EFFECTS OF VITAMIN D SUPPLEMENTATION DURING PREGNANCY ON NEWBORNS AND INFANTS: AN INTEGRATIVE REVIEW

Dutra, Letícia Veríssimo; Souza, Fabíola Isabel Suano de; Konstantyner, Tulio

doi:10.1590/1984-0462/2021/39/2020087

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Brasil

Revista Paulista de Pediatria

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REVIEW ARTICLE • Rev. paul. pediatr. 39 • 2021 • https://doi.org/10.1590/1984-0462/2021/39/2020087 copy

EFFECTS OF VITAMIN D SUPPLEMENTATION DURING PREGNANCY ON NEWBORNS AND INFANTS: AN INTEGRATIVE REVIEW

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Objective:

To identify the effects of vitamin D supplementation during pregnancy on newborns and infants.

Data sources:

The present study is an integrative review of literature based on clinical trials published in journals indexed in the PubMed and Web of Science databases. Two searches were carried out, starting with the association (and) of the health term “vitamin D” with “pregnancy”. In the search for information, selection criteria were established, and there was no language limitation and year of publication.

Data synthesis:

The final selection resulted in 44 clinical trials, most of which were randomized and double blind, which were carried out in outpatient clinics, referral hospitals and universities, mainly in Europe. The samples studied were predominantly of newborns. In these 44 trials, 23 types of different doses of vitamin D during pregnancy, with different doses, regimens and times of use, and 14 different outcomes were studied in newborns (NB) and infants. Of the 44 studies performed, 35 showed statistically significant beneficial effects of vitamin D supplementation during pregnancy on newborns and infants compared to control groups.

Conclusions:

Vitamin D supplementation during pregnancy for at least three months before delivery has the potential of positively influencing calcium metabolism, physical growth and immune system development in newborns and infants. However, there is insufficient knowledge to define the optimal dose and to guarantee the absence of possible long-term adverse effects.

