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Figure 1.
Flowchart of Study Selection Process
Flowchart of Study Selection Process

RCT indicates randomized clinical trial.

Figure 2.
Summary Risk Ratio (RR) of the Association Between Vitamin D Supplementation and Small for Gestational Age (SGA)
Summary Risk Ratio (RR) of the Association Between Vitamin D Supplementation and Small for Gestational Age (SGA)

Subgroup analyses by timing (initiation at <20 or ≥20 weeks of gestation) (A) and dose (>2000 or ≤2000 IU/d) (B). Diamond at the bottom represents the pooled point estimate (95% CIs) for each outcome of interest.

Figure 3.
Summary Risk Ratio (RR) of the Association Between Vitamin D Supplementation and Fetal or Neonatal Mortality
Summary Risk Ratio (RR) of the Association Between Vitamin D Supplementation and Fetal or Neonatal Mortality

Subgroup analyses by timing (initiation at <20 or ≥20 weeks of gestation) (A) and dose (>2000 or ≤2000 IU/d) (B). Diamond at the bottom represents the pooled point estimate (95% CIs) for each outcome of interest.

Table.  
Characteristics of Included Randomized Clinical Trials
Characteristics of Included Randomized Clinical Trials
1.
Urrutia-Pereira  M, Solé  D.  Vitamin D deficiency in pregnancy and its impact on the fetus, the newborn and in childhood [Portuguese].  Rev Paul Pediatr. 2015;33(1):104-113.PubMedGoogle ScholarCrossref
2.
Nair  R, Maseeh  A.  Vitamin D: the “sunshine” vitamin.  J Pharmacol Pharmacother. 2012;3(2):118-126.PubMedGoogle Scholar
3.
Palacios  C, De-Regil  LM, Lombardo  LK, Peña-Rosas  JP.  Vitamin D supplementation during pregnancy: updated meta-analysis on maternal outcomes.  J Steroid Biochem Mol Biol. 2016;164:148-155.PubMedGoogle ScholarCrossref
4.
Thorne-Lyman  A, Fawzi  WW.  Vitamin D during pregnancy and maternal, neonatal and infant health outcomes: a systematic review and meta-analysis.  Paediatr Perinat Epidemiol. 2012;26(suppl 1):75-90.PubMedGoogle ScholarCrossref
5.
Mulligan  ML, Felton  SK, Riek  AE, Bernal-Mizrachi  C.  Implications of vitamin D deficiency in pregnancy and lactation.  Am J Obstet Gynecol. 2010;202(5):429.e1-429.e9.PubMedGoogle ScholarCrossref
6.
Ladipo  OA.  Nutrition in pregnancy: mineral and vitamin supplements.  Am J Clin Nutr. 2000;72(1)(suppl):280S-290S.PubMedGoogle ScholarCrossref
7.
Kaushal  M, Magon  N.  Vitamin D in pregnancy: a metabolic outlook.  Indian J Endocrinol Metab. 2013;17(1):76-82.PubMedGoogle ScholarCrossref
8.
Moher  D, Shamseer  L, Clarke  M,  et al; PRISMA-P Group.  Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) 2015 statement.  Syst Rev. 2015;4:1.PubMedGoogle ScholarCrossref
9.
Higgins  JP, Altman  DG, Gøtzsche  PC,  et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group.  The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.  BMJ. 2011;343:d5928.PubMedGoogle ScholarCrossref
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Higgins  JP, Thompson  SG.  Quantifying heterogeneity in a meta-analysis.  Stat Med. 2002;21(11):1539-1558.PubMedGoogle ScholarCrossref
11.
Manager  R. (RevMan) [computer program]. Version 5.3. Copenhagen, Denmark: The Cochrane Collaboration; 2014.
12.
Brooke  OG, Brown  IR, Bone  CD,  et al.  Vitamin D supplements in pregnant Asian women: effects on calcium status and fetal growth.  BMJ. 1980;280(6216):751-754.PubMedGoogle ScholarCrossref
13.
Chawes  BL, Bønnelykke  K, Stokholm  J,  et al.  Effect of vitamin D3 supplementation during pregnancy on risk of persistent wheeze in the offspring: a randomized clinical trial.  JAMA. 2016;315(4):353-361.PubMedGoogle ScholarCrossref
14.
Cooper  C, Harvey  NC, Bishop  NJ,  et al; MAVIDOS Study Group.  Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial.  Lancet Diabetes Endocrinol. 2016;4(5):393-402.PubMedGoogle ScholarCrossref
15.
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(6):2337-2346.PubMedGoogle ScholarCrossref
16.
Delvin  EE, Salle  BL, Glorieux  FH, Adeleine  P, David  LS.  Vitamin D supplementation during pregnancy: effect on neonatal calcium homeostasis.  J Pediatr. 1986;109(2):328-334.PubMedGoogle ScholarCrossref
17.
Goldring  ST, Griffiths  CJ, Martineau  AR,  et al.  Prenatal vitamin D supplementation and child respiratory health: a randomised controlled trial.  PLoS One. 2013;8(6):e66627.PubMedGoogle ScholarCrossref
18.
Grant  CC, Stewart  AW, Scragg  R,  et al.  Vitamin D during pregnancy and infancy and infant serum 25-hydroxyvitamin D concentration.  Pediatrics. 2014;133(1):e143-e153.PubMedGoogle ScholarCrossref
19.
Hashemipour  S, Ziaee  A, Javadi  A,  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;172:15-19.PubMedGoogle ScholarCrossref
20.
Hollis  BW, Johnson  D, Hulsey  TC, Ebeling  M, Wagner  CL.  Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness.  J Bone Miner Res. 2011;26(10):2341-2357.PubMedGoogle ScholarCrossref
21.
Hossain  N, Kanani  FH, Ramzan  S,  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(7):2448-2455.PubMedGoogle ScholarCrossref
22.
Kalra  P, Das  V, Agarwal  A,  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(6):1052-1058.PubMedGoogle ScholarCrossref
23.
Karamali  M, Beihaghi  E, Mohammadi  AA, Asemi  Z.  Effects of high-dose vitamin D supplementation on metabolic status and pregnancy outcomes in pregnant women at risk for pre-eclampsia.  Horm Metab Res. 2015;47(12):867-872.PubMedGoogle ScholarCrossref
24.
Litonjua  AA, Carey  VJ, Laranjo  N,  et al.  Effect of prenatal supplementation with vitamin D on asthma or recurrent wheezing in offspring by age 3 years: the VDAART randomized clinical trial.  JAMA. 2016;315(4):362-370.PubMedGoogle ScholarCrossref
25.
Mallet  E, Gügi  B, Brunelle  P, Hénocq  A, Basuyau  JP, Lemeur  H.  Vitamin D supplementation in pregnancy: a controlled trial of two methods.  Obstet Gynecol. 1986;68(3):300-304.PubMedGoogle ScholarCrossref
26.
