

Dr Maryam Jannati Moghadam

Tel: +983516240061

Email: [email protected]

Address: Ayatollah Kashani ST 8915635843 Yazd, Islamic Republic of Iran.

Notes

Sponsor: Shahid Sadughi Yazd University of Medical Sciences.

Jelsma 2013

Trial name or title

DALI: vitamin D And lifestyle intervention for gestational diabetes mellitus (GDM) prevention.

Methods

Randomised controlled trial with a factorial design.

Participants

Pregnant women with gestational age at recruitment < 12 weeks, and more than 18 years of age.

Inclusion criteria: pre‐pregnancy BMI (self‐reported weight, measured height) is >= 29 kg/m2), sufficiently fluent in major language of the country of recruitment, being able to be moderately physically active, giving written informed consent, agree to give birth in 1 of the participating hospitals. Exclusion criteria: pre‐existing diabetes, diagnosed with (gestational) diabetes mellitus before randomisation, defined as fasting glucose ≥ 5.1 mmol/L and/or 1 hour glucose ≥ 10 mmol/L and/or 2 hour glucose ≥ 8.5 mmol/L at baseline, not able to walk at least 100 metres safely, requirement for complex diets, advanced chronic conditions (e.g. valvular heart disease), significant psychiatric disease, unable to speak major language of the country of recruitment fluently, known abnormal calcium metabolism (hypo/hyperparathyroidism, nephrolithiasis, hypercalciuria) or hypercalciuria detected at screening (0.6 mmol/mmol creatinine in spot morning urine) and twin pregnancy.

Interventions

The design is that of 2 trials with a factorial design: PA, diet, PA & diet, control, vitamin D, PA & diet and placebo, vitamin D & PA & diet, placebo; to compare the impact of increased PA, enhanced nutrition and vitamin D supplementation either alone or in combination on maternal glucose tolerance, maternal weight gain and insulin sensitivity.

The doses of vitamin D that will be tested in the dosing study are 500, 1000 and 1500 IU/day. 1 of these doses will be used in the trial.

Outcomes

Maternal: weight gain during pregnancy, fasting plasma glucose, HbA1c, fasting C peptide, leptin, triglycerides, free fatty acids, high density lipoprotein cholesterol (HDL‐C) and low density lipoprotein cholesterol (LDL‐C), adiponectin 2. 3 beta‐hydroxybutyrate, blood pressure, C‐reactive protein.

Infant: neonatal growth, adiposity, adipo‐insular axis, glucose‐insulin axis, electrolyte concentrations, clinical outcomes and hypoxia exposure at birth, biparietal diameter, head circumference, abdominal circumference, femur length] and determinants of foetal body composition variables (lean body mass and fat body mass, C‐peptide, glucose, leptin, triglycerides, 3‐ beta‐hydroxybutyric acid, pH and erythropoietin, jaundice, hypocalcaemia, hypomagnesaemia.

Starting date

21/11/2011.

Contact information

Dr David Simmons

Addenbrooke's Treatment Centre
Hills Road, Cambridge CB2 0QQ

United Kingdom

Notes

Sponsor: European Union (EU) (Belgium) ‐ Seventh Framework Programme (FP7).

Judkins 2011

Trial name or title

A randomised double‐blinded interventional trial to determine the effect of 50,000 IU vitamin D supplementation monthly or twice monthly from 20 weeks' gestation.

Methods

Randomised double‐masked clinical trial with randomisation at the individual level. Method of sequence generation: serial tossing of a coin. Allocation will be not concealed.

Participants

Pregnant women seeking maternity care with midwifery services involved in the study. Exclusion criteria: antenatal vitamin D level is > 75 nmol/L when enrolling in study.

Interventions

Participants will be assigned to 1 of 2 groups: group 1: will receive 50,000 IU tablets twice monthly, 2 weeks apart; group 2: will receive 50,000 IU monthly and a placebo monthly, 2 weeks apart from 20 weeks' gestation until delivery of baby.

The placebo tablet contains lactose monohydrate, acacia, calcium carbonate, castor oil, maize starch, povidone, sucrose, purified talc, hydrated silica, powdered cellulose, magnesium stearate, shellac, gelatin, beeswax white, titanium dioxide and prepared theobroma.

Outcomes

Infant: vitamin D levels taken from the cord blood samples at delivery. If emergencies at delivery prevent a cord blood sample being taken then a maternal venous blood sample will be taken for analysis.

Starting date

Status: not yet recruiting participants.

Contact information

Dr Annie Judkins

Newtown Union Health Service
14 Hall Ave, Newtown,. Wellington 6021, New Zealand

Email: [email protected]

Notes

Sponsors: Royal New Zealand College of GP's, New Zealand and Wellington Medical Research Foundation, New Zealand.

ACTR Number: ACTRN12610001044011.

Kachhawa 2014

Trial name or title

A randomised controlled trial to investigate the effects of vitamin D supplementation on maternal and new‐born babies vitamin D status in Asian‐Indian Subjects ‐ VIDIMAN.

Methods

Randomised, parallel group, placebo‐controlled trial.

Participants

Pregnant women between 12‐16 weeks of gestation, aged between 18 to 35 years. Participants agree for delivery conducted at the AIIMS. Exclusion criteria: participants will be excluded from the study if they have more than 1 gestation in current pregnancy, cardiovascular disease, more than 3 abortions, hypertension, pre‐eclampsia or Rh isoimmunisation, prior history of delivery of an infant with chromosomal abnormalities or IUGR in previous pregnancy presence of any diagnosed systemic disease known to affect vitamin D status such as malabsorption states, liver and renal disorders, primary and tertiary hyperparathyroidism, have features suggestive of osteomalacia or severe VDD, pre‐existing hypertension, diabetes (type 1 or 2), are taking or had taken vitamin D supplementation in last 2 months in doses exceeding 600 IU/day, are using medications known to interact with vitamin D metabolism (steroids,thiazide diuretics, phenytoin, phenobarbitone and antitubercular drugs), have known hypersensitivity to vitamin D preparations, have participated in any other investigational drug study in previous 3 months, have past history of bariatric surgery, are using Ultra‐Violet (UV) radiations as a part of medical therapy, are diagnosed with albinism or have other condition associated with decreased skin pigmentation, have any medical condition that in the judgment of the investigator would jeopardise the participants' safety or evaluation of study drug for efficacy or safety. Additional exclusion criteria will be applied after biochemical screening: Having gestational diabetes between 12‐16 weeks of pregnancy, have serum calcium more than 1 mg/dL above the upper limit of normal for age, have serum S.25(OH)D level more than 100 ng/mL.

