Association Between Vitamin D Supplementation During Pregnancy and Offspring Growth, Morbidity, and Mortality

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.


L
2][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. 4Low 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. 3,5,6Sufficient 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. 7uring 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. 2There 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. 4Given 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.

Data Sources and Searches
This systematic review is presented according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. 8Medline, 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. 9Articles 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.

Quality Assessment
We evaluated the methodologic quality of each eligible RCT using the Cochrane Risk Assessment Tool (eTable in the Supplement). 9The 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 I 2 statistic (percentage of variability in the results that is due to heterogeneity) was used to quantify the degree of heterogeneity across studies. 10If the I 2 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). 11Two-tailed P < .05values were considered statistically significant.

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.Twentyfour RCTs  comprising 5405 participants met the inclusion criteria. Two o 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.

Discussion
The main finding of this systematic review and metaanalysis 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. 9Our 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 reviews 3,37,38 reported that vitamin D supplementation during pregnancy increased maternal 25(OH)D levels 3,37 or neonatal 25(OH)D concentrations. 38One systematic review 3 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 review 39 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 review 40 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 formation 41 as well as skeletal muscle 42 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. 44Increased maternal vitamin D status improved fetal skeletal muscle development and myoblast activity. 42Members 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. 43Vitamin D also plays an important role in the modulation of the immune function 45 and oxidative stress 46 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][48][49] which is important for fetal growth.
Vitamin D during pregnancy has been linked to fetal lung maturation in animal models. 50,51Maternal vitamin D may exert its influence during pregnancy on the respiratory and immune systems during lung development in early childhood. 52owever, 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 al 53 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.Longterm 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 months 12,30 ; 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.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.

Figure
Figure 1.Flowchart of Study Selection Process

Figure 2 . 42 42 47 RR
Figure 2. Summary Risk Ratio (RR) of the Association Between Vitamin D Supplementation and Small for Gestational Age (SGA)

1
Subgroup analyses by timing (initiation at <20 or Ն20 weeks of gestation) (A) and dose (>2000 or Յ2000 IU/d) (B).Diamond at the bottom represents the pooled point estimate (95% CIs) for each outcome of interest.

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

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.
1. Flowchart of Study Selection Process Table.Characteristics of Included Randomized Clinical Trials Vitamin D Supplementation During Pregnancy and Offspring Growth, Morbidity, and Mortality Original Investigation Research jamapediatrics.com(Reprinted) JAMA Pediatrics July 2018 Volume 172, Number 7 Downloaded from jamanetwork.comby guest on 08/03/2024