Vitamin D supplementation during pregnancy to prevent vitamin D deficiency in newborns: a systematic review and meta-analysis

Colonetti, Tamy; Paulino, Amabile Scremin; Sartor, Jaíne Paulina; Grande, Antonio Jose; Colonetti, Laura; Rosa, Maria Inês da

doi:10.1590/1806-9304202200020002

Tamy Colonetti

Laboratory of Biomedicine Translational. Graduate Program in Health Sciences. Universidade do Extremo Sul Catarinense. Av. Universitária, 1105. Bairro Universitário. Criciuma, SC, Brazil. CEP: 88.806-000. Email: tamycolonetti@hotmail.com

https://orcid.org/0000-0003-1175-5583

Amabile Scremin Paulino

Universidade do Extremo Sul Catarinense. Criciuma, SC, Brazil

https://orcid.org/0000-0003-0121-1566

Jaíne Paulina Sartor

Universidade do Extremo Sul Catarinense. Criciuma, SC, Brazil

https://orcid.org/0000-0002-5583-7727

Antonio Jose Grande

Laboratory of Evidence-based Practice. Universidade Estadual de Mato Grosso do Sul. Campo Grande, MS, Brazil

https://orcid.org/0000-0001-7182-075X

Laura Colonetti

Laboratory of Biomedicine Translational. Graduate Program in Health Sciences. Universidade do Extremo Sul Catarinense. Av. Universitária, 1105. Bairro Universitário. Criciuma, SC, Brazil. CEP: 88.806-000. Email: tamycolonetti@hotmail.com

https://orcid.org/0000-0001-5267-7492

Maria Inês da Rosa

Laboratory of Biomedicine Translational. Graduate Program in Health Sciences. Universidade do Extremo Sul Catarinense. Av. Universitária, 1105. Bairro Universitário. Criciuma, SC, Brazil. CEP: 88.806-000. Email: tamycolonetti@hotmail.com

https://orcid.org/0000-0001-6124-2538

Authors’ contribution

Colonetti T and Rosa MI: conceptualization, formal analysis, methodology, project administration, validation, writing – original draft, writing – review & editing. Paulino AS and Sartor JP: data curation, formal analysis, investigation, writing – original draft. Grande AJ: formal analysis, methodology, writing – original draft. Colonetti L: investigation, writing – original draft, writing – review & editing. All authors approved the final version of the article and declare no conflict of interest.