March  KM, Chen  NN, Karakochuk  CD,  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(2):402-410.PubMedGoogle ScholarCrossref
27.
Marya  RK, Rathee  S, Dua  V, Sangwan  K.  Effect of vitamin D supplementation during pregnancy on foetal growth.  Indian J Med Res. 1988;88:488-492.PubMedGoogle Scholar
28.
Mojibian  M, Soheilykhah  S, Fallah Zadeh  MA, Jannati Moghadam  M.  The effects of vitamin D supplementation on maternal and neonatal outcome: a randomized clinical trial.  Iran J Reprod Med. 2015;13(11):687-696.PubMedGoogle Scholar
29.
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(3):363-368.PubMedGoogle ScholarCrossref
30.
Roth  DE, Al Mahmud  A, Raqib  R,  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.PubMedGoogle ScholarCrossref
31.
Sablok  A, Batra  A, Thariani  K,  et al.  Supplementation of vitamin D in pregnancy and its correlation with feto-maternal outcome.  Clin Endocrinol (Oxf). 2015;83(4):536-541.PubMedGoogle ScholarCrossref
32.
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(4):464-471.PubMedGoogle ScholarCrossref
33.
Yap  C, Cheung  NW, Gunton  JE,  et al.  Vitamin D supplementation and the effects on glucose metabolism during pregnancy: a randomized controlled trial.  Diabetes Care. 2014;37(7):1837-1844.PubMedGoogle ScholarCrossref
34.
Yesiltepe Mutlu  G, Ozsu  E, Kalaca  S,  et al.  Evaluation of vitamin D supplementation doses during pregnancy in a population at high risk for deficiency.  Horm Res Paediatr. 2014;81(6):402-408.PubMedGoogle ScholarCrossref
35.
Zerofsky  MS, Jacoby  BN, Pedersen  TL, Stephensen  CB.  Daily cholecalciferol supplementation during pregnancy alters markers of regulatory immunity, inflammation, and clinical outcomes in a randomized controlled trial.  J Nutr. 2016;146(11):2388-2397.PubMedGoogle ScholarCrossref
36.
Yu  CK, Sykes  L, Sethi  M, Teoh  TG, Robinson  S.  Vitamin D deficiency and supplementation during pregnancy.  Clin Endocrinol (Oxf). 2009;70(5):685-690.PubMedGoogle ScholarCrossref
37.
Chakhtoura  M, El Ghandour  S, Shawwa  K,  et al.  Vitamin D replacement in children, adolescents and pregnant women in the Middle East and North Africa: a systematic review and meta-analysis of randomized controlled trials.  Metabolism. 2017;70:160-176.PubMedGoogle ScholarCrossref
38.
Yang  N, Wang  L, Li  Z, Chen  S, Li  N, Ye  R.  Effects of vitamin D supplementation during pregnancy on neonatal vitamin D and calcium concentrations: a systematic review and meta-analysis.  Nutr Res. 2015;35(7):547-556.PubMedGoogle ScholarCrossref
39.
De-Regil  LM, Palacios  C, Lombardo  LK, Peña-Rosas  JP.  Vitamin D supplementation for women during pregnancy.  Cochrane Database Syst Rev. 2016;(1):CD008873.PubMedGoogle Scholar
40.
Pérez-López  FR, Pasupuleti  V, Mezones-Holguin  E,  et al.  Effect of vitamin D supplementation during pregnancy on maternal and neonatal outcomes: a systematic review and meta-analysis of randomized controlled trials.  Fertil Steril. 2015;103(5):1278-1288.e4.PubMedGoogle ScholarCrossref
41.
Viljakainen  HT, Saarnio  E, Hytinantti  T,  et al.  Maternal vitamin D status determines bone variables in the newborn.  J Clin Endocrinol Metab. 2010;95(4):1749-1757.PubMedGoogle ScholarCrossref
42.
Hines  EA, Coffey  JD, Starkey  CW, Chung  TK, Starkey  JD.  Improvement of maternal vitamin D status with 25-hydroxycholecalciferol positively impacts porcine fetal skeletal muscle development and myoblast activity.  J Anim Sci. 2013;91(9):4116-4122.PubMedGoogle ScholarCrossref
43.
Crozier  SR, Harvey  NC, Inskip  HM, Godfrey  KM, Cooper  C, Robinson  SM; SWS Study Group.  Maternal vitamin D status in pregnancy is associated with adiposity in the offspring: findings from the Southampton Women’s Survey.  Am J Clin Nutr. 2012;96(1):57-63.PubMedGoogle ScholarCrossref
44.
Kovacs  CS, Kronenberg  HM.  Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation.  Endocr Rev. 1997;18(6):832-872.PubMedGoogle Scholar
45.
Ji  JL, Muyayalo  KP, Zhang  YH, Hu  XH, Liao  AH.  Immunological function of vitamin D during human pregnancy.  Am J Reprod Immunol. 2017;78(2).PubMedGoogle Scholar
46.
Farhangi  MA, Mesgari-Abbasi  M, Hajiluian  G, Nameni  G, Shahabi  P.  Adipose tissue inflammation and oxidative stress: the ameliorative effects of vitamin D.  Inflammation. 2017;40(5):1688-1697.PubMedGoogle ScholarCrossref
47.
Shin  JS, Choi  MY, Longtine  MS, Nelson  DM.  Vitamin D effects on pregnancy and the placenta.  Placenta. 2010;31(12):1027-1034.PubMedGoogle ScholarCrossref
48.
Nguyen  TP, Yong  HE, Chollangi  T, Borg  AJ, Brennecke  SP, Murthi  P.  Placental vitamin D receptor expression is decreased in human idiopathic fetal growth restriction.  J Mol Med (Berl). 2015;93(7):795-805.PubMedGoogle ScholarCrossref
49.
Chan  SY, Susarla  R, Canovas  D,  et al.  Vitamin D promotes human extravillous trophoblast invasion in vitro.  Placenta. 2015;36(4):403-409.PubMedGoogle ScholarCrossref
50.
Nguyen  M, Trubert  CL, Rizk-Rabin  M,  et al.  1,25-Dihydroxyvitamin D3 and fetal lung maturation: immunogold detection of VDR expression in pneumocytes type II cells and effect on fructose 1,6 bisphosphatase.  J Steroid Biochem Mol Biol. 2004;89-90(1-5):93-97.PubMedGoogle ScholarCrossref
51.
Nguyen  TM, Guillozo  H, Marin  L, Tordet  C, Koite  S, Garabedian  M.  Evidence for a vitamin D paracrine system regulating maturation of developing rat lung epithelium.  Am J Physiol. 1996;271(3, pt 1):L392-L399.PubMedGoogle Scholar
52.
Litonjua  AA.  Childhood asthma may be a consequence of vitamin D deficiency.  Curr Opin Allergy Clin Immunol. 2009;9(3):202-207.PubMedGoogle ScholarCrossref
53.
Christensen  N, Søndergaard  J, Fisker  N, Christesen  HT.  Infant respiratory tract infections or wheeze and maternal vitamin D in pregnancy: a systematic review.  Pediatr Infect Dis J. 2017;36(4):384-391.PubMedGoogle ScholarCrossref
Original Investigation
July 2018