Interventions

Participants will be randomly assigned to 1 of 4 groups:group 1: participants will receive 1000 IU of vitamin D per day. Although dose of supplementation has been calculated from daily dose basis, but it will be given, orally as once a month dose (30,000 IU once a month orally,supervised in the hospital), supervised in the hospital till delivery; group 2: participants will receive 2000 IU of vitamin D per day. Although dose of supplementation has been calculated from daily dose basis, but it will be given, orally as once a month dose (60,000 IU once a month orally, supervised in the hospital) till delivery; group 3: participants will receive 4000 IU of vitamin D per day. Although dose of supplementation has been calculated from daily dose basis, but it will be given, orally as once a month dose (120,000 IU once a month orally, supervised in the hospital) till delivery; group 4: control group ‐ participants will receive 600 IU of vitamin D per day. Although dose of supplementation has been calculated from daily dose basis, but it will be given, orally as once a month dose (18,000 IU once a month orally,supervised in the hospital) until delivery.

Outcomes

Maternal: serum 25 hydroxyvitamin D, weight gain, pre‐eclampsia, preterm labour, insulin resistance in mother.

Infant: fetal growth, newborn anthropometry and insulin resistance in newborn.

Starting date

01‐02‐2014.

Contact information

Garima Kachhawa
Address: Department of Obstetrics and Gynecology AIIMS , New Delhi‐29 Department of Obstetrics and Gynecology AIIMS , New Delhi‐29 110029
New Delhi, DELHI India
Tel: 09868398231
Email: [email protected]

All India Institute of Medical Sciences

Notes

Sponsor: Indian Council of Medical Research ICMR.

Lalooha 2012

Trial name or title

The effect of vitamin D supplementation during pregnancy on newborn's anthropometric index.

Methods

An interventional, randomised, not blinded, parallel trial.

Participants

Pregnant women with a singleton pregnancy and gestational age between 24‐28 week; BMI 19‐26; vitamin D < 30 ng/mL. Exclusion criteria: the known history of liver, renal, parathyroid, bone, metabolic diseases or epilepsy or malabsorption, medications that influence the metabolism of vitamin D and calcium, recurrent abortion, diabetes or gestational diabetes, HTN or pre‐eclampsia; fetus with anomalies, polyhydramnios, oligohydramnios or IUGR.

Interventions

Participants will be randomly assigned to 1 of 2 groups: group 1: vitamin D capsule 50,000 U weekly for 8 weeks from 28 gestational age and multivitamin tablet include 400 IU vitamin D daily till termination; group 2: multivitamin tab include 400 IU vitamin D daily till termination.

Outcomes

Infant: height, weight, and head circumference.

Starting date

1991‐11‐22.

Contact information

Dr Fatemeh Lalooha
Valiasr street Qazvin Iran,
Tel: +982812236374
Email: [email protected]
Department of Gynecology, Kosar Hospital, Islamic Republic of Iran

Notes

Sponsor: Qhazvin University of Medical Sciences, Iran.

Irct registration number : IRCT201205119491N2.

Lindqvist 2010

Trial name or title

Vitamin D supplementation for prevention of placenta mediated pregnancy complications.

Methods

Randomised, controlled trial.

Participants

Pregnant women > 18 years of age, from 3 maternal health care units who agree to participate in the study.

Exclusion criteria: < 18 years of age, hyperparathyroidism and sarcoidosis.

Interventions

Participants will be randomly assigned to 1 of 2 groups: group 1: will receive vitamin D, oral drops; group 2: will receive placebo.

Outcomes

Maternal: pre‐eclampsia, blood loss at delivery.

Infant: blood flow in umbilical artery, growth restriction, and prematurity.

Starting date

06/04/2011.

Contact information

N/A

Notes

Sponsor: Karolinska University Hospital.

EudraCT Number: 2010‐019483‐37.

McLean 2012

Trial name or title

Effect of high‐dose versus low‐dose vitamin D supplementation in pregnancy on maternal glucose metabolism and the risk of gestational diabetes.

Methods

Randomised controlled parallel trial.

Participants

Pregnant women, aged 18 or more, with less than 20 weeks' gestation at recruitment. Exclusion criteria: known diabetes, calcium metabolic disorder, multiple pregnancy

Interventions

Participants will be randomly assigned to 1 of 2 groups: group 1: will receive high‐dose vitamin D supplementation (5000 IU/day); group 2: standard dose pregnancy vitamin supplementation (400 IU vitamin D daily), administered as an oral capsule, from the time of the first antenatal clinic visit (around 12 weeks' gestation) until delivery.

Outcomes

Maternal: diagnosis of gestational diabetes, determined by an oral glucose tolerance test (blood analysis after ingestion of 75 g oral glucose) performed at 26‐28 weeks' gestation, or other evidence of hyperglycaemia recorded throughout pregnancy. Maternal glucose metabolism in late second trimester (26‐28 weeks' gestation) assessed by glucose tolerance test (blood analysis after ingestion of 75 g oral glucose).

Infant: weight at birth, infant length (assessed with a newborn stadiometer) and head circumference.

Starting date

10/02/2010

Contact information

Mark McLean
Address: Professor Mark McLean

University of Western Sydney‐ Blacktown Clinical School
Blacktown Hospital PO Box 6105 BLACKTOWN NSW 2148, Australia
Tel: +61 2 9851 6073
Email: [email protected]

Notes

Sponsor: Hospital Westmead, Australia and University of Western Sydney, Australia.

ACTRN 12612001145897.

Mirghafourvand 2013

Trial name or title

The effect of vitamin D and calcium plus vitamin D for leg cramps in pregnant women: a randomised controlled trial.

Methods

Randomised controlled trial.

Participants

Pregnant women with gestational age of 25‐30 weeks aged 18 to 35 years old; having leg cramps at least twice a week; being literate. Exclusion criteria: having known thyroid, cardio‐vascular, diabetes or renal diseases; intake of calcium and vitamin D supplementation during pregnancy; having allergy history to studied drugs.

Interventions

Eligible women will be selected with convenience sampling and will be randomly assigned into 3 groups of 42 participants with block sizes of 3 and 6: group 1: will receive Vitamin D tablets (1000 units); group 2: will receive calcium‐vitamin D tablets (300 mg calcium carbonate plus 1000 units vitamin D); group 3: the control group will receive placebo.

Outcomes

Maternal: the number, severity and duration of leg cramps.

Starting date

2013‐04‐30.

Contact information

Dr. Mozhgan Mirghafourvand
Address: Nursing & Midwifery Faculty,South Shariati Street 347‐51745 Tabriz Iran, Islamic Republic Of Iran.
Tel: +984114796770
Email: [email protected]; [email protected]
Affiliation: Tabriz University of Medical of Sciences

Notes

Sponsor: Tabriz University of Medical Sciences (Project number: 388).

IRCT 2013040810324N12.

Mozzafari 2010

Trial name or title

Effect of vitamin D supplementation on glucose status, lipid profiles and inflammatory factors in mothers with a history of gestational diabetes.

Methods

Randomised parallel trial.