Keywords:
Vitamin D; Pregnancy; Infant, newborn; Infant; Dietary supplements

Author, year	Methods			Main results
Author, year	Design	Outcome	Intervention	Main results
Delvin, 1986¹⁹19. Delvin EE, Salle BL, Glorieux FH, Adeleine P, David LS. Vitamin D supplementation during pregnancy: effect on neonatal calcium homeostasis. J Pediatr. 1986;109:328-34. https://doi.org/10.1016/s0022-3476(86)80396-1 https://doi.org/https://doi.org/10.1016/...	RCT B n=40	25(OH)D, Ca, P and PTH	IG: 1,000 IU/day; PG. IT: 3^rd trimester until delivery	$\bar{x}$ [25(OH)D] of UC: IG 18 versus PG 7 ng/mL (p<0.001); $\bar{x}$ [25(OH)D] (4 days): IG 13 versus PG 5 ng/mL (p<0.001); $\bar{x}$ [Ca], [P] and UC [PTH], and 4 days: p>0.05
Yu, 2009²⁰20. Yu CK, Sykes L, Sethi M, Teoh TG, Robinson S. Vitamin D deficiency and supplementation during pregnancy. Clin Endocrinol (Oxf). 2009;70:685-90. https://doi.org/10.1111/j.1365-2265.2008.03403.x https://doi.org/https://doi.org/10.1111/...	RCT n=180	25(OH)D	IG1: 1x 200,000 IU; GI2: 800 UI/day; PG IT: GA 26-27 weeks until delivery	$\bar{x}$ [25(OH)D] of UC: IG2=26 versus IG1 25 versus PG 17 nmol/L (p=0.001)
Roth, 2012²¹21. Roth DE, Al Mahmud A, Raqib R, Black RE, Baqui AH. Pharmacokinetics of a single oral dose of vitamin D3 (70,000 IU) in pregnant and non-pregnant women. Nutr J. 2012;11:114. https://doi.org/10.1186/1475-2891-11-114 https://doi.org/https://doi.org/10.1186/...	RCT n=27	25(OH)D	IG: 1x 70,000 IU. IT: GA 27-30 weeks	[25(OH)D] of UC and maternal (close to delivery): Pearson’s correlation =0.64 (p=0.02)
Hashemipour, 2013²²22. Hashemipour S, Lalooha F, Zahir Mirdamadi S, Ziaee A, Dabaghi Ghaleh T. Effect of vitamin D administration in vitamin D-deficient pregnant women on maternal and neonatal serum calcium and vitamin D concentrations: a randomised clinical trial. Br J Nutr. 2013;110:1611-6. https://doi.org/10.1017/s0007114513001244 https://doi.org/https://doi.org/10.1017/...	RCT O n=109	25(OH)D and Ca	IG (<30 ng/mL): 8x 50,000 IU/week; PG: 400 IU/day+200 mg of Ca/day. IT: GA 24-26 weeks until delivery	$\bar{x}$ [25(OH)D]: IG 27.7 versus PG 9 ng/mL (p<0.01) $\bar{x}$ [Ca]: IG 99 versus PG 91 mg/L (p<0.001)
Roth, 2013²³23. 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;5:788-810. https://doi.org/10.3390/nu5030788 https://doi.org/https://doi.org/10.3390/...	RCT n=28	25(OH)D	IG1: 1x 70,000 IU+35,000 IU/week until delivery; IG2: 14,000 IU/week until delivery. IT: GA 27-30 for 10 weeks	$\bar{x}$ [25(OH)D]: IG1 17 versus IG2 98 ng/mL (p=0.074) [25(OH)D] ≥ 50 nmol/L: 100% IG1 and IG2
Roth, 2012²⁴24. Roth DE, Mahmud AA, 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 J. 2012;26 (Suppl 1):392-3. https://doi.org/10.1096/fasebj.26.1_supplement.392.3 https://doi.org/https://doi.org/10.1096/...	RCT DB PC n=130	25(OH)D and Ca	IG: 35,000 IU/week; PG. IT: GA 26-29 weeks until delivery	$\bar{x}$ [25(OH)D]: IG 103 versus PG 39 nmol/L (p<0.001) % [25(OH)D] >50 nmol/L: IG 95 and PG 19