Association Between Vitamin D Supplementation During Pregnancy and Offspring Growth, Morbidity, and Mortality: A Systematic Review and Meta-analysis

Author Affiliations
  • 1Centre Hospitalier Universitaire Saint-Justine Research Center, University of Montréal, Montréal, Quebec, Canada
  • 2Department of Obstetrics and Gynecology, University of Montréal, Montréal, Quebec, Canada
  • 3Department of Pediatrics; Faculty of Medicine, University of Montréal, Montréal, Quebec, Canada
  • 4School of Human Nutrition, McGill University, Montréal, Quebec, Canada
JAMA Pediatr. 2018;172(7):635-645. doi:10.1001/jamapediatrics.2018.0302
Key Points

Question  Is vitamin D supplementation during pregnancy beneficial and safe for offspring?

Findings  In this systematic review and meta-analysis of 24 randomized clinical trials including 5405 individuals, vitamin D supplementation during pregnancy was associated with a lower risk of infants being small for gestational age and improved growth during infancy without an increased risk of fetal or neonatal mortality or congenital abnormality.

Meaning  Vitamin D supplementation during pregnancy may reduce the risk of infants being small for gestational age and improve growth during infancy without an increased risk of fetal or neonatal mortality or congenital abnormality.

Abstract

Importance  Whether vitamin D supplementation during pregnancy is beneficial and safe for offspring is unclear.

Objective  To systematically review studies of the effects of vitamin D supplementation during pregnancy on offspring growth, morbidity, and mortality.

Data Sources  Searches of Medline, Embase, and the Cochrane Database of Systematic Reviews were conducted up to October 31, 2017. Key search terms were vitamin D, pregnancy, randomized controlled trials, and offspring outcomes.