Participants

Women between 20‐45 years of age with gestational diabetes at their recent pregnancy from the list of GDM Diabetes Research Center of Yazd University, and without thyroid disease, kidney disease, bone disease, PCO, liver disease and not using anti‐epilepsy drugs, glucocorticoids, and statins. Exclusion criteria: risk of any illness that requires medication and lack of any willingness to cooperate.

Interventions

Participants will be randomly assigned to 1 of 2 groups:group 1: intramuscular injection of vitamin D with 300,000 IU dose; group 2: control: not receive any intervention.

Outcomes

Maternal: glucose status, lipid profiles and inflammatory factors.

Starting date

2010‐01‐25.

Contact information

Dr Hassan Mozaffari
Address: 3rd floor, Centeral Building of Shahid Sadughi University of Medical Sciences and Health Services, Shahid Bahonar sq.YAZD Iran, Islamic Republic of Iran.
Tel: +983517249333
Email: [email protected]
Affiliation: Shahid Sadughi University of Medical Sciences and Health Services

Notes

Sponsor: Shahid Sadughi University of Medical Sciences and Health Services.

IRCT138902113840N1.

Nausheen 2014

Trial name or title

Assessment of dose effectiveness of vitamin D supplementation during pregnancy: a dose‐comparison trial.

Methods

Blind, randomised controlled trial with 3 arms.

Participants

315 pregnant women aged 15‐45 years with less than 16 weeks of gestation in a hospital in Pakistan.

Pregnant women with pre‐existing type 1 or type II diabetes, pre‐existing hypertension, multiple fetuses, babies (twins, triplets) or with a diagnosis of pregnancy with a fetal anomaly in scan will be excluded.

Interventions

Participants will be randomly assigned to 1 of 3 groups: groups 1 will receive a dose of 400 IU/day till the time of delivery; group 2 will receive 2000 IU/ day till the time of delivery; group 3 will receive 4000 IU/ day till the time of delivery.

Outcomes

Vitamin D deficiency, pre‐eclampsia, preterm labour, preterm birth, low birthweight, stillbirths.

Starting date

June 2013.

Contact information

Dr Sidrah Nausheen,

Division of Women & Child Health, Aga Khan University, Karachi, Pakistan.

Notes

Sponsor: Aga Khan University, Pakistan.

Rasmussen 2009

Trial name or title

Effects of vitamin D supplement before and during and after pregnancy on complications, birthweight and bone mineral density during lactation.

Methods

Double‐blind, randomised, placebo‐controlled trial.

Participants

400 apparently healthy women 30‐35 years of age, all with concentrations of P‐25‐hydroxyvitamin D (25OHD)‐ lower than 50 nmol/L. All women included attempts to get pregnant. Visits take place at Clinic of Osteoporosis, Department of Endocrinology, at Aarhus University Hospital, Aarhus, Denmark.

Women with infertility, an intake of 400 IU or more vitamin D/day, cancer, history of alcohol or drug abuse, calcium metabolic disturbances or spontaneous abortion within last 6 months will be excluded.

Interventions

Participants will be randomly assigned to 1 of 3 groups: group 1: will receive 35 µg per day cholecalciferol; group 2: will receive 70 µg per day cholecalciferol; group 3: will receive placebo. All women will receive 2 tablets daily from baseline until 16 weeks after delivery.

Intervention with cholecalciferol or placebo starts before pregnancy is achieved and continues until 4 months after the women has given birth.  

Outcomes

Primary:

Infant: birthweight.

Maternal: none.

Secondary:

Infant: weight, crown‐heel length and head circumference, and infections within 16 weeks after birth. Concentration of 25OHD in umbilical cord and venous sample 16 weeks after birth.

Maternal: postpartum effects of vitamin D supplement on maternal bone mineral density, concentration of 25OHD in mothers milk, incidence of pre‐eclampsia and abortions.

Starting date

Date of start: 12/2009.

Status: recruiting participants.

Estimated study completion date: December 2011.

Contact information

Gitte Bloch Rasmussen, MD

Department of Endocrinology, Aarhus University Hospital

University of Aarhus

Tel: +45 89 4976 81

Email: [email protected]

Notes

Sponsor: University of Aarhus, Denmark.

Roth 2013b

Trial name or title

Randomised placebo‐controlled trial of maternal vitamin D supplementation during pregnancy and lactation to improve infant linear growth in Dhaka, Bangladesh (MDIG).

Methods

Randomised placebo‐controlled trial.

Participants

Women aged 18 years and above with a gestational age of 17 to 24 completed weeks estimated based on recalled last menstrual period and/or ultrasound, who Intend to permanently reside in the trial catchment area for at least 18 months. Exclusion criteria: history of medical conditions that may predispose the participant to vitamin D sensitivity, altered vitamin D metabolism and/or hypercalcaemia, or history of renal calculi, high‐risk pregnancy based on 1 or more of the following findings by point‐of‐care testing: Severe anaemia: haemoglobin < 70 g/L assessed by Hemocue, Moderate‐severe proteinuria: ≥ 300 mg/dL (3+ or 4+) based on urine dipstick, Hypertension: systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg, multiple gestation, major congenital anomaly, or severe oligohydramnios based on maternal history and/or ultrasound, unwillingness to stop taking non‐study vitamin D or calcium supplements or a multivitamin with calcium and/or vitamin D, currently prescribed vitamin D supplements as part of a physician's treatment plan for vitamin D deficiency and previous participation in the same study.

Interventions

Participants will be randomly assigned to one of 5 groups: group 1: prenatal period 0 IU; postpartum period 0 IU (placebo); group 2: prenatal period 4200 IU/week of vitamin D3 (= 600 IU/d); postpartum period 0 IU/week (placebo); group 3: prenatal period 16,800 IU/week of vitamin D3 (= 2400 IU/d); postpartum period 0 IU/week (placebo).

Group 4: prenatal period 28,000 IU/week of vitamin D3 (= 4000 IU/d); postpartum period 0 IU/week (placebo); group 5: prenatal period 28,000 IU/week of vitamin D3 (= 4000 IU/d); postpartum period 28,000 IU/week (= 4000 IU/d).

Overall: the prenatal period will start at enrolment (17‐24 weeks' gestation) and last until delivery. The postpartum period will last from delivery until 6 months postpartum.

Outcomes

Infant: infant length‐for‐age Z‐Scores with prenatal supplementation, infant length‐for‐age Z‐Scores with postpartum supplementation, serum calcium, stunting (LAZ < ‐2 SD below the median) at 1 and 2 years of age, attained length and LAZ at 2 years of age, birthweight, low birthweight %, small‐for‐gestational age %, preterm birth %, stillbirth %, acute respiratory infections and diarrhoea, biomarker concentrations, perinatal, neonatal and infant severe morbidity and mortality, epigenetic patterns of genes involved in vitamin D metabolism.

Maternal: severe morbidity and mortality.

Starting date

March 2014.