Shakiba, 2013²⁵25. Shakiba M, Iranmanesh MR. Vitamin D requirement in pregnancy to prevent deficiency in neonates: a randomised trial. Singapore Med J. 2013;54:285-8. https://doi.org/10.11622/smedj.2013110 https://doi.org/https://doi.org/10.11622...	RCT n=51	25(OH)D	IG1: 50,000 IU/month; IG2: 50,000 IU every two weeks; IG3 4x 50,000 IU/week+50,000 IU/month. IT: GA 13 weeks until delivery	% [25(OH)D] UC >30 ng/mL: IG1 35; IG2 59; IG3 82 (p<0.01) $\bar{x}$ [25(OH)D] UC: IG1 25 ng/mL versus IG2 32 ng/mL (p=0.03)
Wagner, 2013²⁶26. Wagner CL, McNeil RB, Johnson DD, Hulsey TC, Robinson C, Hamilton SA, et al. Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis. J Steroid Biochem Mol Biol. 2013;136:313-20. https://doi.org/10.1016/j.jsbmb.2013.01.002 https://doi.org/https://doi.org/10.1016/...	RCT DB PC n=504	25(OH)D	IG1: 2,000 IU/day; IG2: 4,000 IU/day; PG: 400 IU/day IT: GA 16 weeks until delivery	% [25(OH)D] of UC ≥20 ng/mL: PG 39.2; IG1 58.2; IG2 76 (p<0.001) [25(OH)D] of UC ≥32 ng/mL: PG 12.7%, IG1 15.2%, IG2 26% (p=0.020)
Dawodu, 2013²⁷27. 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. J Clin Endocrinol Metab. 2013;98:2337-46. https://doi.org/10.1210/jc.2013-1154 https://doi.org/https://doi.org/10.1210/...	RCT n=162	25(OH)D	PG: 400 IU/day; IG1: 2,000 IU/day; IG2: 4,000 IU/day IT: GA 12-16 weeks until delivery	% [25(OH)D] ≥20 ng/mL UC: PG 9; IG1 18; IG2 34 (p<0.001)
Mutlu, 2014²⁸28. 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. Horm Res Paediatr. 2014;81:402-8. https://doi.org/10.1159/000358833 https://doi.org/https://doi.org/10.1159/...	RCT n=91	25(OH)D	IG1: 600 IU/day; IG2: 1,200 IU/day; IG3: 2,000 IU/day IT: GA 13-32 weeks until delivery	$\bar{x}$ [25(OH)D]: IG1 18.8 ng/mL; IG2 23.6 ng/mL; IG3 34 ng/mL (p=0.015) % [25(OH)D] >30 ng/mL: IG1 36; IG2 52; IG3 92 (p=0.023)
Hossain, 2014²⁹29. 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;99:2448-55. https://doi.org/10.1210/jc.2013-3491 https://doi.org/https://doi.org/10.1210/...	RCT n=175	25(OH)D	IG: 4,000 IU/day; PG. IT: GA 20 weeks until delivery	$\bar{x}$ [25(OH)D]: IG 19.22 ng/dL; PG 6.27 ng/dL (p<0.05)
Grant, 2014³⁰30. 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:e143-53. https://doi.org/10.1542/peds.2013-2602 https://doi.org/https://doi.org/10.1542/...	RCT DB PC n=260	25(OH)D	IG1: 1,000 IU/day (mother)+400 IU/day (baby); IG2: 2,000 IU/day (mother)+800 IU/day (baby); PG IT: GA 27 weeks until delivery and from birth until baby is six months old	$\bar{x}$ [25(OH)D] UC: PG 13 ng/mL; IG1 24 ng/mL; IG2 26 ng/mL (p<0.01) 6 months: PG 31 ng/mL; IG1 34 ng/mL; IG2 38 ng/mL (p=0.004)
Rodda, 2015³¹31. 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;83:363-8. https://doi.org/10.1111/cen.12762 https://doi.org/https://doi.org/10.1111/...	RCT O PC n=78	25(OH)D	Pregnant women (<75 nmol/L). IG: 2,000 IU/day until 28 weeks; PG. IT: GA 12-16 weeks until delivery	$\bar{x}$ [25(OH)D] UC: IG: 81 nmol/L versus PG: 42 nmol/L (p<0.01) [25(OH)D] maternal at delivery and UC (Spearman’s correlation: 0.880; p<0.0001)
Sablok, 2015³²32. 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;83:536-41. https://doi.org/10.1111/cen.12751 https://doi.org/https://doi.org/10.1111/...	RCT DB PC n=180	25(OH)D	IG (≥50 nmol/L): 1x 60,000 IU GA 20 weeks or (<50 nmol/L) 2-4x 120,000 IU/month start at 20 weeks; PG	$\bar{x}$ [25(OH)D] UC: PG 43.1 nmol/L versus IG 56.8 nmol/L (p<0.001) % [25(OH)D] >50 nmol/L: PG 14 versus IG 46.2 (p<0.001)