Study Selection  Randomized clinical trials of vitamin D supplementation during pregnancy and offspring outcomes.

Data Extraction and Synthesis  Two authors independently extracted data, and the quality of the studies was assessed. Summary risk ratio (RR), risk difference (RD) or mean difference (MD), and 95% CI were calculated using fixed-effects or random-effects meta-analysis.

Main Outcomes and Measures  Main outcomes were fetal or neonatal mortality, small for gestational age (SGA), congenital malformation, admission to a neonatal intensive care unit, birth weight, Apgar scores, neonatal 25-hydroxyvitamin D (25[OH]D) and calcium concentrations, gestational age, preterm birth, infant anthropometry, and respiratory morbidity during childhood.

Results  Twenty-four clinical trials involving 5405 participants met inclusion criteria. Vitamin D supplementation during pregnancy was associated with a lower risk of SGA (RR, 0.72; 95% CI, 0.52 to 0.99; RD, −5.60%; 95% CI, −0.86% to −10.34%) without risk of fetal or neonatal mortality (RR, 0.72; 95% CI, 0.47 to 1.11) or congenital abnormality (RR, 0.94; 95% CI, 0.61 to 1.43). Neonates with prenatal vitamin D supplementation had higher 25(OH)D levels (MD, 13.50 ng/mL; 95% CI, 10.12 to 16.87 ng/mL), calcium levels (MD, 0.19 mg/dL; 95% CI, 0.003 to 0.38 mg/dL), and weight at birth (MD, 75.38 g; 95% CI, 22.88 to 127.88 g), 3 months (MD, 0.21 kg; 95% CI, 0.13 to 0.28 kg), 6 months (MD, 0.46 kg; 95% CI, 0.33 to 0.58 kg), 9 months (MD, 0.50 kg; 95% CI, 0.01 to 0.99 kg), and 12 months (MD, 0.32 kg; 95% CI, 0.12 to 0.52 kg). Subgroup analysis by doses showed that low-dose vitamin D supplementation (≤2000 IU/d) was associated with a reduced risk of fetal or neonatal mortality (RR, 0.35; 95% CI, 0.15 to 0.80), but higher doses (>2000 IU/d) did not reduce this risk (RR, 0.95; 95% CI, 0.59 to 1.54).

Conclusions and Relevance  Vitamin D supplementation during pregnancy is associated with a reduced risk of SGA and improved infant growth without risk of fetal or neonatal mortality or congenital abnormality. Vitamin D supplementation with doses of 2000 IU/d or lower during pregnancy may reduce the risk of fetal or neonatal mortality.

Introduction

Low maternal vitamin D level status is common during pregnancy and is a public health issue worldwide.1-3 Vitamin D, a fat-soluble nutrient and prohormone,2 has classic functions of calcium absorption, metabolism, and bone health and nonclassic actions that may affect various other aspects of health.4 Low vitamin D level status during pregnancy may expose the offspring to a suboptimal nutritional environment during critical phases of fetal development and may have long-term effects on offspring health outcomes.3,5,6 Sufficient vitamin D concentrations are needed during pregnancy to address the increased demand of fetal growth and development because the mother provides all of the vitamin D for the fetus.7

During the past few decades, emerging randomized clinical trials (RCTs) have assessed the effect of vitamin D supplementation during pregnancy on maternal, neonatal, infant, or child outcomes. However, the results of the RCTs are inconsistent.2 There is a lack of evidence from systematic reviews and meta-analyses to evaluate the association between vitamin D supplementation during pregnancy and offspring growth, morbidity, and mortality.4 Given the high prevalence of low vitamin D level status during pregnancy and the public health importance of clarifying the role of vitamin D during pregnancy in offspring health, we conducted a systematic review and meta-analysis of RCTs with aims to evaluate the effectiveness and safety of vitamin D supplementation during pregnancy on offspring outcomes.

Methods
Data Sources and Searches

This systematic review is presented according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.8 Medline, Embase, and the Cochrane Database of Systematic Reviews were searched up to October 31, 2017. The key words used were vitamin D, pregnancy, randomized controlled trials, and offspring outcomes. References cited in these articles were manually searched to identify additional RCTs.

Study Selection

Two investigators (W.G.B. and S.Q.W.) independently scrutinized the electronic searches and obtained full articles of all citations that were potentially eligible studies for inclusion. Full-length articles of studies evaluating maternal vitamin D supplementation in pregnancy and offspring outcomes were examined and subsequently selected if they fulfilled the following inclusion criteria: (1) the design was an RCT; (2) population was healthy, pregnant women without prior vitamin D supplementation of more than 400 IU/d; (3) vitamin D protocol was specified in the treatment group; (4) outcomes were offspring growth, morbidity, and mortality; (5) the study contained relevant data to calculate the effect size; and (6) the study met the methodologic quality assessment criteria for RCTs.9 Articles were excluded if (1) they were reviews, observational studies, case reports, letters, or comments; (2) there was no appropriate control group; (3) vitamin D dose in the intervention group was 400 IU/d or less; or (4) data were incomplete or conflicting.