Contact information

Daniel Roth, MD

Tel: +1 416 8135795

Email: [email protected]

Notes

Sponsors: The Hospital for Sick Children, Canada; International Centre for Diarrhoeal Disease Research, Bangladesh; Shimantik; Bill & Melinda Gates Foundation, USA.

ClinicalTrials.gov Identifier: NCT01924013.

Simsek 2011

Trial name or title

Vitamin D supplementation in gestational diabetes mellitus.

Methods

Randomised clinical trial.

Participants

Women with gestational diabetes, defined by the WHO criteria: fasting glucose ≥ 7.0 mmol/L or; oral glucose tolerance test: 75 g glucose, 2‐hour glucose ≥ 7.8 mmol/L recognised during pregnancy with a written informed consent, aged between 18‐42. Exclusion criteria: impaired renal function: creatinine * 150 *mol/L or a creatinine clearance < 50 ml/min, to the discretion of the investigator, cardiac problems: decompensated heart failure (NYHA III and IV); diagnosis of unstable angina pectoris; myocardial infarction within the last 12 months. Mental retardation, or psychiatric treatment for schizophrenia, organic mental disorder or bipolar disorder currently or in the past; Iinsufficient knowledge of the Dutch language; vitamin D plasma level ≥ 100 nmol/L or < 15 nmol/L; hypercalcaemia of any reason; granulomatous diseases influencing vitamin D levels; urolithiasis; pre‐existent diabetes mellitus of any type; substance abuse, other than nicotine; participation in any other trials, involving investigational products within 30 days prior to trial entry; any condition that the Investigator and/or co‐ordinating Investigator feels would interfere with trial participation or evaluation of results.

Interventions

Participants will be randomly assigned to 1 of 2 groups: group 1: cholecalciferol 15,000 IU once a week during pregnancy; group 2: placebo 15,000 IU once a week during pregnancy.

Outcomes

Primary:

Maternal: insulin sensitivity (HOMA‐index and β‐cell function) measured through fasting insulin and blood glucose levels.

Secondary:

Maternal: serum 25OHD, HbA1c values, blood pressure, thyroid function, lipid profile and BMI, pregnancy characteristics, maternal outcomes, and adverse effects.

Infant: neonatal outcome.

Starting date

1 Jul 2012.

Contact information

Drs. Y.H.M. Poel

Medisch Centrum Alkmaar

Wilhelminalaan 12

Tel: +31 (0)72 5484444

Email: [email protected]

Notes

Sponsor: Medisch Centrum Alkmaar.

NTR Number: NTR3158.

Wagner 2013

Trial name or title

Preventing health disparities during pregnancy through vitamin D supplementation.

Methods

Randomised control trial with 2 arms.

Participants

450 pregnant women (18‐45 years of age) who presents to her obstetrician or midwife at the Medical University of SC (MUSC), Charleston, United States of America obstetrical facilities within the first 14 weeks after her last menstrual period with confirmation of a singleton pregnancy will be eligible for enrolment in the study. Women with diverse ethnic backgrounds (African‐American, Asian, Caucasian and Hispanic) will be actively recruited.

Women with pre‐existing calcium, uncontrolled thyroid disease, parathyroid conditions, or who require chronic diuretic or cardiac medication therapy including calcium channel blockers will not be eligible for enrolment into the study. Mothers with pre‐existing sickle cell disease (not trait only), sarcoidosis, Crohn's disease, or ulcerative colitis may not participate in the study. In addition, because of the potentially confounding effect of multiple fetuses, mothers with multiple gestations will not be eligible for participation in the study.

A subgroup of approximately 100 participants with known diabetes, hypertension, HIV, or morbid obesity (BMI > 49) will participate in the study.

Interventions

Participants will be randomly assigned to 1 of 2 groups: group 1 will receive vitamin D3 4000 IU in gummy form (participants will be asked to consume 4 gummies/day beginning at 10‐14 weeks of your pregnancy) plus the daily multiple micronutrient supplement; group 2 will receive placebo gummy plus the standard multiple micronutrient supplement (containing also 400 IU vitamin D3.

Outcomes

Maternal and neonatal health status as a function of maternal and infant vitamin D status.

Starting date

January 2013.

Contact information

Dr Carol Wagner

Medical University of South Carolina

Charleston, South Carolina, United States, 29425

Tel: +1 843‐792‐2401

Email: [email protected]

Notes

Sponsor: Medical University of South Carolina, USA and W.K. Kellogg Foundation, USA.

BMI: body mass index
DRI: dietary references intakes
GDM: gestational diabetes mellitus
HTN: hypertension
IU: international units
IUGR intrauterine growth restriction
LMP: last menstrual period
PA: physical activity
PCO: polycystic ovary
PTH: parathyroid hormone
Rh: Rhesus
SD: standard deviation
VDD: Vitamin D deficiency
25OHD: 25‐hydroxycholecalciferol

Data and analyses

Open in table viewer
Comparison 1. Vitamin D alone versus no treatment/placebo (no vitamins or minerals)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Pre‐eclampsia (ALL) Show forest plot

2

219

Risk Ratio (M‐H, Random, 95% CI)

0.52 [0.25, 1.05]

Analysis 1.1

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 1 Pre‐eclampsia (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 1 Pre‐eclampsia (ALL).

2 Gestational diabetes (ALL) Show forest plot

2

219

Risk Ratio (M‐H, Random, 95% CI)

0.43 [0.05, 3.45]

Analysis 1.2

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 2 Gestational diabetes (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 2 Gestational diabetes (ALL).

3 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (ALL) Show forest plot

7

868

Mean Difference (IV, Random, 95% CI)

54.73 [36.60, 72.86]

Analysis 1.3

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 3 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 3 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (ALL).

4 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by start of supplementation) Show forest plot

7

868

Mean Difference (IV, Random, 95% CI)

47.24 [35.17, 59.31]

Analysis 1.4

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 4 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by start of supplementation).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 4 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by start of supplementation).

4.1 Less than 20 weeks of pregnancy

1

32

Mean Difference (IV, Random, 95% CI)

32.45 [19.48, 45.42]

4.2 20 weeks of pregnancy or more

6

836

Mean Difference (IV, Random, 95% CI)

49.70 [36.62, 62.78]

4.3 Unknown/unreported/mixed

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

5 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by pre‐gestational body mass index (kg/m2)) Show forest plot

7

868

Mean Difference (IV, Random, 95% CI)

47.24 [35.17, 59.31]

Analysis 1.5

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 5 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by pre‐gestational body mass index (kg/m2)).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 5 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by pre‐gestational body mass index (kg/m2)).

5.1 Underweight (lower than 18.5)

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

5.2 Normal weight (18.5 to 24.9)

1

165

Mean Difference (IV, Random, 95% CI)

34.09 [12.51, 55.67]

5.3 Overweight (25 or higher)

2

308

Mean Difference (IV, Random, 95% CI)

19.54 [18.34, 20.74]

5.4 Unknown/unreported/mixed

4

395

Mean Difference (IV, Random, 95% CI)

73.18 [21.00, 125.36]

6 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by supplementation scheme/regimen) Show forest plot

8

1043

Mean Difference (IV, Random, 95% CI)

44.12 [30.24, 58.00]

Analysis 1.6

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 6 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by supplementation scheme/regimen).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 6 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by supplementation scheme/regimen).

6.1 Single dose

3

340

Mean Difference (IV, Random, 95% CI)

15.16 [5.68, 24.63]

6.2 Daily

6

703

Mean Difference (IV, Random, 95% CI)

57.80 [38.37, 77.23]

6.3 Weekly

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

7 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by skin pigmentation based on Fitzpatrick skin tone chart) Show forest plot

7

868

Mean Difference (IV, Random, 95% CI)

47.24 [35.17, 59.31]

Analysis 1.7

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 7 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by skin pigmentation based on Fitzpatrick skin tone chart).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 7 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by skin pigmentation based on Fitzpatrick skin tone chart).

7.1 Three or less

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

7.2 Four or more

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

7.3 Unknown/unreported/mixed

7

868

Mean Difference (IV, Random, 95% CI)

47.24 [35.17, 59.31]

8 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by latitude) Show forest plot

7

868

Mean Difference (IV, Random, 95% CI)

47.24 [35.17, 59.31]

Analysis 1.8

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 8 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by latitude).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 8 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by latitude).

8.1 Between Tropics of Cancer and Capricorn

1

260

Mean Difference (IV, Random, 95% CI)

19.13 [17.79, 20.47]

8.2 North of the Tropic of Cancer or South of the Tropic of Capricorn

6

608

Mean Difference (IV, Random, 95% CI)

55.73 [35.67, 75.80]

8.3 Unknown/unreported

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

9 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by season at the start of pregnancy) Show forest plot

7

868

Mean Difference (IV, Random, 95% CI)

47.24 [35.17, 59.31]

Analysis 1.9

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 9 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by season at the start of pregnancy).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 9 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by season at the start of pregnancy).

9.1 Summer

1

160

Mean Difference (IV, Random, 95% CI)

96.0 [88.19, 103.81]

9.2 Winter

1

77

Mean Difference (IV, Random, 95% CI)

16.30 [13.61, 18.99]

9.3 Mixed seasons

5

631

Mean Difference (IV, Random, 95% CI)

37.24 [27.46, 47.02]

10 Preterm birth (less than 37 weeks' gestation) (ALL) Show forest plot

3

477

Risk Ratio (M‐H, Random, 95% CI)

0.36 [0.14, 0.93]

Analysis 1.10

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 10 Preterm birth (less than 37 weeks' gestation) (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 10 Preterm birth (less than 37 weeks' gestation) (ALL).

11 Low birthweight (less than 2500 g) (ALL) Show forest plot

3

493

Risk Ratio (M‐H, Random, 95% CI)

0.40 [0.24, 0.67]

Analysis 1.11

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 11 Low birthweight (less than 2500 g) (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 11 Low birthweight (less than 2500 g) (ALL).

12 Impaired glucose tolerance

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

13 Caesarean section Show forest plot

2

312

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.69, 1.31]

Analysis 1.13

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 13 Caesarean section.

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 13 Caesarean section.

14 Gestational hypertension

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

15 Adverse effects (nephritic syndrome) (ALL) Show forest plot

1

135

Risk Ratio (M‐H, Random, 95% CI)

0.17 [0.01, 4.06]

Analysis 1.15

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 15 Adverse effects (nephritic syndrome) (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 15 Adverse effects (nephritic syndrome) (ALL).

16 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL) Show forest plot

1

180

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Analysis 1.16

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 16 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 16 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL).

17 Birth length (cm) (ALL) Show forest plot

4

638

Mean Difference (IV, Random, 95% CI)

0.70 [‐0.02, 1.43]

Analysis 1.17

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 17 Birth length (cm) (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 17 Birth length (cm) (ALL).

18 Head circumference at birth (cm) (ALL) Show forest plot

4

638

Mean Difference (IV, Random, 95% CI)

0.43 [0.03, 0.83]

Analysis 1.18

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 18 Head circumference at birth (cm) (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 18 Head circumference at birth (cm) (ALL).

19 Birthweight (g) (ALL) Show forest plot

5

715

Mean Difference (IV, Random, 95% CI)

66.60 [‐137.22, 270.41]

Analysis 1.19

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 19 Birthweight (g) (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 19 Birthweight (g) (ALL).

20 Admission to special care (including intensive care) during the neonatal period (within 28 days after delivery) (ALL)

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

21 Stillbirth (ALL) Show forest plot

3

540

Risk Ratio (M‐H, Random, 95% CI)

0.35 [0.06, 1.99]

Analysis 1.21

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 21 Stillbirth (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 21 Stillbirth (ALL).

22 Neonatal death (ALL) Show forest plot

2

282

Risk Ratio (M‐H, Random, 95% CI)

0.27 [0.04, 1.67]

Analysis 1.22

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 22 Neonatal death (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 22 Neonatal death (ALL).

23 Apgar score less than seven at five minutes Show forest plot

1

165

Risk Ratio (M‐H, Random, 95% CI)

0.53 [0.11, 2.53]

Analysis 1.23

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 23 Apgar score less than seven at five minutes.

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 23 Apgar score less than seven at five minutes.

24 Neonatal infection

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

25 Very preterm birth

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Open in table viewer
Comparison 2. Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Pre‐eclampsia (ALL) Show forest plot

3

1114

Risk Ratio (M‐H, Random, 95% CI)

0.51 [0.32, 0.80]

Analysis 2.1

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 1 Pre‐eclampsia (ALL).

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 1 Pre‐eclampsia (ALL).

2 Gestational diabetes (ALL) Show forest plot

1

54

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.01, 7.84]

Analysis 2.2

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 2 Gestational diabetes (ALL).

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 2 Gestational diabetes (ALL).

3 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (ALL)

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

4 Preterm birth (less than 37 weeks' gestation) (ALL) Show forest plot

3

798

Risk Ratio (M‐H, Random, 95% CI)

1.57 [1.02, 2.43]

Analysis 2.4

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 4 Preterm birth (less than 37 weeks' gestation) (ALL).

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 4 Preterm birth (less than 37 weeks' gestation) (ALL).

5 Low birthweight (less than 2500 g) (ALL)

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

6 Impaired glucose tolerance

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

7 Caesarean section

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

8 Gestational hypertension Show forest plot

1

59

Risk Ratio (M‐H, Random, 95% CI)

0.26 [0.06, 1.12]

Analysis 2.8

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 8 Gestational hypertension.

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 8 Gestational hypertension.