March, 2016³³33. March KM, Chen NN, Karakochuk CD, Shand AW, Innis SM, Dadelszen P, et al. Maternal vitamin D₃ supplementation at 50 µg/d protects against low serum 25-hydroxyvitamin D in infants at 8 wk of age: a randomized controlled trial of 3 doses of vitamin D beginning in gestation and continued in lactation. Am J Clin Nutr. 2015;102:402-10. https://doi.org/10.3945/ajcn.114.106385 https://doi.org/https://doi.org/10.3945/...	RCT DB PC n=226	25(OH)D	IG1: 400 IU/day; IG2: 1,000 IU/day; IG3: 2,000 IU/day; PG. IT: GA 13-24 weeks until 8 weeks	$\bar{x}$ [25(OH)D] (8 weeks): IG1 69 nmol/L versus IG2 78 nmol/L versus IG3 88 nmol/L (p<0.05) [25(OH)D] >30 nmol/L (8 weeks): IG3 ∼98%
Wall, 2016³⁴34. Wall CR, Stewart AW, Camargo CA Jr, Scragg R, Mitchell EA, Ekeroma A, et al. Vitamin D activity of breast milk in women randomly assigned to vitamin D3 supplementation during pregnancy. Am J Clin Nutr. 2016;103:382-8. https://doi.org/10.3945/ajcn.115.114603 https://doi.org/https://doi.org/10.3945/...	RCT DB PC n=75	25(OH)D	IG1: 1,000 IU/day; IG2: 2,000 IU/day; PG IT: GA 27 weeks until delivery	$\bar{x}$ [25(OH)D] UC: PG 44 nmol/L versus IG1 64 nmol/L versus IG2 78 nmol/L (p=0.002)
Perumal, 2017³⁵35. Perumal N, Al Mahmud A, Baqui AH, Roth DE. Prenatal vitamin D supplementation and infant vitamin D status in Bangladesh. Public Health Nutr. 2017;20:1865-73. https://doi.org/10.1017/s1368980015003092 https://doi.org/https://doi.org/10.1017/...	RCT n=160	25(OH)D	IG: 35,000 IU/week; PG. IT: GA 26-29 weeks until delivery	$\bar{x}$ [25(OH)D] <1 month: IG 80 nmol/L versus PG 22 nmol/L (p<0.01)
Thiele, 2017³⁶36. 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;46:135-47. https://doi.org/10.1016/j.jogn.2016.02.016 https://doi.org/https://doi.org/10.1016/...	RCT DB n=13	25(OH)D	IG: 3,800 IU/day; G2: 400 IU/day IT: GA 24-28 weeks until 4-6 weeks postpartum	$\bar{x}$ [25(OH)D] UC: G2 23.4 nmol/L versus IG 32.6 ng/mL (p=0.017) $\bar{x}$ [25(OH)D] 4-6 weeks + EBF: G2 17.0 nmol/L versus IG 24.9 ng/mL (p=0.256)
Motamed, 2019³⁷37. Motamed S, Nikooyeh B, Kashanian M, Hollis BW, Neyestani TR. Efficacy of two different doses of oral vitamin D supplementation on inflammatory biomarkers, and maternal and neonatal outcomes. Matern Child Nutr. 2019;15:e12867. https://doi.org/10.1111/mcn.12867 https://doi.org/https://doi.org/10.1111/...	RCT O n=84	25(OH)D	IG1: 1,000 IU/day; IG2: 2,000 IU/day IT: GA 12 weeks until delivery	$\bar{x}$ [25(OH)D]: IG1 24.0 nmol/L versus IG2 46.7 nmol/L (p=0.001)
Enkhmaa, 2019³⁸38. Enkhmaa D, Tanz L, Ganmaa D, Enkhtur S, Oyun-Erdene B, Stuart J, et al. Randomized trial of three doses of vitamin D to reduce deficiency in pregnant Mongolian women. EBioMedicine. 2019;39:510-9. https://doi.org/10.1016/j.ebiom.2018.11.060 https://doi.org/https://doi.org/10.1016/...	RCT PC n=119	25(OH)D	IG1: 600 IU/day; IG2: 2,000 IU/day; IG3: 4,000 IU/day IT: GA 12-16 weeks until delivery	% [25(OH)D] UC >50 nmol/L: IG1 17, IG2 71, and IG3 80 (p<0.001)

Author, year	Methods			Main results
Author, year	Design	Outcome	Intervention	Main results
Brooke, 1980¹⁰10. 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;280:751-4. https://doi.org/10.1136/bmj.280.6216.751 https://doi.org/https://doi.org/10.1136/...	RCT DB n=126	Anthropometry	IG: 1,000 IU/day; PG IT: 3^rd trimester until delivery	Weight, forearm length and CP: PG versus IG (p>0.05) Fontanelle area: PG (6.1 cm) versus IG (4.1 cm) (p<0.05)
Kalra, 2012¹⁸18. 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;108:1052-8. https://doi.org/10.1017/S0007114511006246 https://doi.org/https://doi.org/10.1017/...	RCT n=140	Ca, AP and 25(OH)D, and anthropometry at birth	IG1: 1x 60,000 IU at the beginning; IG2: 2x 120,000 IU at the beginning, and IG at 28 weeks; PG: 1g of Ca/day IT: GA 12-24 weeks until delivery	$\bar{x}$ [AP] of UC: IG1 41.9 µkat/L; IG2 38.9 µkat/L; PG 66.7 µkat/L (p=0.031) $\bar{x}$ weight: IG1 3.08 kg; IG2 3.03 kg; PG 2.77 kg (p=0.03); $\bar{x}$ height: IG1 50.3 cm; IG2 50.1 cm; PG 49.4 cm (p<0.01); $\bar{x}$ fontanelle: IG1 2.6 cm; IG2 2.5 cm; PG 3.3 cm (p<0.01). $\bar{x}$ [Ca]: IG1 versus IG2 versus PG (p=0.48) [25(OH)]: IG1 26.2 nmol/L; IG2 58.7 nmol/L (p<0.001)
Roth, 2013¹¹11. 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. Nutr J. 2013;12:47. https://doi.org/10.1186/1475-2891-12-47 https://doi.org/https://doi.org/10.1186/...	RCT DB PC n=160	Anthropometry at birth	IG: 35,000 IU/week; PG IT: GA 26-29 weeks	$\bar{x}$ Weight, height, and CP: PG versus IG (p=0.86, p=0.55, and p=0.71)
Roth, 2013¹²12. Roth DE, Perumal N, Al Mahmud 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. J Pediatr. 2013;163:1605-11. https://doi.org/10.1016/j.jpeds.2013.07.030 https://doi.org/https://doi.org/10.1016/...	RCT n=160	H/A from birth to one year old	IG: 35,000 IU/week; PG IT: GA 26<30 weeks until delivery	Z score H/A at birth: IG -0.56 versus PG -0.82 (p=0.14) Z score H/A (1 year old): IG -0.89 versus PG -1.33 (p=0.02)
Harrington, 2014³⁹39. 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;76:302-9. https://doi.org/10.1038/pr.2014.83 https://doi.org/https://doi.org/10.1038/...	RCT DB PC n=132	Ca and 25(OH)D	IG: 35,000 IU/week; PG IT: GA 26-30 weeks until delivery	$\bar{x}$ [25(OH)D] of UC: IG 102.8 nmol/L versus PG 39 nmol/L (p<0.01) $\bar{x}$ [Ca] of UC: IG: 2.66 nmol/L versus PG: 2.61 mmol/L (p=0.04) $\bar{x}$ [Ca] 3^rd day of life: IG 2.53 nmol/L versus PG 2.45 mmol/L (p=0.08)
Hashemipour, 2014¹⁶16. 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. Eur J Obstet Gynecol Reprod Biol. 2014;172:15-9. https://doi.org/10.1016/j.ejogrb.2013.10.010 https://doi.org/https://doi.org/10.1016/...	RCT O n=109	Anthropometry at birth	IG: 50,000 IU/week for eight weeks; PG: 400 IU/day+200 mg of calcium/day IT: GA 24-26 weeks until delivery	$\bar{x}$ height: IG 49 cm versus PG 48.2 cm (p=0.001), CP: IG 35.9 cm versus PG 35.3 cm (p=0.001), and weight: IG 3,429 g versus PG 3,258.8 g (p=0.01)
Asemi, 2015¹³13. 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. Horm Metab Res. 2015;47:565-70. https://doi.org/10.1055/s-0034-1394414 https://doi.org/https://doi.org/10.1055/...	RCT DB PC n=45	Anthropometry at birth and hyperbilirubinemia	Pregnant women with GDM. IG: 2x of 50,000 IU; PG IT: GA 24-28 weeks	Weight, height, and CP: PG versus IG (p=0.39, p=0.46, and p=0.62) Neonatal hyperbilirubinemia: PG 60.9% versus IG 27.3% (p=0.02)
Diogenes, 2015⁴⁰40. 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;145:1515-23. https://doi.org/10.3945/jn.114.208140 https://doi.org/https://doi.org/10.3945/...	RCT PC n=52	Bone pattern (5 weeks)	Pregnant adolescents. IG: 200 IU/day+600 mg/day of Ca; PG. IT: GA 21-29 weeks until delivery	$\bar{x}$ BMC, BA, and BMD: IG versus PG (p=0.63; p=0.55, and p=0.34)
Vaziri, 2016¹⁴14. Vaziri F, Dabbaghmanesh MH, Samsami A, Nasiri S, Shirazi PT. Vitamin D supplementation during pregnancy on infant anthropometric measurements and bone mass of mother-infant pairs: a randomized placebo clinical trial. Early Hum Dev. 2016;103:61-8. https://doi.org/10.1016/j.earlhumdev.2016.07.011 https://doi.org/https://doi.org/10.1016/...	RCT DB PC n=127	Anthropometry	IG: 2,000 IU/day until delivery; PG IT: GA 26-28 weeks until delivery	$\bar{x}$ Weight, height, and CP (at birth, 4 and 8 weeks): IG versus PG (p>0.05)
Cooper, 2016⁴¹41. Cooper C, Harvey NC, Bishop NJ, Kennedy S, Papageorghiou AT, Schoenmakers I, et al. Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial. Lancet Diabetes Endocrinol. 2016;4:393-402. https://doi.org/10.1016/S2213-8587(16)00044-9 https://doi.org/https://doi.org/10.1016/...	RCT DB PC n=965	Bone pattern at birth	IG: 1,000 IU/day; PG IT: IG 14 weeks until delivery	Bone mineral content (DXA): IG 61.6 g versus PG 60.5 g (p=0.21)
Abotorabi, 2017¹⁵15. Abotorabi S, Poor S, Esmailzadehha N, Ziaee A, Khoeiniha M. Effect of treatment with vitamin D on maternal and neonatal indices in pregnant women with hypocalcemia: a randomized controlled trial. Int J Pediatr. 2017;5:5733-9. https://doi.org/10.22038/IJP.2017.22146.1851 https://doi.org/https://doi.org/10.22038...	RCT n=110	Anthropometry at birth	Pregnant women with mild hypocalcemia and VDD IG: 50,000 IU/week for eight weeks; PG IT: GA 22-26 weeks until delivery	$\bar{x}$ Weight, height, and CP: G1 versus PG (p>0.05)
Sahoo, 2017⁴²42. Sahoo SK, Katam KK, Das V, Agarwal A, Bhatia V. Maternal vitamin D supplementation in pregnancy and offspring outcomes: a double-blind randomized placebo-controlled trial. J Bone Miner Metab. 2017;35:464-71. https://doi.org/10.1007/s00774-016-0777-4 https://doi.org/https://doi.org/10.1007/...	RCT DB PC n=150 with severe VDD	25(OH)D and bone pattern (12-16 months)	IG1: 60,000 IU/week (D3) for four weeks + 1 g Ca; IG2: 60,000 IU/week for eight weeks+1 g Ca; PG: 400 IU/day. IT: GA 14-20 weeks until delivery	[25(OH)D] of UC: IG1 47.8 17.8 nmol/L versus IG2 31 17.8 nmol/L versus PG 17.8 nmol/L (p<0.01) Entire body BMC: IG1 213.1 g versus IG2 202.9 g versus PG 250.8 g (p=0.006) BMD: IG1 0.295 g/cm² versus IG2 0.287 g/cm² versus PG 0.335 g/cm² (p=0.001)
Roth, 2018¹⁷17. Roth DE, Morris SK, Zlotkin S, Gernand AD, Ahmed T, Shanta SS, et al. Vitamin D supplementation in pregnancy and lactation and infant growth. N Engl J Med. 2018;379:535-46. https://doi.org/10.1056/NEJMoa1800927 https://doi.org/https://doi.org/10.1056/...	RCT DB PC n=1,300	Anthropometry at birth and follow-up	IG1: 4,200 IU/week; IG2: 16,800 IU/week; IG3: 28,000 IU/week from 17-24 weeks until delivery IG4: 28,000 IU/day of birth to 26 weeks; PG	$\bar{x}$ Weight, height, and CP at birth and at 12 months old (p>0.05)