Primary outcomes were (1) small for gestational age (SGA), indicated by birth weight less than the 10th percentile for gestational age, and (2) fetal or neonatal mortality. Secondary outcomes were (1) neonatal 25-hydroxyvitamin D (25[OH]D) levels, (2) congenital malformation, (3) admission to a neonatal intensive care unit (NICU), (4) Apgar scores, (5) neonatal calcium levels, (6) birth weight, (7) low birth weight, (8) gestational age, (9) preterm birth, (10) infant growth, (11) asthma, (12) respiratory infection, (13) eczema, and (14) allergy.

Quality Assessment

We evaluated the methodologic quality of each eligible RCT using the Cochrane Risk Assessment Tool (eTable in the Supplement).9 The following items were evaluated: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other biases. For all RCTs, each item was described as having a low risk of bias, a high risk of bias, or an unclear risk of bias.9

Data Extraction and Synthesis

The following information was extracted from the study reports: the first author’s last name, year of publication, country of origin, study design, total sample size, characteristics of participants, timing of supplementation, interventions, and outcomes. When the study had 2 or more intervention groups with different doses of vitamin D supplementation, we combined them into 1 intervention group. Two of us (W.G.B. and S.Q.W.) extracted the data independently and in duplicate. Discrepancies were resolved through discussion to achieve a consensus.

Subgroup analyses were performed according to timing (initiation at <20 or ≥20 weeks’ gestation), dose (>2000 or ≤2000 IU/d), and method (regular or bolus doses) of vitamin D supplementation for the outcomes of SGA, fetal or neonatal mortality, neonatal blood 25(OH)D concentration, and birth weight.

Statistical Analysis

Data on dichotomous outcomes were combined using the Mantel-Haenszel method, and measures of effect are presented as risk ratios (RRs) or risk differences with 95% CIs. For continuous data, we calculated the sample size–weighted mean difference (MD) when outcomes were measured in the same way between studies. We used forest plots to show the point estimate (95% CIs) for each study. The I2 statistic (percentage of variability in the results that is due to heterogeneity) was used to quantify the degree of heterogeneity across studies.10 If the I2 value was 50% or greater, the heterogeneity was considered significant and we pooled results using a random-effects model. Otherwise, a fixed-effect model was applied. Funnel plots were applied to evaluate publication bias. The data were extracted and statistical analysis was carried out using Review Manager, version 5.3 (RevMan).11 Two-tailed P < .05 values were considered statistically significant.

Results
Study Selection

The search strategy resulted in 728 potentially relevant citations. The PRISMA flow diagram (Figure 1) summarizes the process of the literature search and selection of studies. After screening the titles and abstracts, we read 56 articles. Twenty-four RCTs12-36 comprising 5405 participants met the inclusion criteria. Two of these trials are from the same RCT with different outcomes.17,36 The assessment of methodologic quality of each eligible RCT by the Cochrane Risk Assessment Tool is summarized in the eTable in the Supplement.

Study Characteristics

The characteristics of the included RCTs are summarized in the Table. Vitamin D supplementation was in the form of cholecalciferol in 22 RCTs13-24,26-35 and in the form of ergocalciferol in 3 RCTs.12,17,25 For the intervention group, the daily doses were 800 IU in 1 RCT,17 1000 IU in 6 RCTs,12,14,16,18,25,26 1200 IU in 1 RCT,34 2000 IU in 7 RCTs,15,18,20,26,29,34,35 2800 IU in 1 RCT,13 4000 IU in 4 RCTs,15,20,21,29 4400 in 1 RCT,24 or 5000 IU in 1 RCT33; the weekly doses were 35 000 IU30 or 50 000 IU19; the fortnightly dose was 50 000 IU in 2 RCTs23,28; the monthly dose was 60 000 IU32; the bimonthly dose was 60 000 IU32; and the bolus doses were 60 000 IU in 3 RCTs,22,27,31 120 000 IU in 2 RCTs,22,31 or 200 000 IU in 2 RCTs.17,25 In studies comprising 3 or more groups, as was the case in 9 RCTs,15,17,18,20,22,25,26,32,34 the higher-dose groups were combined into 1 cohort as the intervention group and the lowest dose groups as the control cohort. There were no toxic effects on offspring in the included RCTs and no evidence of publication bias.

The vitamin D supplementation group had a significantly lower risk of SGA (RR, 0.72; 95% CI, 0.52 to 0.99; I2 = 0%) in 6 RCTs12,15,19,21,31,36 with 898 participants (Figure 2). Risk difference was −5.60%; 95% CI, −0.86% to −10.34%. Subgroup analysis by doses showed that vitamin D supplementation at 2000 IU/d or lower was associated with a reduced risk of SGA (RR, 0.45; 95% CI, 0.23 to 0.90), while vitamin D supplementation at doses larger than 2000 IU/d was not associated with a reduced risk of SGA (RR, 0.83; 95% CI, 0.57 to 1.19). Testing of subgroups showed no significant differences, but significant heterogeneity was present (P = .13; I2 = 56.5%) (Figure 2B). Timing (early or late) (Figure 2A) and method (regular or bolus doses) (eFigure 1 in the Supplement) of vitamin D supplementation had no association with the risk of SGA.