9 Adverse effects (ALL)

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

10 Maternal death (death while pregnant or within 42 days of termination of pregnancy)

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

11 Birth length (cm) (ALL)

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

12 Head circumference at birth (cm) (ALL)

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

13 Birthweight (g) (ALL)

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

14 Admission to special care (including intensive care) during the neonatal period (within 28 days after delivery) (ALL)

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

15 Stillbirth (ALL)

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

16 Neonatal death (ALL) Show forest plot

1

660

Risk Ratio (M‐H, Random, 95% CI)

0.2 [0.01, 4.15]

Analysis 2.16

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 16 Neonatal death (ALL).

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 16 Neonatal death (ALL).

17 Apgar score less than seven at five minutes

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

18 Neonatal infection

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

19 Very preterm birth

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Study flow diagram for this update
Figuras y tablas -
Figure 1

Study flow diagram for this update

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 2

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 3

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 1 Pre‐eclampsia (ALL).
Figuras y tablas -
Analysis 1.1

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 1 Pre‐eclampsia (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 2 Gestational diabetes (ALL).
Figuras y tablas -
Analysis 1.2

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 2 Gestational diabetes (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 3 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (ALL).
Figuras y tablas -
Analysis 1.3

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 3 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 4 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by start of supplementation).
Figuras y tablas -
Analysis 1.4

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 4 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by start of supplementation).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 5 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by pre‐gestational body mass index (kg/m2)).
Figuras y tablas -
Analysis 1.5

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 5 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by pre‐gestational body mass index (kg/m2)).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 6 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by supplementation scheme/regimen).
Figuras y tablas -
Analysis 1.6

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 6 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by supplementation scheme/regimen).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 7 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by skin pigmentation based on Fitzpatrick skin tone chart).
Figuras y tablas -
Analysis 1.7

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 7 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by skin pigmentation based on Fitzpatrick skin tone chart).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 8 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by latitude).
Figuras y tablas -
Analysis 1.8

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 8 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by latitude).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 9 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by season at the start of pregnancy).
Figuras y tablas -
Analysis 1.9

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 9 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by season at the start of pregnancy).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 10 Preterm birth (less than 37 weeks' gestation) (ALL).
Figuras y tablas -
Analysis 1.10

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 10 Preterm birth (less than 37 weeks' gestation) (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 11 Low birthweight (less than 2500 g) (ALL).
Figuras y tablas -
Analysis 1.11

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 11 Low birthweight (less than 2500 g) (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 13 Caesarean section.
Figuras y tablas -
Analysis 1.13

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 13 Caesarean section.

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 15 Adverse effects (nephritic syndrome) (ALL).
Figuras y tablas -
Analysis 1.15

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 15 Adverse effects (nephritic syndrome) (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 16 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL).
Figuras y tablas -
Analysis 1.16

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 16 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 17 Birth length (cm) (ALL).
Figuras y tablas -
Analysis 1.17

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 17 Birth length (cm) (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 18 Head circumference at birth (cm) (ALL).
Figuras y tablas -
Analysis 1.18

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 18 Head circumference at birth (cm) (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 19 Birthweight (g) (ALL).
Figuras y tablas -
Analysis 1.19

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 19 Birthweight (g) (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 21 Stillbirth (ALL).
Figuras y tablas -
Analysis 1.21

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 21 Stillbirth (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 22 Neonatal death (ALL).
Figuras y tablas -
Analysis 1.22

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 22 Neonatal death (ALL).

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 23 Apgar score less than seven at five minutes.
Figuras y tablas -
Analysis 1.23

Comparison 1 Vitamin D alone versus no treatment/placebo (no vitamins or minerals), Outcome 23 Apgar score less than seven at five minutes.

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 1 Pre‐eclampsia (ALL).
Figuras y tablas -
Analysis 2.1

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 1 Pre‐eclampsia (ALL).

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 2 Gestational diabetes (ALL).
Figuras y tablas -
Analysis 2.2

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 2 Gestational diabetes (ALL).

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 4 Preterm birth (less than 37 weeks' gestation) (ALL).
Figuras y tablas -
Analysis 2.4

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 4 Preterm birth (less than 37 weeks' gestation) (ALL).

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 8 Gestational hypertension.
Figuras y tablas -
Analysis 2.8

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 8 Gestational hypertension.

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 16 Neonatal death (ALL).
Figuras y tablas -
Analysis 2.16

Comparison 2 Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals), Outcome 16 Neonatal death (ALL).

Summary of findings for the main comparison. Vitamin D alone versus no treatment/placebo (no vitamins or minerals)

Population: women during pregnancy
Setting: India, Iran, New Zealand, UK
Intervention: vitamin D alone
Comparison: no treatment/placebo (no vitamins or minerals)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with no treatment/placebo (no vitamins or minerals)

Risk with vitamin D alone

Pre‐eclampsia (ALL)

Study population

RR 0.52
(0.25 to 1.05)

219
(2 RCTs)

⊕⊕⊝⊝
LOW 1, 2

155 per 1000

80 per 1000
(39 to 163)

Moderate

124 per 1000

64 per 1000
(31 to 130)

Gestational diabetes (ALL)

Study population

RR 0.43
(0.05 to 3.45)

219
(2 RCTs)

⊕⊝⊝⊝
VERY LOW 1, 3

24 per 1000

10 per 1000
(1 to 82)

Moderate

27 per 1000

12 per 1000
(1 to 94)

Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (ALL)

The mean maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (ALL) in the intervention group was 47.24 higher (35.17 to 59.31 higher)

868
(7 RCTs)

⊕⊕⊝⊝
LOW 1, 4

Adverse effects

Study population

RR 0.17

(0.01 to 4.06)

135

(1 RCT)

⊕⊕⊝⊝
LOW 3

22 per 1000

4 per 1000

(0 to 90)

Preterm birth (less than 37 weeks' gestation) (ALL)

Study population

RR 0.36
(0.14 to 0.93)

477
(3 RCTs)

⊕⊕⊕⊝
MODERATE 1

99 per 1000

36 per 1000
(14 to 92)

Moderate

46 per 1000

17 per 1000
(6 to 43)

Low birthweight (less than 2500 g) (ALL)

Study population

RR 0.40
(0.24 to 0.67)

493
(3 RCTs)

⊕⊕⊕⊝
MODERATE 1

199 per 1000

80 per 1000
(48 to 133)

Moderate

193 per 1000

77 per 1000
(46 to 129)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Most studies contributing data had design limitations (high risk for allocation concealment and attrition bias).