Author, year	Methods			Main results
Author, year	Design	Outcome	Intervention	Main results
Griffiths, 2015⁴⁹49. Griffiths M, Goldring S, Griffiths C, Shaheen SO, Martineau A, Cross L, et al. Effects of pre-natal vitamin D supplementation with partial correction of vitamin d deficiency on early life healthcare utilisation: a randomised controlled trial. PLoS One. 2015;10:e0145303. https://doi.org/10.1371/journal.pone.0145303 https://doi.org/https://doi.org/10.1371/...	RCT PC n=180	Cost of health services (for three years)	IG1: 800 IU/day (D2) until delivery; IG2: 1x of 200,000 IU (D3); PG IT: GA 27 weeks until delivery	Mean difference in total costs: IG1 versus PG (1.07; 95%CI -1.62; 1.86); IG2 versus PG (1.06; -1.40, 95%CI -2.45; 1.24)
Grant, 2015⁴⁴44. Grant CC, Kaur S, Waymouth E, Mitchell EA, Scragg R, Ekeroma A, et al. Reduced primary care respiratory infection visits following pregnancy and infancy vitamin D supplementation: a randomised controlled trial. Acta Paediatr. 2015;104:396-404. https://doi.org/10.1111/apa.12819 https://doi.org/https://doi.org/10.1111/...	RCT DB PC n=236	Acute respiratory infection	IG1: 1,000 IU/day (mother)/400 IU/day (baby) (D3); IG2: 2,000 IU/day (mother)/800 IU/day (baby) (D3); PG IT: GA 27 weeks until delivery and until babies are six months old	% of children who visited the hospital due to acute respiratory infection: PG 99% versus IG2 87% (p=0.004), and PG 99% versus IG1 76% (p=0.17) No. of visits between 6 and 18 months old: PG 4 versus IG1 3 versus IG2 2.5 (p=0.048)
Grant, 2016⁴⁵45. Grant CC, Crane J, Mitchell EA, Sinclair J, Stewart A, Milne T, et al. Vitamin D supplementation during pregnancy and infancy reduces aeroallergen sensitization: a randomized controlled trial. Allergy. 2016;71:1325-34. https://doi.org/10.1111/all.12909 https://doi.org/https://doi.org/10.1111/...	RCT DB PC n=260	Sensitization to aeroallergens and atopic respiratory diseases	IG1: 1,000 IU/day (mother)/400 IU/day (baby) (D3); IG2: 2,000 IU/day (mother)/800 IU/day (baby) (D3); PG. IT: GA 27 weeks until delivery and until babies are six months old	Sensitized children differed for four mite antigens: Der-f1, Der-f2, Der-p1, and Der-p2: PG, IG1, and IG2, respectively (all with p<0.05): Der-f1 (18, 10, 2%); Der-f2 (14, 3, 2%); Der-p1 (19, 14, 3%); and Der-p2 (12, 2, 3%). Visits to the hospital due to asthma: PG 11%, IG1 0%, IG2 4%, p=0.002
Chawes, 2016⁴⁶46. Chawes BL, Bønnelykke K, Stokholm J, Vissing NH, Bjarnadóttir E, Schoos AM, et al. Effect of Vitamin D3 supplementation during pregnancy on risk of persistent wheeze in the offspring: a randomized clinical trial. JAMA. 2016;315:353-61. https://doi.org/10.1001/jama.2015.18318 https://doi.org/https://doi.org/10.1001/...	RCT DB PC n=581	Persistent wheezing	IG: 2,800 IU/day (D3); PG: 400 IU/day (D3) IT: GA 24 weeks until one week postpartum	Persistent wheezing: IG 47 (16%) versus PG 57 (20%) (HR 0.76; p=0.16). $\bar{x}$ of symptom episodes: IG 5.9 versus PG 7.2 (IRR 0.83; p=0.02)
Anderson, 2018⁵⁰50. 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;13:371-80. https://doi.org/10.1089/bfm.2017.0231 https://doi.org/https://doi.org/10.1089/...	RCT DB PC n=29	DNA methylation	IG: 3,800 IU/day; PG: 400 IU/day IT: GA 24-28 weeks to six weeks postpartum	$\bar{x}$ [25(OH)D] of UC: IG: 32.3 ng/mL / PG: 23.7 ng/mL (p<0.05) and at 4-6 weeks of life: IG: 24.9 ng/mL / PG: 11.4 ng/mL (p<0.10) DNA methylation at 4-6 weeks of life: IG 217 CpGs expressed collagen metabolic processes and 213 CpGs failed to express apoptosis regulation (p<0.05)