Author/Year	Country	Type of Study	Mean age	Total number of participants	Number of participants supplemented group	Type of supplementation and dose	Comparison	Time	Outcomes evaluated by the authors
Akhtar et al.,²¹21 Akhtar E, Mily A, Haq A, Al-Mahmud A, El-Arifeen S, Baqui Ah, et al. Prenatal high-dose vitamin D3 supplementation has balanced effects on cord blood Th1 and Th2 responses. Nutr J. 2016; 15 (1): 75. 2016	Bangladesh	RCT	Vitamin D group:22.43 ± 3.75; Placebo group: 22.85 ± 1.47	80	40	Vitamin D3 Pill 3500IU/week	Placebo oil (Miglyol oil, Merck)	26-29 weeks of gestation until childbirth	1) Serum concentration of vitamin D at umbilical cord 2) Effect of prenatal supplementation at T and B cells of the umbilical cord function 3) Cytokine concentrations in stimulated umbilical cord blood lymphocytes
Anderson et al.,¹⁹19 Anderson CM, Gillespie SL, Thiele DK, Ralph JL, Ohm JE. Effects of maternal vitamin D supplementation on the maternal and infant epigenome. Breastfeed Med. 2018 Jun; 13 (5): 371-380. 2018	USA	RCT	Not informed by the authors	13	7	Vitamin D3 pill 400IU + 3.400IU/ day	Prenatal vitamins containing 400IU vitamin D3 + placebo pill/day	24-28 weeks until 4-6 weeks after	1) maternal serum concentration of vitamin D at at birth and 4-6 weeks after 2) Neonatal serum concentration of vitamin D of at 4-6 weeks after 3) Effect of prenatal supplementation at maternal DNA methylation and breastfeeding
Brooke et al.,²⁰20 Brooke OG, Brown IR, Bone CD, Carter ND, Cleeve HJ, Maxwell JD, et al. Vitamin D supplements in pregnant Asian women: effects on calcium status and fetal growth. Br Med J. 1980 Mar; 280 (6216): 751-4. 1980	England	ECR	Vitamin D group: 23.9±4-8; Control group: 23.7±3-1	126	59	Calciferol (D2) 1000i U/day	Placebo not specified by the author	28-32 weeks until term	1) Serum concentration of maternal vitamin D, calcium, phosphate, albumin, phosphatase alkaline, andvitamin D carrier globulin at term 2) Serum concentration in the umbilical cord of vitamin D, calcium, phosphate, albumin, alkaline phosphatase, placental and vit D carrier globulin 3) Anthropometric of the newborns
Roth,¹⁶16 Roth DE, Al Mahmud 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 Mar; 5 (3): 788-810. 2013	Bangladesh	RCT	22.2 (±3.1)	160	80	Liquid formulation of Vitamin D3 Group 1: Single dose of 70.000IU at day 0 followed by 35000IU/week starting on day 7 until childbirth Group 2: 14,000IU/week starting at day 0 until childbirth	Non-pregnant women that received a single dose of 70,000IU at day 0 followed by 35000IU/week starting on day 7 (10 weeks of supplementation)	27-30 weeks until childbirth	1) Maternal serum concentration of vitamin D, calcium, PTH, adjusted calcium-albumin, and urinary calcium-creatinine ratio at childbirth 2) Serum vitamin D concentration in the umbilical cord
Sablok et al.,²⁹29 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. Clin Endocrinol (Oxf). 2015 Oct; 83 (4): 536-41. 2015	Índia	RCT	Not informed by the authors	165	108	Cholecalciferol 1) Sufficient>50nmol/L: (1 dose) 60000IU with 20 weeks 2) lnsufficient 25-50nmol/L: (2 doses) 120000IU with 20 and 24 weeks 3)Deficient<25nmol/L: (4 doses) 120000IU with 20, 24, 28, 32 weeks	Placebo not specified by author	14-20 weeks until 32 weeks of gestation	1) Maternal serum vitamin D concentration 2) Serum concentration of vitamin D in the umbilical cord 3) Birth weight and Apgar 4) Gestational complications
Thiele et al.,¹⁸18 Thiele DK, Ralph J, El-Masri M, Anderson CM. Vitamin D3 supplementation during pregnancy and lactation improves vitamin d status of the mother-infant dyad. J Obstet Gynecol Neonatal Nurs. 2017 Jan/Feb; 46 (1): 135-47. 2017	USA	RCT	Vitamin D group: 30 ± 6.0 Control: 27 ± 5.5	13	7	Pill of Vitamin D3 400IU vitamin D3 + 3400IU of vitamin D in pill /day	Prenatal vitamin containing 400IU vitamin D3 plus a placebo pill, both taken daily	24-28 weeks until 4-6 weeks after childbirth	1) Concentration of vitamin D, calcium and maternal PTH at birth and 4-6 weeks after 2) Concentration of neonatal vitamin D 24-72 hours after birth and 4-6 weeks after 3) Anthropometric measurements of the newborn