2 Wide confidence interval crossing the line of no effect.

3 Wide confidence interval crossing the line of no effect & few events.

4 Statistical heterogeneity (I² > 60%). Considerable variation in size of effect.

Figuras y tablas -
Summary of findings for the main comparison. Vitamin D alone versus no treatment/placebo (no vitamins or minerals)
Summary of findings 2. Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals)

Population: women during pregnancy
Setting: Brazil, India, Iran
Intervention: Vitamin D + calcium + other vitamins and minerals
Comparison: other vitamins and minerals (but no vitamin D+ calcium)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with no treatment/placebo (no vitamin or minerals)

Risk with vitamin D + calcium

Pre‐eclampsia (ALL)

Study population

RR 0.51
(0.32 to 0.80)

1114
(3 RCTs)

⊕⊕⊕⊝
MODERATE 1

93 per 1000

48 per 1000
(30 to 75)

Moderate

90 per 1000

46 per 1000
(29 to 72)

Gestational diabetes (ALL)

Study population

RR 0.33
(0.01 to 7.84)

54
(1 RCT)

⊕⊕⊝⊝
LOW 2

37 per 1000

12 per 1000
(0 to 290)

Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (ALL)

(0 studies)

No trial assessed this outcome.

Adverse effects

(0 studies)

No trial assessed this outcome.

Preterm birth (less than 37 weeks' gestation) (ALL)

Study population

RR 1.57
(1.02 to 2.43)

798
(3 RCTs)

⊕⊕⊕⊝
MODERATE 1

**Because there were zero events in some of the groups in two out of three of the included trials, GRADEpro GDT did not produce corresponding risks for a moderate risk population.

73 per 1000

114 per 1000
(74 to 177)

Moderate

**

**

Low birthweight (less than 2500 g) (ALL)

Study population

Not estimable

(0 studies)

No trial assessed this outcome.

Not pooled

Not pooled

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Most studies contributing data had design limitations (selection bias was unclear and high risk of attrition bias)

2 Wide confidence interval crossing the line of no effect, few events & small sample size.

Figuras y tablas -
Summary of findings 2. Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals)
Table 1. Review of excluded trials testing different vitamin D doses without a placebo group

Author

Location and setting

Participants (age, number, gestational week)

Randomisation process

Vitamin D supplement dose(s)

Type of vitamin D supplement

Results

Bhatia 2012a

India (antenatal clinics)

299 pregnant women; 12‐24 weeks of gestation (lower middle and middle socio‐economic)

Random number tables

60,000 IU; 120,000 IU;

Usual care

Cholecalciferol

25OHD at term was higher in those on the higher dose compared to the lower dose. Birthweight, length and HC were greater in the supplemented groups versus usual care.

Dawodu 2013

United Arab Emirates (primary and tertiary perinatal care centres)

192 pregnant women; 12‐16 weeks of gestation

Stratified block design (seasonally balanced) using computer‐generated lists

400 IU/d; 2,000 IU/d;

4000 IU/d

Cholecalciferol

25OHD at term was higher with 4000 IU/d versus 2000 IUd versus 400 IU/d (P < 0.001).

Hashemipour 2013

Iran (obstetric clinic)

160 pregnant women; 24–26 weeks of gestation; singleton pregnancy and BMI:19–26 kg/m2

Computer‐generated random numbers (open‐label randomised)

400 IU/d (+200 mg calcium;

50,000 IU/week (+ calcium)

Cholecalciferol

Length, HC and weight were significantly higher in the intervention group compared with the control group.

Litonjua 2014

US (prenatal clinical centres in Boston, Saint Louis, San Diego)

881 pregnant women, history of asthma/allergies; aged 18‐40 years; 10‐18 weeks' gestation

Stratified permuted blocks with randomly varied block sizes of 4 and 6, and 1 block allocation list per stratum

400 IU/d; 4400 IU/d

Cholecalciferol

Not published yet.

Marya 1981

India

45 Hindu pregnant women

Not reported

No vitamin D;

1200 IU/d (+375 mg calcium); 600,000 IU (at 7th and 8th month).

Ergocalciferol

Supplementation with 1200 U/d led to significantly higher birthweight and this was even higher in those taking the 2 doses of 600,000.

Mutlu 2013

Turkey (Hospital)

91 pregnant women; aged 16‐42 years; singleton

Reported: simple randomisation method

600 IU/d;

1,200 IU/d; 2,000 IU/d

Cholecalciferol

25OHD was significantly higher in the 2,000 IU/d group versus the other groups

Roth 2013a

Bangladesh (maternal health clinic)

28 pregnant women; aged 18‐34 years; 27 to 30 weeks

Not specified

70,000 IU (single dose on day 0) + 35,000 IU/week (from day 7); 14,000 IU/week (from day 0; control group)

Cholecalciferol

A dose‐response effect was observed in 25OHD with the higher dose versus control

Shakiba 2013

Iran (2 primary care clinics)

51 healthy pregnant women; second trimester of pregnancy; autumn and winter

Not specified

50,000 IU/month; 100,000 IU/month

Cholecalciferol

76% of neonates in group with 50,000 IU/d month and 100% of neonates in group with 100,000 IU/month had 25OHD > 20 ng/mL.

Soheilykhah 2011

Iran (2 prenatal clinics)

120 healthy non‐obese pregnant women; < 12th week of pregnancy

Not specified

200 IU/d;

50,000 IU/month;

50,000 IU every 2 weeks

Cholecalciferol

25OHD was higher in those on the higher dose versus middle versus lower doses. Supplementation with 50,000 IU every 2 weeks significantly improved insulin resistance

Stephensen 2011

USA (Research Center and university care centres)

57 healthy pregnant women; <20 weeks' gestation;>18 years

Not specified

400 IU/d; 2,000 IU/d

Cholecalciferol

Greater increase in 25OHD and higher infant birthweight among those on the 2000 IU/d group.

Wagner 2010b

USA (University prenatal care)

494 healthy pregnant women; aged 16‐45 years; 12‐16 weeks of gestation; singleton

Stratified blocked randomisation to balance by ethnicity.

400 IU/d; 2000 IU/d; 4000 IU/d.

All women received daily multiple micronutrients supplements

Cholecalciferol

Greater increase in 25OHD among those on the 2000 IU/d and 4000 IU/d groups.

Wagner 2010c

USA (University prenatal care)

257 healthy pregnant women; aged 16‐45 years; 12‐16 weeks of gestation; singleton

Randomisation stratified based on initial 25OHD, using lists generated by computer prior to the start of the study.

2000 IU/d; 4000 IU/d.

All women received daily multiple micronutrients supplements

Cholecalciferol

25OHD significantly increase in both groups from baseline. Preterm birth was inversely associated with 25OHD at delivery

Yap 2014

Australia

179 pregnant women; 18 years of age or older; singleton pregnancy; with low baseline 25OHD; < 20 weeks of gestation

Randomisation was in a 1:1 ratio, with a permuted block size of 6 and sequential assignment.

400 IU/d; 5000 IU/d

Cholecalciferol

No difference in maternal OGTT between groups.