Vitamin D supplementation during pregnancy was not associated with a risk of fetal or neonatal mortality (RR, 0.72; 95% CI, 0.47-1.11; I2 = 0%) in 10 RCTs13,14,17-21,24,30,33 with 3780 participants (Figure 3). Subgroup analysis by doses showed that vitamin D supplementation at 2000 IU/d or less was associated with reduced risk of fetal or neonatal mortality (RR, 0.35; 95% CI, 0.15-0.80), while vitamin D supplementation at doses larger than 2000 IU/d did not reduce the risk of fetal or neonatal mortality (RR, 0.95; 95% CI, 0.59-1.54). Testing for subgroup difference was statistically significant (RR, 0.73; 95% CI, 0.49-1.10; P = .04) (Figure 3B). Timing (early or late) (Figure 3A) and method (regular or bolus doses) (eFigure 2 in the Supplement) of vitamin D supplementation had no association with the risk of fetal or neonatal mortality.

There was no significant difference between neonates who received prenatal vitamin D supplementation and those who had not in the outcomes of congenital malformation (RR, 0.94; 95% CI, 0.61-1.43; I2 = 0%) in 3 RCTs13,14,24 with 2355 participants and admission to a NICU (RR, 1.11; 95% CI, 0.82-1.51; I2 = 0%) in 3 RCTs13,20,24 with 1740 participants; however, the supplementation group had significantly higher Apgar scores at 1 minute (MD, 0.09; 95% CI, 0.01-0.17; I2 = 40%) in 4 RCTs21,23,28,35 with 670 participants and at 5 minutes (MD, 0.08; 95% CI, 0.02-0.14; I2 = 13%) in 4 RCTs21,23,28,35 with 668 participants.

Results show that, compared with the control group, the vitamin D supplementation group had higher 25(OH)D concentrations (MD, 13.50 ng/mL; 95% CI, 10.12-16.87 ng/mL; I2 = 97%) in 14 RCTs12,16,17,19,20,24-26,28-30,32-34 with 2361 participants and had more neonates achieving levels of 20 ng/mL (RR, 2.81; 95% CI, 1.92-4.12; I2 = 68%) in 7 RCTs15,17,18,20,30,31,34 with 1107 participants or 30 ng/mL (RR, 5.20; 95% CI, 3.34-8.10; I2 = 47%) in 3 RCTs18,19,21 with 485 participants. Subgroup analysis for neonatal 25(OH)D concentrations by supplementation timing, dose, or method showed that vitamin D supplementation increased neonatal blood 25(OH)D levels whether the supplementation was initiated early (<20 weeks’ gestation) or late (≥20 weeks’ gestation), at higher doses (>2000 IU/d) or lower doses (≤2000 IU/d), or as bolus or regular doses (eFigure 3 in the Supplement).

Neonates who received prenatal vitamin D supplementation had higher calcium concentrations (to convert to millimoles per liter, multiply by 0.25) than those who received no intervention or placebo (MD, 0.19 mg/dL; 95% CI, 0.003-0.38 mg/dL; I2 = 74%) in 9 RCTs12,16,18,22,25,27,32-34 with 1007 participants) (eFigure 4 in the Supplement).

Neonates who received prenatal vitamin D supplementation had significantly greater birth weight (MD, 75.38 g; 95% CI, 22.88 to 127.88 g; I2 = 44%) in 17 RCTs12,14,17,19-24,27,28,30-35 with 4087 participants, greater neonatal femur length (MD, 0.12 cm; 95% CI, 0.01 to 0.23 cm; I2 = 0%) in 2 RCTs30,33 with 316 participants, and greater skinfold thickness (MD, 0.34 mm; 95% CI, 0.17 to 0.51 mm; I2 = 34%) in 2 RCTs12,27 with 326 participants, but no significant difference was observed for crown heel length (MD, 0.33 cm; 95% CI, −0.05 to 0.70 cm; I2 = 74%) in 12 RCTs12,14,19,21-24,27,28,30,32,33 with 3301 participants or head circumference (MD, 0.20 cm; 95% CI, −0.04 to 0.43 cm; I2 = 78%) in 11 RCTs12,14,19,21-24,27,28,30,33 with 3240 participants. Subgroup analysis by supplementation timing showed that vitamin D supplementation increased birth weight only in the group with therapy initiated late (≥20 weeks’ gestation) (MD 97.74 g; 95% CI, 29.40 to 166.08 g). Test for subgroup differences between early and late supplementation showed significant differences (χ2 = 5.911; P = .02; I2 = 83.1%) (eFigure 5A in the Supplement). Test for subgroup differences by dose showed no significant difference between higher dose and lower dose (χ2 = 0.131; P = .72; I2 = 0%) (eFigure 5B in the Supplement). Test for subgroup differences by supplementation method showed no significant difference in effect between regular and bolus dose (χ2 = 0.071; P = .79; I2 = 0%) (eFigure 5C in the Supplement).

There was no significant difference between neonates who received prenatal vitamin D supplementation and those who had not in the outcomes of low birth weight (RR, 0.52; 95% CI, 0.20 to 1.37; I2 = 65%) in 4 RCTs12,23,27,28 with 775 participants, gestational age (MD, −0.08 weeks; 95% CI, −0.68 to 0.53 weeks; I2 = 81%) in 9 RCTs12,17,20,21,23,27,30,33,35 with 1441 participants, or preterm birth (RR, 0.98; 95% CI, 0.77 to 1.26; I2 = 33%) in 11 RCTs13,14,18,19,21,23,24,28,30,31,33 with 3822 participants).

On infant anthropometry, 2 RCTs12,22 reported on outcomes at 3 months (216 participants), 6 months (199 participants), and 9 months (179 participants), and 2 RCTs12,30 reported at 12 months. Results showed that infants who received prenatal vitamin D supplementation had significantly greater weight at 3 months (MD, 0.21 kg; 95% CI, 0.13 to 0.28 kg; I2 = 0%) (eFigure 6A in the Supplement), 6 months (MD, 0.46 kg; 95% CI, 0.33 to 0.58 kg; I2 = 0%) (eFigure 6B in the Supplement), 9 months (MD, 0.50 kg; 95% CI, 0.01 to 0.99 kg; I2 = 89%) (eFigure 6C in the Supplement), and 12 months (MD, 0.32 kg; 95% CI, 0.12 to 0.52 kg; I2 = 47%; 252 participants) (eFigure 6D in the Supplement); significantly greater height at 3 months (MD, 1.09 cm; 95% CI, 0.64 to 1.54; cm; I2 = 16%), 9 months (MD, 1.47 cm; 95% CI, 0.13 to 2.82 cm; I2 = 80%), and 12 months (MD, 1.36 cm; 95% CI, 0.81 to 1.92 cm; I2 = 40%; 251 participants) but not at 6 months (MD, 1.35 cm; 95% CI, −0.30 to 3.00 cm; I2 = 87%); and significantly greater head circumference at 3 months (MD, 0.71 cm; 95% CI, 0.23 to 1.18 cm; I2 = 64%) but not at 6 months (MD, 0.54 cm; 95% CI, −0.04 to 1.13 cm; I2 = 72%), 9 months (MD, 0.36 cm; 95% CI, −0.16 to 0.88 cm; I2 = 15%), or 12 months (MD, 0.09 cm; 95% CI, −0.28 to 0.45 cm; I2 = 0%; 248 participants).

Vitamin D supplementation showed no association with the infants’ outcomes of asthma (RR, 0.63; 95% CI, 0.36-1.11; I2 = 71%) in 3 RCTs13,18,24 with 1591 participants, eczema (RR, 0.92; 95% CI, 0.77-1.11; I2 = 0%) in 3 RCTs13,17,24 with 1538 participants, upper respiratory tract infection (RR, 0.94; 95% CI, 0.79-1.12; I2 = 27%) in 2 RCTs17,18 with 389 participants, lower respiratory tract infection (RR, 0.97; 95% CI, 0.85-1.12; I2 = 0%) in 4 RCTs13,17,18,24 with 1769 participants, allergy skin prick test (RR, 0.88; 95% CI, 0.52-1.49; I2 = 60%) in 3 RCTs13,18,24 with 1304 participants, or presence of allergy-specific immunoglobulin E (RR, 0.80; 95% CI, 0.39-1.67; I2 = 78%) in 3 RCTs13,18,24 with 1298 participants. The funnel plots for the primary outcomes showed no publication bias in SGA and fetal or neonatal mortality (eFigure 7 in the Supplement).

Discussion

The main finding of this systematic review and meta-analysis of RCTs was that vitamin D supplementation during pregnancy was associated with a reduced risk of SGA (RR, 0.72) without an increased risk of fetal or neonatal mortality and congenital malformation. Vitamin D supplementation during pregnancy with lower doses (≤2000 IU/d) was associated with a reduced risk of fetal and neonatal mortality. Vitamin D supplementation was associated with higher neonatal vitamin D status (bolus- or regular-dose supplement and early or late timing were equally effective in attaining improvement in vitamin D levels), higher calcium levels, higher Apgar scores, greater neonatal skinfold thickness, greater weight (at birth, 3 months, 6 months, 9 months, and 12 months), and greater height (at 3 months, 9 months, and 12 months) in the offspring. Timing of vitamin D supplementation affected birth weight. There was no significant difference in the offspring outcomes of gestational age, preterm birth, asthma, eczema, respiratory tract infection, or allergy. Based on the results from this meta-analysis, the number needed to treat for SGA was 18: 1 offspring SGA case could be avoided for every 18 pregnant women receiving vitamin D supplementation during pregnancy.

The quality of systematic reviews depends on the quality of the studies included. We evaluated the risk of bias in the RCTs analyzed. Methodologic issues may affect the study quality. We scrutinized the selected studies of good methodologic quality using strict quality assessment criteria.9 Our systematic review is a comprehensive quantitative review of 24 RCTs that reported the effects of maternal vitamin D supplementation in offspring health outcomes, including SGA, fetal or neonatal mortality, congenital malformation, admission to a NICU, Apgar scores, neonatal 25(OH)D and calcium concentrations, preterm birth, anthropometric indicators (weight, height, head circumference, or skinfold thickness) during infancy (at birth and ages 3, 6, 9, and 12 months), asthma, eczema, respiratory tract infection, and allergy in the first 3 years of life.

Previous systematic reviews3,37,38 reported that vitamin D supplementation during pregnancy increased maternal 25(OH)D levels3,37 or neonatal 25(OH)D concentrations.38 One systematic review3 evaluated the outcome of vitamin D supplementation during pregnancy for maternal 25(OH)D levels, risk of preeclampsia, gestational diabetes, and other maternal complications but lacked review on offspring outcomes. A Cochrane review39 studied the association between supplementing vitamin D in pregnant women alone or in combination with calcium along with maternal complications and neonatal outcomes and showed no association between vitamin D supplementation and birth weight in 5 RCTs. Another systematic review40 assessed maternal and neonatal outcomes and showed that birth weight in 8 RCTs and length in 6 RCTs were greater in the vitamin D supplementation group; however, this review had no information on infant follow-up.

The present review adds to the existing literature by including a greater number of recent RCTs and, to our knowledge, is the first meta-analysis of RCTs reporting that vitamin D supplementation during pregnancy was safe (without increased risk of fetal or neonatal mortality, congenital abnormality, or admission to a NICU) and effective in reducing the risk of SGA and improving neonatal calcium levels, skinfold thickness, and postnatal growth (greater weight and height at ages 3, 6, 9, or 12 months). We found that maternal vitamin D supplementation timing, dose, and administration method did not affect cord blood vitamin D concentration. Late vitamin D supplementation (initiation at ≥20 weeks’ gestation) improved birth weight, but early supplementation (initiation at <20 weeks’ gestation) did not. Most importantly, we found that the lower dose of vitamin D supplementation (≤2000 IU/d) reduced the risk of fetal or neonatal mortality and SGA, but the higher dose (>2000 IU/d) did not.

Our findings that maternal vitamin D supplementation during pregnancy reduced the risk of SGA and improved infant growth are biologically plausible. Maternal vitamin D levels during pregnancy positively affect infant bone formation41 as well as skeletal muscle42 and adiposity development,43 which are important for infant growth and development. Vitamin D is needed in maintaining normal levels of calcium and phosphate in blood, which in turn facilitate the process of mineral ion homeostasis and bone formation during early life.44 Increased maternal vitamin D status improved fetal skeletal muscle development and myoblast activity.42 Members of the Southampton Developmental Origins of Health and Disease research group reported that low maternal vitamin D status at 34 weeks’ gestation was associated with lower fat mass at birth.43 Vitamin D also plays an important role in the modulation of the immune function45 and oxidative stress46 that may link to fetal growth. In addition, vitamin D regulates genes responsible for trophoblast invasion and angiogenesis critical for placental implantation and function,47-49 which is important for fetal growth.

Vitamin D during pregnancy has been linked to fetal lung maturation in animal models.50,51 Maternal vitamin D may exert its influence during pregnancy on the respiratory and immune systems during lung development in early childhood.52 However, the results of this meta-analysis show that vitamin D supplementation during pregnancy was not associated with childhood respiratory or immune outcomes, including upper or lower respiratory tract infections, asthma, eczema, or allergy, in children at age 3 years. Christensen et al53 conducted a meta-analysis of maternal vitamin D supplementation during pregnancy and infant respiratory tract infections; their results were in line with ours with respect to respiratory tract infections, but they did not have results on asthma. Long-term follow-up of children is needed to determine the effect of vitamin D supplementation during pregnancy on other health outcomes.

Limitations

This study has limitations. First, there were limited data on maternal vitamin D supplementation during pregnancy regarding long-term offspring outcomes, and the longest follow-up in the included RCTs was 3 years. Second, there were only 2 studies on the outcomes of infant growth at age 3 months,12,22 6 months,12,22 9 months,12,22 and 12 months12,30; this result has to be interpreted cautiously. In addition, there was heterogeneity in the result of weight in infants at age 9 months; it is not clear why these 2 studies show different patterns in infants at this age. From a developmental perspective, at 9 months, infants’ weight may differ because of transition to solid food and the total intake, and some infants will begin to walk. Third, the included RCTs differed in several aspects, such as the population studied, ethnicity, altitude, latitude, the outcomes chosen, the clinical setting, the timing of the intervention, and the dose of vitamin D administered during pregnancy. Fourth, the variability in the assay methods for 25(OH)D measurement in each study may contribute to the heterogeneity of the neonatal vitamin D levels. Finally, there were limited data on adherence to the respective protocols.

Conclusions

Vitamin D supplementation during pregnancy was associated with reduced risk of SGA, improved infant growth, and no risk of fetal or neonatal mortality and congenital abnormality. Vitamin D supplementation (≤2000 IU/d) during pregnancy may reduce the risk of fetal or neonatal mortality.

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Article Information

Corresponding Author: Shu Qin Wei, MD, PhD, CHU Sainte-Justine Research Center, Department of Obstetrics and Gynecology, University of Montréal, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada (shu.qin.wei@umontreal.ca).

Accepted for Publication: January 31, 2018.

Published Online: May 29, 2018. doi:10.1001/jamapediatrics.2018.0302

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Bi WG et al. JAMA Pediatrics.

Author Contributions: Mr Bi and Dr Wei had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Bi, Nuyt, Weiler, Wei.

Acquisition, analysis, or interpretation of data: Bi, Weiler, Leduc, Santamaria, Wei.

Drafting of the manuscript: Bi, Weiler, Wei.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Bi, Weiler, Santamaria, Wei.

Obtained funding: Wei.

Administrative, technical, or material support: Leduc, Wei.

Study supervision: Leduc, Wei.

Conflict of Interest Disclosures: None reported.

Funding/Support: Dr Weiler is supported by an award from Canada Research Chair in Nutrition and Development. Dr Wei is supported by a research award from the Fonds de Recherche en Santé du Quebec.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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