Yesiltepe-Mutlu et al.,³⁰30 Yesiltepe-Mutlu G, 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. Horm Res Paediatr. 2014; 81 (6): 402-8. 2014	Turkey	RCT	Vitamin D Group 1: 26.2 ± 4.5 Vitamin D Group 2: 26.6 ± 4.8 Control Group: 29 ± 5.7	91	63	Cholecalciferol in drops (50000IU in 15ml) Group 1: n=31 → 1200IU/day Group 2: n=32 → 2000IU/day	600IUI/day of Cholecalciferol	Starting at 13-32 weeks until 3 months after the initiation of vitamin D supplementation	1) Maternal serum concentration of vitamin D, calcium, PTH, phosphorus and alkaline phosphatase 2) Neonatal serum concentration of vitamin D, calcium, PTH, phosphorus and alkaline phosphatase 3) Birth weight
Yu et al.,²⁶26 Yu CK, Sykes L, Sethi M, Teoh TG, Robinson S. Vitamin D deficiency and supplementation during pregnancy. Clin Endocrinol (Oxf). 2009 May; 70 (5): 685-90. 2009	England	RCT	Asians: Mean of 29 years Middle East: Mean of 31 years Black: Mean of 31 years Caucasians: Mean of 33 years	179	120	Calciferol Group 1: n=60->800IU/ day ergocalciferol Group 2: n=60 → 200000IU/single dose calciferol	No supplementation	27 weeks until childbirth	1) Serum concentration of vitamin D, corrected calcium, maternal PTH at childbirth 2) Serum concentration of vitamin D and corrected calcium in the umbilical cord
O'Callaghan et al.,¹⁵15 O’Callaghan KM, Hennessy Á, Hull GLJ, Healy K, Ritz C, Kenny LC, et al. Estimation of the maternal vitamin D intake that maintains circulating 25-hydroxyvitamin D in late gestation at a concentration sufficient to keep umbilical cord sera ≥25-30nmol/L: a dose-response, double-blind, randomized placebo-controlled trial in pregnant women at northern latitude. Am J Clin Nutr. 2018 Jul; 108 (1): 77-91. 2018	Ireland	RCT	Vitamin D Group 1: 34 ± 4 Vitamin D Group 2: 35 ± 3 Placebo group: 32 ± 4	144	Group 1 and 2 Final: 48/48	Vitamin D3 pill Group 1: 400IU/day Group 2: 800IU/day	Placebo with <0.02 ug/day of Vitamin D3	Starting at<18 weeks (mean of 14) until 34-38 weeks (mean of 36)	1) Maternal serum concentration of 25 (OH) D, PTH and Ca before and after supplementation 2) Dosage of 25 (OH) D in the umbilical cord
Roth et al.,¹⁷17 Roth DE, Gernand AD, Al Mahmud A. Vitamin D supplementation in pregnancy and lactation and infant growth. N Engl J Med. 2018 Aug; 379 (19): 1881. 2018	India	RCT	23 years	1300	Group 1: 260 (4.200IU/week) Group 2: 259 (16.800IU/week) Group 3: 260 (28.000IU/week) Group 4: 260 (28.000IU/week + 26 week after childbirth)	Vitamin D3 pill Group 1: 4.200IU/week Group 2: 16.800IU/week Group 3 : 28.000IU/week Group 4: 28.000IU/week until 26 weeks after childbirth	Placebo not specified by the author	Starting between 17-24 weeks until childbirth (group 1,2 3, 4) or until 26 weeks after postpartum (group)	1) Maternal concentration of 25 (OH) D and PTH 2) Anthropometric data of the NB and growth monitoring up to 1 year of age
Rodda et al.,²⁸28 Rodda CP, Benson JE, Vincent AJ, Whitehead CL, Polykov A, Vollenhoven B. Maternal vitamin D supplementation during pregnancy prevents vitamin D deficiency in the newborn: an open-label randomized controlled trial. Clin Endocrinol (Oxf). 2015 Sep; 83 (3): 363-8. 2015	Australia	RCT	Vitamin D group: 28.3 Control group: 29.2	45	22	Vitamin D3 pill 2000IU/day → 4000IU/day for those who were still deficient at 28 weeks	No supplementation	Starting between 12-16 weeks until 28 weeks. Women who were still deficient at 28 weeks had the dose doubled to 4000IU/day	1) Maternal serum concentration before and after supplementation 2) Dosing of 25 (OH) D in the umbilical cord
Mojibian et al.²⁵25 Mojibian M, Soheilykhah S, Zadeh MAF, Moghadam MJ. The effects of vitamin D supplementation on maternal and neonatal outcome: a randomized clinical trial. Iran J Reprod Med. 2015 Nov; 13 (11): 687-96. 2015	Iran	RCT	Vitamin D group: 27.8 ± 5 Control group: 27.3 ± 4.9	470	224	Cholecalciferol pill 50000IU each 2 weeks	400IU/day of Cholecalciferol	Starting at 12 weeks until delivery	1) Maternal 25 (OH) D concentration + maternal TTGO 2) Concentration of umbilical cord 25 (OH) D 3) Anthropometric data of NB and Apgar