Sordillo, 2017⁵³53. Sordillo JE, Zhou Y, McGeachie MJ, Ziniti J, Lange N, Laranjo N, et al. Factors influencing the infant gut microbiome at age 3-6 months: findings from the ethnically diverse Vitamin D Antenatal Asthma Reduction Trial (VDAART). J Allergy Clin Immunol. 2017;139:482-91. https://doi.org/10.1016/j.jaci.2016.08.045 https://doi.org/https://doi.org/10.1016/...	RCT DB PC n=333	Intestinal microbiota	IG 4,000 IU/day; PG 400 IU/day IT: GA 10-18 weeks until delivery	VD of the UC was linked to an increase in Lachnobacterium (p=0.039), but decreased Lactococcus (p=0.03)
Mirzakhani, 2019⁴⁷47. Mirzakhani H, Al-Garawi AA, Carey VJ, Qiu W, Litonjua AA, Weiss ST. Expression network analysis reveals cord blood vitamin D-associated genes affecting risk of early life wheeze. Thorax. 2019;74:200-2. http://dx.doi.org/10.1136/thoraxjnl-2018-211962 https://doi.org/http://dx.doi.org/10.113...	RCT DB PC n=169	Expression of VD of the UC associated genes and wheezing risk (1^st year)	IG: 4,400 IU/day; PG: 400 IU/day IT: between 10 and 18 weeks	Mutation in the Lyn, Notch1, and PHF12 genes was significantly associated to the risk of wheezing in the first year of life (p<0.01). Median [25(OH)D] (>31 ng/mL versus <13 ng/mL) (p=0.03)
Newton, 2019⁵¹51. Newton DA, Baatz JE, Kindy MS, Gattoni-Celli S, Shary JR, Hollis BW, et al. Vitamin D binding protein polymorphisms significantly impact vitamin D status in children. Pediatr Res. 2019;86:662-9. https://doi.org/10.1038/s41390-019-0322-y https://doi.org/https://doi.org/10.1038/...	RCT DB PC n=513	25(OH)D with SNV of GC	IG1: 2,000 IU/day; IG2: 4,000 IU/day PG: 400 IU/day IT: GA between 12 and 16 weeks	African-American children: $\bar{x}$ 25(OH)D higher for the 20% carriers of the VDBP 1S allele (77 versus 61 nmol/L; p=0.038). Children with homozygous Gc1S/1S genotype who reached ADR of VD: $\bar{x}$ 25(OH)D 51% higher (p<0.001)
Schoos, 2019⁴⁸48. Schoos AM, Vinther C, Nørgaard S, Brustad N, Stokholm J, Bonnelykke K, et al. Environmental and genetic determinants of serum 25(oh)-vitamin D levels during pregnancy and early childhood. Children (Basel). 2019;6:116. https://doi.org/10.3390/children6100116 https://doi.org/https://doi.org/10.3390/...	RCT DB PC n=623	SNV of GC and 25(OH)D related to asthma	IG: 2,800 IU/day; PG: 400 IU/day IT: GA 24 weeks to one week postpartum	There was variation in the concentration of 25(OH)D in pregnant women with SNV rs4588, at 24 weeks postpartum (p<0.001)
Nørrisgaard, 2019⁴³43. Nørrisgaard PE, Haubek D, Kühnisch J, Chawes BL, Stokholm J, Bønnelykke K, et al. Association of high-dose vitamin D supplementation during pregnancy with the risk of enamel defects in offspring: a 6-year follow-up of a randomized clinical trial. JAMA Pediatr. 2019;173:924-30. https://doi.org/10.1001/jamapediatrics.2019.2545 https://doi.org/https://doi.org/10.1001/...	RCT DB PC n=623	Dental enamel and caries	IG: 2,800 IU/day; PG: 400 IU/day IT: GA 24 weeks to one week postpartum	Enamel defects in permanent dentition: IG 15.1% versus PG 27.5%; Odds Ratio=0.47; (95%CI, 0.27-0.81). Caries (p>0.05)
Bilic, 2019⁵²52. Bilic M, Qamar H, Onoyovwi A, Korsiak J, Papp E, Mahmud A, et al. Prenatal vitamin D and cord blood insulin-like growth factors in Dhaka, Bangladesh. Endocr Connect. 2019;8:745-53. https://doi.org/10.1530/EC-19-0123 https://doi.org/https://doi.org/10.1530/...	RCT PC n=559	IGF at birth (UC)	IG1: 4,200 IU/week; IG2: 16,800 IU/week IG3: 28,000 IU/week; PG TI: GA 17-24 weeks until delivery	IGF-I (p=0.398), IGF-II (p=0.525), binding proteins (BPs) IGFBP-1 (p=0.170), IGFBP-3 (p=0.203), or the molar ratio of IGF-I/IGFBP-3 (p=0.941)

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[1] *Corresponding author. E-mail: tkmed@uol.com.br (T. Konstantyner).