Abbreviations used

25OHD: 25‐hydroxycholecalciferol
HC: head circumference
IU: international units
OGTT: oral glucose tolerance test

Figuras y tablas -
Table 1. Review of excluded trials testing different vitamin D doses without a placebo group
Comparison 1. Vitamin D alone versus no treatment/placebo (no vitamins or minerals)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Pre‐eclampsia (ALL) Show forest plot

2

219

Risk Ratio (M‐H, Random, 95% CI)

0.52 [0.25, 1.05]

2 Gestational diabetes (ALL) Show forest plot

2

219

Risk Ratio (M‐H, Random, 95% CI)

0.43 [0.05, 3.45]

3 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (ALL) Show forest plot

7

868

Mean Difference (IV, Random, 95% CI)

54.73 [36.60, 72.86]

4 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by start of supplementation) Show forest plot

7

868

Mean Difference (IV, Random, 95% CI)

47.24 [35.17, 59.31]

4.1 Less than 20 weeks of pregnancy

1

32

Mean Difference (IV, Random, 95% CI)

32.45 [19.48, 45.42]

4.2 20 weeks of pregnancy or more

6

836

Mean Difference (IV, Random, 95% CI)

49.70 [36.62, 62.78]

4.3 Unknown/unreported/mixed

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

5 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by pre‐gestational body mass index (kg/m2)) Show forest plot

7

868

Mean Difference (IV, Random, 95% CI)

47.24 [35.17, 59.31]

5.1 Underweight (lower than 18.5)

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

5.2 Normal weight (18.5 to 24.9)

1

165

Mean Difference (IV, Random, 95% CI)

34.09 [12.51, 55.67]

5.3 Overweight (25 or higher)

2

308

Mean Difference (IV, Random, 95% CI)

19.54 [18.34, 20.74]

5.4 Unknown/unreported/mixed

4

395

Mean Difference (IV, Random, 95% CI)

73.18 [21.00, 125.36]

6 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by supplementation scheme/regimen) Show forest plot

8

1043

Mean Difference (IV, Random, 95% CI)

44.12 [30.24, 58.00]

6.1 Single dose

3

340

Mean Difference (IV, Random, 95% CI)

15.16 [5.68, 24.63]

6.2 Daily

6

703

Mean Difference (IV, Random, 95% CI)

57.80 [38.37, 77.23]

6.3 Weekly

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

7 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by skin pigmentation based on Fitzpatrick skin tone chart) Show forest plot

7

868

Mean Difference (IV, Random, 95% CI)

47.24 [35.17, 59.31]

7.1 Three or less

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

7.2 Four or more

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

7.3 Unknown/unreported/mixed

7

868

Mean Difference (IV, Random, 95% CI)

47.24 [35.17, 59.31]

8 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by latitude) Show forest plot

7

868

Mean Difference (IV, Random, 95% CI)

47.24 [35.17, 59.31]

8.1 Between Tropics of Cancer and Capricorn

1

260

Mean Difference (IV, Random, 95% CI)

19.13 [17.79, 20.47]

8.2 North of the Tropic of Cancer or South of the Tropic of Capricorn

6

608

Mean Difference (IV, Random, 95% CI)

55.73 [35.67, 75.80]

8.3 Unknown/unreported

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

9 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (by season at the start of pregnancy) Show forest plot

7

868

Mean Difference (IV, Random, 95% CI)

47.24 [35.17, 59.31]

9.1 Summer

1

160

Mean Difference (IV, Random, 95% CI)

96.0 [88.19, 103.81]

9.2 Winter

1

77

Mean Difference (IV, Random, 95% CI)

16.30 [13.61, 18.99]

9.3 Mixed seasons

5

631

Mean Difference (IV, Random, 95% CI)

37.24 [27.46, 47.02]

10 Preterm birth (less than 37 weeks' gestation) (ALL) Show forest plot

3

477

Risk Ratio (M‐H, Random, 95% CI)

0.36 [0.14, 0.93]

11 Low birthweight (less than 2500 g) (ALL) Show forest plot

3

493

Risk Ratio (M‐H, Random, 95% CI)

0.40 [0.24, 0.67]

12 Impaired glucose tolerance

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

13 Caesarean section Show forest plot

2

312

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.69, 1.31]

14 Gestational hypertension

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

15 Adverse effects (nephritic syndrome) (ALL) Show forest plot

1

135

Risk Ratio (M‐H, Random, 95% CI)

0.17 [0.01, 4.06]

16 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL) Show forest plot

1

180

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

17 Birth length (cm) (ALL) Show forest plot

4

638

Mean Difference (IV, Random, 95% CI)

0.70 [‐0.02, 1.43]

18 Head circumference at birth (cm) (ALL) Show forest plot

4

638

Mean Difference (IV, Random, 95% CI)

0.43 [0.03, 0.83]

19 Birthweight (g) (ALL) Show forest plot

5

715

Mean Difference (IV, Random, 95% CI)

66.60 [‐137.22, 270.41]

20 Admission to special care (including intensive care) during the neonatal period (within 28 days after delivery) (ALL)

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

21 Stillbirth (ALL) Show forest plot

3

540

Risk Ratio (M‐H, Random, 95% CI)

0.35 [0.06, 1.99]

22 Neonatal death (ALL) Show forest plot

2

282

Risk Ratio (M‐H, Random, 95% CI)

0.27 [0.04, 1.67]

23 Apgar score less than seven at five minutes Show forest plot

1

165

Risk Ratio (M‐H, Random, 95% CI)

0.53 [0.11, 2.53]

24 Neonatal infection

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

25 Very preterm birth

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 1. Vitamin D alone versus no treatment/placebo (no vitamins or minerals)
Comparison 2. Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Pre‐eclampsia (ALL) Show forest plot

3

1114

Risk Ratio (M‐H, Random, 95% CI)

0.51 [0.32, 0.80]

2 Gestational diabetes (ALL) Show forest plot

1

54

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.01, 7.84]

3 Maternal vitamin D concentration at term (25‐hydroxyvitamin D) (nmol/L) (ALL)

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

4 Preterm birth (less than 37 weeks' gestation) (ALL) Show forest plot

3

798

Risk Ratio (M‐H, Random, 95% CI)

1.57 [1.02, 2.43]

5 Low birthweight (less than 2500 g) (ALL)

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

6 Impaired glucose tolerance

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

7 Caesarean section

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

8 Gestational hypertension Show forest plot

1

59

Risk Ratio (M‐H, Random, 95% CI)

0.26 [0.06, 1.12]

9 Adverse effects (ALL)

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

10 Maternal death (death while pregnant or within 42 days of termination of pregnancy)

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

11 Birth length (cm) (ALL)

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

12 Head circumference at birth (cm) (ALL)

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

13 Birthweight (g) (ALL)

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

14 Admission to special care (including intensive care) during the neonatal period (within 28 days after delivery) (ALL)

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

15 Stillbirth (ALL)

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

16 Neonatal death (ALL) Show forest plot

1

660

Risk Ratio (M‐H, Random, 95% CI)

0.2 [0.01, 4.15]

17 Apgar score less than seven at five minutes

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

18 Neonatal infection

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

19 Very preterm birth

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 2. Vitamin D + calcium versus no treatment/placebo (no vitamin or minerals)