Hossain et al.,²⁴24 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, randomized controlled trial of antenatal vitamin D supplementation in Pakistani women. J Clin Endocrinol Metab. 2014 Jul; 99 (7): 2448-55. 2014	Pakistan	RCT	Vitamin D group: 25.96 ± 3.13 Control group: 25.19 ± 4.36	175	86	Vitamin D3 capsule + routine antenatal care 4000IU/day + 400mg/ dayof ferrous sulfate and 600mg/day of calcium lactate	Routine antenatal care	Starting at 20 weeks until childbirth	1) Maternal concentration of 25 (OH) D 2) Complications during pregnancy 3) Concentration of 25 (OH) D in the neonate 4) Anthropometric data of the NB and Apgar
Kalra et al.,²⁷27 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. Br J Nutr. 2012 Sep; 108 (6): 1052-8. 2012	Índia	RCT	Vitamin Group 1: 26.3 ± 4.2 Vitamin Group 2: 27.0 ± 3.8 Usual care (Group 3): 26.2 ± 3.7	139	Group 1: 48 Group 2: 49 Group 3: 43	Cholecalciferol oil pill Group 1: 60.000IU, single dose at 2nd trimester Group 2: 120.000IU double dose, at 2nd trimester and another at 3rd trimester and 1 g/day of Ca	Usual care (no vitamin D supplementation)	Group 1: single dose at 2^nd trimester Group 2: double dose, one at 2^nd and another at 3^rd trimester	1) Concentration of 25 (OH) D, PTH and maternal Ca 2) Complications during pregnancy 3) Concentration of 25 (OH) and Ca in the umbilical cord 4) Anthropometric data of the NB
Diogenes et al.,²²22 Diogenes ME, Bezerra FF, Rezende EP, Donangelo CM. Calcium plus vitamin D supplementation during the third trimester of pregnancy in adolescents accustomed to low calcium diets does not affect infant bone mass at early lactation in a randomized controlled trial. J Nutr. 2015 Jul; 145 (7): 1515-23. 2015	Brazil	RCT	Intervention group: 16.8 ± 1.5 Placebo group: 17.2 ± 1.0	56	30	Cholecalciferol + Calcium 200IU/day + 600mg/day	Placebo not specified by the authors	Start ing between 21-29 weeks until childbirth	1) Concentration of 25 (OH) D and maternal Ca 2) Concentration of 25 (OH) D in the umbilical cord 3) Anthropometric data 4) Growth assessment during pregnancy (femur size)
Harrington et al.,¹⁴14 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. Pediatr Res. 2014 Sep; 76 (3): 302-9. 2014	Bangladesh	RCT	Not informed by the authors	130	67	Cholecalciferol 35.000IU/week (5.000IU/ day)	Adminstrated Oil-based no vitamin D3	Starting between 26 and 30 weeks until childbirth	1) Maternal concentration of 25 (OH) D, Ca, albumin, PTH 2) Concentration 25 (OH) D, Ca, albumin, and PTH in umbilical cord
Hashemipour et al.,²³23 Hashemipour S, Lalooha F, Mirdamadi SZ, Ziaee A, Ghaleh TD. Effect of vitamin D administration in vitamin D-deficient pregnant women on maternal and neonatal serum calcium and vitamin D concentrations: a randomized clinical trial. Br J Nutr. 2013 Nov; 110 (9): 1611-6. 2013	Iran	RCT	Vitamin D group: 25.05 ± 4.62 Control group: 27.62 ± 4.63	109	54	Cholecalciferol 50.000IU/week for 8 weeks (starting between 26-28 weeks)	Multivitamin containing 400IU vitamin D3 plus 200mg/day of Ca until the end of pregnancy	Starting supplementation of 50.000 between 26-28 weeks during 8 weeks	1) Concentration of 25 (OH) D and maternal Ca 2) Concentration of 25 (OH) D in the umbilical cord and serum Ca of the NB

[1] Authors’ contribution

Colonetti T and Rosa MI: conceptualization, formal analysis, methodology, project administration, validation, writing – original draft, writing – review & editing. Paulino AS and Sartor JP: data curation, formal analysis, investigation, writing – original draft. Grande AJ: formal analysis, methodology, writing – original draft. Colonetti L: investigation, writing – original draft, writing – review & editing. All authors approved the final version of the article and declare no conflict of interest.

Brasil

Brasil

Vitamin D supplementation during pregnancy to prevent vitamin D deficiency in newborns: a systematic review and meta-analysis

Abstract

Objectives:

Methods:

Results:

Conclusion: