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Multivitamin use and adverse birth outcomes in high-income countries: a systematic review and meta-analysis

American Journal of Obstetrics and Gynecology, October 2017, Volume 217, Issue 4, Pages 404.e1-404.e30

Materials and Methods

This systematic review and meta-analysis was conducted in adherence to the Prospective, Randomized Trial on Intensive Self-Monitoring Blood Glucose Management Added Value in Non-Insulin Treated Type 2 Diabetes Mellitus Patients guidelines 12 and the Meta-analysis Of Observational Studies in Epidemiology guidelines. 13 The review protocol was registered through PROSPERO (number CRD42015024460).

Two authors (H.T.W. and H.K.H.) independently performed the literature search. Data extraction was done by all authors, while the quality assessment of the included studies was performed by H.T.W. and A.B.P. Any disagreement was resolved by discussion among all the authors.

Search strategy

With guidance from a librarian, we searched MEDLINE, Embase, Cochrane, Scopus, and CINAHL up to June 17, 2016. The search strategy clustered terms used to describe the design of the study, the intervention with multivitamins, and the event of pregnancy. The search strategy was initially developed for use in MEDLINE and was then adapted for searching the other databases (see Supplemental Table 1 for the search strategy). We screened the reference lists of all identified studies. If published studies had inadequate data, we contacted the authors for clarification and possible data sharing. No restrictions were applied to date or language.

Eligibility criteria and outcome measures

Eligible studies were randomized, controlled trials (RCT), cohort studies, and case-control studies performed in HICs defined as countries listed as members of the Organization for Economic Co-Operation and Development with the World Bank. 14 Eligible studies should investigate the association between the multivitamin use (3 or more vitamins or minerals in tablets or capsules) and adverse birth outcomes and report estimates of odds ratio, risk ratio, or hazard ratio, or provide sufficient data for these to be calculated. In both RCTs and observational studies, the comparison group should consist of women taken placebo drug or supplements containing less than 3 kinds of vitamins or minerals.

Studies in which the intervention was fortified products were excluded as were case-control studies with less than 100 cases. Conference proceedings, case reports, and commentaries were excluded. Systematic reviews and meta-analyses were included only as background. For multiple and/or duplicate publication of the same data set, only the most recent or most complete study was included.

The primary outcome measure was PTB (delivery <37 weeks of gestational age [GA]). Secondary outcomes were LBW (birthweight <2500 g), SGA (birthweight <10th centile), stillbirth (GA ≥28 weeks), early neonatal death (<7 days), perinatal mortality (stillbirth or early neonatal death), late neonatal death (7–28 days), neonatal death (<28 days), and congenital birth anomalies without further specification.

Data extraction and quality assessment

At data extraction, information on setting, study design, number of participants, exclusion criteria, confounders, and outcomes were collected. Exposure details for RCTs included the contents of the multivitamin and the placebo drug, GA at the start, and duration of the use; for observational studies we recorded the definition of multivitamin use and time of assessment.

We aimed to extract odds ratios (ORs) or relative risks (RRs) with 95% confidence intervals (CIs). If ORs or RRs were not available, absolute P values were presented instead. In case the P value was not calculated by the authors of the study, the χ 2 test or the Fisher exact test (when expected cell values were less than 5) was applied using SAS (version 9.4; SAS Institute, Cary, NC).

The methodological quality in terms of risk of bias of the included RCTs was evaluated using the Cochrane Collaboration tool. 15 The risk of bias in the observational studies was assessed using the Newcastle-Ottawa Scale 16 as recommended by the Cochrane Non-Randomized Studies Methods Working Group. 15 This scale uses a star system (with a maximum of 9 stars) to evaluate a study in 3 domains: selection of study groups, comparability of study groups, and the ascertainment of either the exposure or outcome of interest for case-control or cohort studies respectively.

We defined studies with full scores or 1 missing star to be at low risk of bias, studies that had 1 missing star in more than 1 domain to be at moderate risk of bias, and studies with more than 1 missing star in a domain to be at high risk of bias. The quality of evidence was assessed using the Grades of Research, Assessment, Development and Evaluation (GRADE) 17 and was categorized into 4 levels, from very low (⊕⊝⊝⊝) to high (⊕⊕⊕⊕).

Statistical analysis

We conducted meta-analyses including RCTs or observational studies without combining the 2 types of studies. Meta-analyses were applied on raw data for outcomes with data for at least 2 studies and were conducted using RevMan (version 5.3). We used random-effects models to calculate summary estimates for all outcomes. Statistical heterogeneity was assessed with the I 2 statistic.

Also as recommended by the Cochrane handbook, we considered an I 2 value of 0–40% to represent low heterogeneity, 30–60% moderate heterogeneity, 50–90% substantial heterogeneity, and 75–100% considerable heterogeneity. 15 Statistical significance was defined at the 0.05 level.

Sensitivity analyses were undertaken to study the effect of multivitamin use on various outcomes by excluding studies with a moderate-high risk of bias. No unpublished studies were identified. We did not show funnel plots because of the small numbers of studies (n < 10) in all the meta-analyses. 15

Results

Of the 9461 citations identified, we selected 91 full-text papers for detailed assessment ( Figure 1 ). Of these, 56 studies were excluded for various reasons ( Supplemental Table 2 ). We identified 35 eligible studies including 98,926 women.

gr1
 

Figure 1
Flowchart of search results
Flow chart of search results and process for identification, selection, and inclusion of references in systematic review is shown.
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017 .

 

The risk of adverse birth outcome after maternal periconceptional multivitamin use was assessed in 4 RCTs and in 31 observational studies. The number of women who received multivitamins varied in the RCTs from 50 to 914 18 and in the cohort studies from 211 19 to 22,285. 20 The number of studied cases in case-control studies varied from 112 21 to 958. 22

Studies on birth defects were mainly conducted in the United States, while other adverse outcomes were equally assessed in studies from the United States and Europe. Only 8 18 19 23 24 25 26 27 28 of 35 studies stated the exact content of the used supplements, and of these, only 1 study used folic acid compatible to the current daily recommended intake 24 ( Supplemental Table 3 ). None of the studies compared the use of folic acid and iron vs the use of multivitamins, nor did they describe possible side effects associated with multivitamins. Supplemental Tables 4–7 summarize characteristics and results of the included studies.

Preterm birth

The risk of PTB was assessed in 1 RCT 24 and in 7 cohort studies. 27 29 30 31 32 33 34 In the RCT involving 402 women, an unchanged risk of PTB was found. 24 The results of the cohort studies were contradictory ( Supplemental Table 5 ). In 3 studies, a significant decrease in the risk of PTB was seen after periconceptional multivitamin use. 30 31 33 However, in one of these studies, the significant decreased risk was limited to births before GA 34 weeks. 30 A similar risk of PTB in multivitamin users and nonusers was seen in 3 other studies, 27 32 34 and finally, one study found an increased risk of PTB in case of multivitamin use in the third trimester. 29

Only 4 studies provided data usable for a meta-analysis. 27 30 31 33 The summary RR involving 42,592 women with 2280 events was 0.84 (95% CI, 0.69–1.03), with a high degree of statistical heterogeneity (I 2 = 73%) ( Figure 2 ). All cohort studies had a low risk of bias. The GRADE estimate for quality of evidence was very low (⊕⊝⊝⊝).

gr2
 

Figure 2
Forest plot of effect estimates for certain conditions
Forest plot of the effect estimates for preterm birth, low birthweight, and small for gestational age are shown.
CI , confidence interval; M-H , Mantel-Haenszel.
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017 .

 

Low birthweight

The risk of LBW after multivitamin use was assessed in 1 RCT 24 and in 3 cohort studies. 27 33 34 In the RCT, an unchanged risk of LBW was seen in multivitamin users vs nonusers. 24 The risk of bias in this study was unclear because of insufficient information on how the random sequence generation and the allocation concealment were performed. In the 3 cohort studies, the results varied. In 1 study a decreased risk of LBW was seen after periconceptional multivitamin use, 33 but in 2 studies the risk was not affected by periconceptional multivitamin use. 27 34

Two studies supplied data for a meta-analysis. 27 33 The summary RR involving 7498 women with 452 events was 0.79 (95% CI, 0.45-1.41, I 2 = 89%) ( Figure 2 ). The risk of bias was low in all of the studies. The GRADE estimate for quality of evidence was very low (⊕⊝⊝⊝).

Small for gestational age

The risk of SGA in relation to multivitamin use was assessed in 1 RCT 24 and in 4 cohort studies. 29 30 31 33 In the RCT an unchanged risk of SGA was found using an intention-to-treat analysis, but a significant decrease in risk was seen when using a per-protocol analysis. 24 In 3 of the cohort studies, the findings did not support the use of a multivitamin. 29 30 33 However, in a large cohort study from Denmark, Catov et al 31 found a decreased risk of SGA both for pre- and periconceptional multivitamin use. This resulted in a significant decreased risk when pooling the individual study data.

The risk of bias was low in the 3 studies providing data usable for a meta-analysis. 30 31 33 The summary RR for the meta-analysis of these studies involving 36,965 women with 1413 events was 0.77 (95% CI, 0.63-0.93, I 2 = 43%) ( Figure 2 ). The GRADE estimate for quality of evidence was very low (⊕⊝⊝⊝).

Stillbirth and mortality

A small RCT found a similar risk of stillbirth in multivitamin users and nonusers. 35 Likewise, 2 cohort studies from the Czech Republic and Denmark found a similar risk of stillbirth when multivitamin use was restricted to the periconceptional period. 20 27 However, the Danish study found an increased risk of stillbirth in the case of multivitamin use for 5–6 weeks within the preconceptional period and a decreased risk in the case of postconceptional use. 20

Two studies both with low risk of bias supplied data for a meta-analysis. The summary RR involving 39,845 women with 208 events was 0.78 (95% CI, 0.59–1.03, I 2 = 0%). The GRADE estimate for quality of evidence was low (⊕⊕⊝⊝).

No studies on multivitamin use and the risk of perinatal and neonatal mortality were found.

Congenital birth defects

Multiple congenital anomalies

The association between multivitamin use and multiple congenital anomalies was examined in one smaller case-control study, and the study demonstrated an unchanged risk of a wide range of anomalies. 21 The GRADE estimate for quality of evidence was very low (⊕⊝⊝⊝).

Neural tube defect

Six observational studies examined the association between multivitamin use and the occurrence of neural tube defects (NTDs). 27 36 37 38 39 40 The studies included women with a periconceptional use of multivitamin except for 1 study including women with either preconceptional or first-trimester use. 38 All studies had a low risk of bias and all provided data for a meta-analysis.

Pooling the results involving 12,524 women with 1907 events led to an RR for NTDs of 0.67 (95% CI, 0.52–0.87, I 2 = 81%) ( Figure 3 ). Removing the study without data on periconceptional multivitamin use 38 did not alter the estimated relative effect (RR, 0.59 [95% CI, 0.36–0.96]). The GRADE estimate for quality of evidence was very low (⊕⊝⊝⊝).

gr3
 

Figure 3
Forest plot of the effect estimates for neural tube defects
CI , confidence interval.
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017 .

 

The association between preconceptional multivitamin use and the recurrence of NTDs was assessed in 1 RCT, 35 while periconceptional multivitamin use was assessed in 1 RCT and in 1 cohort study. 18 41 One study had a high risk of bias because of a missing response rate and missing adjustments. 41 The summary RR of recurrence of NTDs after pre- and periconceptional multivitamin use studied in RCTs and involving 1549 women with 28 events was 0.83 (95% CI, 0.40–1.72, I 2 = 0%) ( Figure 3 ). The GRADE estimate for quality of evidence was moderate (⊕⊕⊕⊝).

Orofacial defects

We could not find any RCTs examining the association between periconceptional multivitamin use and orofacial defects (cleft lip with or without cleft palate), but 7 observational studies were found. 27 42 43 44 45 46 47 One of these studies found a significant decreased risk restricted to postconceptional multivitamin use, 43 while another study found a significant decreased risk after periconceptional use. 45 The remaining studies all failed to demonstrate any significant risk reduction. 27 42 44 46 47

Six studies provided data for a meta-analysis. 42 43 44 46 47 48 The summary RR involving 13,680 women with 1418 events was 0.88 (95% CI, 0.77–1.01, I 2 = 23%) ( Figure 3 ). Removing the only study with a high risk of bias 42 resulted in a significant RR (0.86 [95% CI, 0.77–0.96) and a reduced statistical heterogeneity ( Supplemental Figure 1 ). The GRADE estimate for quality of evidence was low (⊕⊕⊝⊝).

The association between periconceptional multivitamin use and cleft palate without cleft lip was assessed in the same studies. The summary RR for cleft palate was 1.12 (95% CI, 0.94–1.33, I 2 = 0%) ( Supplemental Figure 1 ). The GRADE estimate for quality of evidence was low (⊕⊕⊝⊝).

Recurrence of cleft lip with or without cleft palate

In 2 cohort studies both with high risk of bias, the association between periconceptional multivitamin use and the recurrence of cleft lip with or without cleft palate was assessed. 19 23

Both studies provided data for the meta-analysis. The summary RR involving 2767 women with 110 events was 0.61 (95% CI, 0.22–1.64, I 2 = 55%) ( Supplemental Figure 1 ). The GRADE estimate for quality of evidence was very low (⊕⊝⊝⊝).

Cardiovascular defects

Six observational studies examined the association between periconceptional multivitamin use and congenital cardiovascular defects. 22 27 46 49 50 51 One study included only cases with tetralogy of Fallot and d-transposition of the great arteries, 51 while in the other studies, a very broad definition of cardiovascular defects including septal defects, stenosis, etc was used. All studies but one 49 had a low risk of bias.

The summary RR of these 6 studies involving 11,902 women with 1377 events was 0.83 (95% CI, 0.70–0.98, I 2 = 56%) ( Supplemental Figure 2 ). Excluding the study including only cases of tetralogy of Fallot and d-transposition of the great arteries 51 did not change the result. However, excluding the study with the high risk of bias 49 resulted in a nonsignificant RR of 0.88 (95% CI, 0.77–1.01). The GRADE estimate for quality of evidence was low (⊕⊕⊝⊝).

Urinary tract defects

Three observational studies all with a low risk of bias examined the association between periconceptional multivitamin use and urinary tract defects and provided data for the meta-analysis. 27 46 52

The summary RR including 6880 women and 230 events was 0.60 (95% CI, 0.46–0.78, I 2 = 0%) ( Supplemental Figure 3 ). The GRADE estimate for quality of evidence was very low (⊕⊝⊝⊝).

Limb deficiencies

Three observational studies examined the association between periconceptional multivitamin use and limb deficiencies. 27 50 53 All studies had a low risk of bias and supplied data for the meta-analysis. The summary RR including 8299 women and 207 events was 0.68 (95% CI, 0.52–0.89, I 2 = 0%) ( Supplemental Figure 4 ). The GRADE estimate for quality of evidence was very low (⊕⊝⊝⊝).

Hydrocephalus

Two observational studies examined the association between periconceptional multivitamin use and hydrocephalus and provided data for the meta-analysis. 27 49 The summary RR using the random-effect model including 7719 women and 206 events was 0.74 (95% CI, 0.13–4.30, I 2 =87%) ( Supplemental Figure 5 ). Removing a study with a high risk of bias 49 did not affect the result. The GRADE estimate for quality of evidence was very low (⊕⊝⊝⊝).

Trisomy 21

Three observational studies examined the association between periconceptional multivitamin use and trisomy 21 and provided data for the meta-analysis. 27 28 54

The summary RR including 10,653 women and 216 events was 0.98 (95% CI, 0.70–1.37, I 2 = 0%) ( Supplemental Figure 6 ). Removing the only study with a high risk of bias 28 did not affect the result. The GRADE estimate for quality of evidence was very low (⊕⊝⊝⊝).

A summary of all results is presented in the Table .

Outcome Studies, n Studies in meta-analysis, n Participants, n Events, n I 2 (corresponding P value) RR (95% CI) Grade
PTB 8 4 42,592 2280 73% (.01) 0.84 (0.69–1.03) Very low
LBW 5 2 7498 452 89% (.003) 0.79 (0.45–1.41) Very low
SGA 5 3 36,965 1413 43% (.17) 0.77 (0.63–0.93) Very low
Stillbirth 3 2 39,845 208 0% (.76) 0.78 (0.59–1.03) Low
Mortality 0 NA NA NA NA NA NA
Multiple congenital anomalies 1 NA NA NA NA NA Low
NTDs 6 6 12,524 1907 81% (< .0001) 0.67 (0.52–0.87) Very low
Recurrence of NTDs 3 2 1549 28 0% (.72) 0.83 (0.40–1.72) Moderate
Cleft lip with or without cleft palate 7 6 13,680 1418 23% (0.26) 0.88 (0.77–1.01) Low
Cleft palate 7 6 13,042 777 0% (0.51) 1.12 (0.94–1.33) Low
Recurrence of clefts 2 2 2767 110 55% (0.14) 0.61 (0.22–1.64) Very low
Cardiovascular defects 6 6 11,902 1377 56% (0.04) 0.83 (0.70–0.98) Low
Urinary tract defects 3 3 6880 230 0% (0.51) 0.60 (0.46–0.78) Very low
Limb deficiencies 3 3 8299 207 0% (0.44) 0.68 (0.52–0.89) Very low
Hydrocephalus 2 2 7719 206 87% (0.006) 0.74 (0.13–4.30) Very low
Trisomy 21 3 3 10,653 216 0% (0.61) 0.98 (0.70–1.37) Very low

Table

 

Comment

Main findings

To the best of our knowledge, this is the first systematic review and meta-analysis to examine maternal multivitamin use before and during pregnancy exclusively in HICs. The review and meta-analysis yielded 3 main findings. First, we found a decreased risk of SGA but an unchanged risk of PTB and LBW with multivitamin use. Second, we found that periconceptional multivitamin use led to a decreased risk of 4 different congenital birth defects (NTDs, cardiovascular defects, urinary tract defects, and limb deficiencies). Third, very few RCTs were found, resulting in a very low to low degree of clinical evidence according to the GRADE system for all outcomes except for the recurrence of NTDs in which a moderate quality of clinical evidence was found.

Strengths and limitations

We recognize several strengths and limitations in relation to this systematic review. This is a comprehensive assessment of the evidence, incorporating both RCTs and observational studies from HICs. Strengths also include the strict use of Prospective, Randomized Trial on Intensive Self-Monitoring Blood Glucose Management Added Value in Non-Insulin Treated Type 2 Diabetes Mellitus Patients guidelines for meta-analyses, the use of bias assessment tools (Newcastle-Ottawa Scale and Cochrane), and the use of the GRADE approach to link evidence-quality evaluations to clinical recommendations.

An important limitation is the fact that the majority of the included studies were observational in design, which makes inferences of causality difficult, especially in the case-control studies in which multivitamin use relied on maternal recall. Also, the GA relied in some studies on maternal recall because the GA in these studies was based on the last menstrual period. 20 27 31 32 This is likely to have caused bias. Even though the majority of included observational studies had a low risk of bias, limitations apply because of insufficient confounder control. As an example, only 1 study 20 controlled for assisted reproductive technology, which is a known risk factor for adverse birth outcome. 55

Another limitation is the clinical heterogeneity of the included studies. We used a wide definition of multivitamin use (3 or more vitamins or minerals in tablets or capsules), and therefore, we might have introduced clinical heterogeneity because of slightly different intervention profiles. However, we excluded several studies in which the intervention was either folic acid or multivitamin without possibility of separating the treatment regimes.

Clinical heterogeneity among the studies also applied to the definition of GA. We were able to include only studies from Europe and the United States. Nevertheless, the generalizability was only vaguely limited because the vast majority of HICs according to our definition are localized in this part of the world. 14

Finally, we were unable to assess the effect of multivitamin use, depending on baseline diet because this information was missing in the studies evaluated.

A limitation of this meta-analysis is that we have pooled unadjusted estimates, so we could not account for other covariates possibly associated with preeclampsia/eclampsia, such as maternal age and body mass index (BMI). In this regard, we note that the demographic data of the study populations in most of the studies did not differ when stratified by fetal sex, suggesting that the lack of adjustment for these covariates may be less relevant to our results.

Interpretation

In line with meta-analyses including studies from low- and middle-income countries, 6 7 9 10 we found an unchanged risk of PTB. Also in line with the previous results, we found that periconceptional multivitamin use reduces the risk of SGA. This seems biologically plausible, given that nutrition is known to affect the placental function. 56 57 Contrary to previous meta-analyses, we found that the risk of LBW remained unchanged. This result, however, should be interpreted with caution because only 2 studies supplied data to the meta-analysis on LBW. In addition, the GRADE estimate of quality for this outcome was very low.

Goh et al 11 found in a previous meta-analysis on multivitamin use and the risk of congenital anomalies, significant reduced rates of NTDs, orofacial defects, urinary tract defects, congenital heart defects, hydrocephalus, and limb deficiencies. Unfortunately, Goh et al did not define multivitamin use and did not assess the risk of bias.

In agreement with Goh et al, we found significant reduced rates of NTDs, urinary tract defects, and limb deficiencies, but the quality of clinical evidence for these outcomes was very low; hence, this result should be interpreted with caution. Furthermore, we found the rate of congenital heart defects to be significantly reduced, but the quality of evidence was low. We did not confirm the positive effect on orofacial defects and hydrocephalus. This probably was due to differences in search and eligibility criteria.

Our search did not reveal any studies from HICs comparing multivitamin use with the use of folic acid in combination with iron. Hence, we do not know whether the possible protective effect of multivitamin is in fact only due to the content of iron and folic acid. Haider and Bhutta 6 found in a Cochrane review including studies from low- to middle-income countries that multivitamin users had a an unchanged risk of PTB but a decreased risk of LBW and SGA compared with users of iron and folic acid in combination.

They also found that women with a BMI ≥20 kg/m 2 or a height ≥155 cm had a greater effect of multivitamin use than women with a BMI <20 kg/m 2 or a height <155 cm. In HICs the vast majority of women have a BMI ≥20 kg/m 2 and a height ≥155 cm, 58 59 60 suggesting that this population might have a positive effect of multivitamin use compared with iron and folic acid alone.

Conclusion

Because there seems to be a protective effect of periconceptional multivitamin use on certain adverse birth outcomes, routine multivitamin use in HICs can be recommended but with caution because of the low quality of clinical evidence and because of uncertainty about which components in the multivitamin that are responsible for the protective effect. Also, it may be that clinically, lifestyle and dietary assessment should be made before any supplementation other than folic acid is prescribed.

More data are needed, preferably from RCTs or from large, prospective cohort studies in which the intervention is clearly defined. Multivitamin use should be compared with no use and with use of iron and folic acid in combination. GA should be assessed based on ultrasound. Future cohort studies should include sufficient confounder control including assisted reproduction technology, body mass index, parity, smoking, and the use of alcohol and drugs.

Appendix

 

Database Search strategy Date Hits
Medline (((((“Pregnant Women” [Mesh]) or “Pregnancy”[Mesh] or pregnant* [tiab] or “gravid” [tiab] or obstetric [tiab] or antenatal [tiab] or “antepartum” [tiab] or gestation* [tiab]))) and (((((((((“Longitudinal Studies”[Mesh]) or “Follow-Up Studies”[Mesh]) or “Prospective Studies”[Mesh]) or “Controlled Clinical Trial” [Publication Type]) or “Cohort Studies”[Mesh]) or “Randomized Controlled Trial” [Publication Type]) or “Clinical Trial” [Publication Type]) or cohort* [tiab] or longitudinal [tiab] or prospective [tiab] or incidence studies [tiab] or incidence study [tiab] or concurrent studies [tiab] or concurrent study [tiab] OR “Follow up” [tiab] or random* [tiab] or trial* [tiab]))) and (((((((“Micronutrients”[Mesh]) or “Dietary Supplements”[Mesh:noexp])) or ((multivitamin* or micronutrient* or supplementation* or “multivitamin-mineral*”))))) Filters:Humans June 17, 2016 5850
Embase (“Pregnant Women” OR Pregnancy OR pregnant* OR gravid OR obstetric OR antenatal OR antepartum OR gestation*) AND (“Micronutrients” OR “Dietary Supplements” OR multivitamin* OR micronutrient* OR supplementation* OR “multivitamin-mineral*”) AND (“Longitudinal Studies” OR “Follow-Up Studies” OR “Prospective Studies” OR “Controlled Clinical Trial” OR “Cohort Studies” OR “Randomized Controlled Trial” OR “Clinical Trial” OR cohort* OR longitudinal OR prospective OR “incidence studies” OR “incidence study” OR “concurrent studies” OR “concurrent study” OR “Follow up” OR random* OR trial*)
Limitations: humans, duplicates from Pubmed
June 17, 2016 408
CINAHL ((MH “Expectant Mothers”) OR (MH “Pregnancy”) OR “obstetric” OR “antenatal” OR “antepartum” OR “gestation”) AND (“micronutrient” OR “dietary supplement” OR “multivitamin” OR “supplementation*” OR “multivitamin-mineral”) AND (“longitudinal studies” OR (MH “prospective studies”) OR (MH “Clinical Trials”)). Limitations: MEDLINE records, human June 17, 2016 15
Cochrane ((Mesh descriptor: [micronutrients] explode all trees) OR multivitamin OR micronutrient OR supplementation OR multivitamin-mineral) AND (gravid OR antenatal OR antepartum OR gestation OR pregnancy OR pregnant OR pregnant women OR obstetrics) AND (prospective studies OR prospective study OR randomised controlled trials OR longitudinal studies OR longitudinal study OR follow-up studies OR follow-up study OR cohort study OR cohort studies OR concurrent study OR concurrent studies OR incidence study OR incidence studies). Limitation: trials June 17, 2016 958
SCOPUS ((ALL (concurrent study OR follow up OR random OR trial*)) OR (ALL ((longitudinal studies OR follow-up studies OR prospective studies OR controlled clinical trial* OR cohort studies OR randomized controlled trial* OR clinical trial* OR cohort OR longitudinal OR prospective OR incidence studies OR incidence study)))) AND (ALL ((dietary supplements OR multivitamin* OR micronutrient* OR supplementation* OR multivitamin-mineral*))) AND (ALL ((pregnant women OR pregnancy OR pregnant* OR gravid OR obstetric OR antenatal OR antepartum OR gestation*))) AND (LIMIT-TO (DOCTYPE, “ar”) OR LIMIT-TO (DOCTYOE, “re”)) June 17, 2016 2229

Supplemental Table 1

Author, year Reason for exclusion
Chen et al, 2015 1 Not correct intervention
Aronsson et al, 2013 2 Not correct intervention
Carmichael et al, 2013 3 Not correct intervention
Leung et al, 2013 4 Not relevant study outcome
Wallenstein et al, 2013 5 Not correct intervention
Haider and Bhutta, 2012 6 Review and all relevant studies included
Ramakrishnan et al, 2012 7 Review and all relevant studies included
Ramakrishnan et al, 2012 8 Review and all relevant studies included
Carmichael et al, 2012 9 Not correct intervention
Dunlop et al, 2012 10 Not correct intervention
Siegfried et al, 2012 11 Review and all relevant studies included
Roy et al, 2012 12 Not relevant study outcome
Avalos et al, 2011 13 Not relevant study outcome
Czeizel, 2011 14 Review and all relevant studies included
Meltzer et al, 2011 15 Not correct intervention
Haider et al, 2011 16 Review and all relevant studies included
Czeizel and Bánhidy, 2011 17 Review and all relevant studies included
Christian, 2010 18 Review and all relevant studies included
Allen and Peerson, 2009 19 Not relevant study outcome
Burris et al, 2010 20 Not relevant study outcome
Watson and McDonald, 2010 21 Not correct intervention
Shah et al, 2009 22 Review and all relevant studies included
Czeizel, 2009 23 Review and all relevant studies included
Smedts et al, 2008 24 Not correct (unsure) intervention. Data not available from authors.
Bitsko and Sachdev, 2007 25 Not correct intervention
Bille et al, 2007 26 Not correct intervention
Goh et al, 2006 27 Review and all relevant studies included
Shah et al, 2004 28 Review and all relevant studies included
Lagiou et al, 2005 29 Not relevant study outcome
Yuskiv et al, 2005 30 Includes less than 100 cases
Lammer et al, 2004 31 Double data
Czeizel and Medveczky, 2003 32 Double data
Merialdi et al, 2003 33 Review and all relevant studies included
Shaw et al, 2002 34 Double data
Lumley et al, 2011 35 Article withdrawn
Black, 2001 36 Review and all relevant studies included
Mathews et al, 1999 37 Not correct intervention
Velie et al, 1999 38 Not correct intervention
Shaw et al, 2010 39 Double data
Khoury et al, 1996 40 Double data
Czeizel et al, 1994 41 Not correct intervention
Czeizel et al, 1993 42 Not correct intervention
Bower and Stanley, 1992 43 Includes less than100 cases
Czeizel and Dudás, 1992 44 Not correct intervention
Milunsky et al, 1989 45 Not correct intervention
Sheppard et al, 1989 46 Not correct intervention
Hill et al, 1988 47 Not correct intervention
Wild et al, 1986 48 Double data
Simpson and Robertson, 1985 49 Commentary
Czeizel and Rodé, 1984 50 Study protocol
Seller and Nevin, 1984 51 Double data
Chalmer and Nevin, 1982 52 Commentary
Viegas et al, 1982 53 Not correct intervention
Smithells et al, 1981 54 Double data
Jacobson, 1980 55 Not correct intervention
Conway, 1958 56 Includes less than 100 cases

1 Chen L-W, Lim AL, Colega M, et al. Maternal folate status, but not that of vitamins B-12 or B-6, is associated with gestational age and preterm birth risk in a multiethnic Asian population. J Nutr 2015;145:113-20

2 Aronsson CA, Vehik K, Yang J, et al. Use of dietary supplements in pregnant women in relation to sociodemographic factors—a report from The Environmental Determinants of Diabetes in the Young (TEDDY) study. Public Health Nutr 2013;16:1390-402

3 Carmichael SL, Yang W, Shaw GM, National Birth Defects Prevention Study. Maternal dietary nutrient intake and risk of preterm delivery. Am J Perinatol 2013;30:579-88

4 Leung BMY, Kaplan BJ, Field CJ, et al. Prenatal micronutrient supplementation and postpartum depressive symptoms in a pregnancy cohort. BMC Pregnancy Childbirth 2013;13:2

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23 Czeizel AE. Periconceptional folic acid and multivitamin supplementation for the prevention of neural tube defects and other congenital abnormalities. Birth Defects Res A Clin Mol Teratol 2009;85:260-8

24 Smedts HPM, Rakhshandehroo M, Verkleij-Hagoort AC, et al. Maternal intake of fat, riboflavin and nicotinamide and the risk of having offspring with congenital heart defects. Eur J Nutr 2008;47:357-65

25 Bitsko RH, Reefhuis J, Romitti PA, Moore CA, Honein MA. Periconceptional consumption of vitamins containing folic acid and risk for multiple congenital anomalies. Am J Med Genet A 2007;143A:2397-405

26 Bille C, Olsen J, Vach W, et al. Oral clefts and life style factors—a case-cohort study based on prospective Danish data. Eur J Epidemiol 2007;22:173-81

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28 Shah D, Sachdev HPS. Maternal micronutrients and fetal outcome. Indian J Pediatr 2004;71:985-90

29 Lagiou P, Mucci L, Tamimi R, et al. Micronutrient intake during pregnancy in relation to birth size. Eur J Nutr 2005;44:52-9

30 Yuskiv N, Honein MA, Moore CA. Reported multivitamin consumption and the occurrence of multiple congenital anomalies. Am J Med Genet A 2005;136:1-7

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Supplemental Table 2

Study, year Content of vitamins
Alwan, 2010 Multivitamin, CNS
Botto, 2000, 2003 Multivitamin, CNS
Briggs, 1976 Vitamin B1 10 mg, B2 10 mg, B6 2 mg, B12 4 μg, niacinamide 100 mg, C 300 mg, calcium pantothenate 20 mg
Brough, 2010 β-carotene 3 mg, thiamin 3 mg, riboflavin 2 mg, niacin 20 mg, B6 10 mg, B12 6 μg, C 70 mg, D 5 μg , E 20 mg, K 70 μg, folic acid 400 μg, Fe 20 mg, Zn 15 mg, Mg 150 mg, iodine 140 μg, Cu 1 mg
Catov, 2007, 2011 Multivitamin, CNS
Correa, 2003 Multivitamin, CNS
Czeizel 2004, 2005 Vitamin A(6000 IU in 1984-1989, 4000 IU in 1990-1992), B1 1.6 mg, B2 1.8 mg, nicotinamide 19 mg, B6 2.6 mg, folic acid 0.8 mg, B12 4 μg, C 100 mg, D 500 IU, E 15 mg, calcium panthothenate 10 mg, biotin 0.2 mg, calcium 125 mg, phosphorous 125 mg, magnesium 100 mg, iron 60 mg, copper 1mg, manganese 1 mg, zinc 7.5 mg
Hayes, 1996 Vitamins containing folic acid
Hininger, 2004 Vitamin C 60 mg, β-carotene 4.8 mg, E 10 mg, thiamin 1.4 mg, riboflavin 1.6 mg, niacin 15 mg, pantothenic acid 6 mg, folic acid 200 μg, cobalamin 1 μg, zinc 15 mg, magnesium 87.5 mg, calcium 100 mg
Itikala, 2001 Multivitamin, CNS
Kirke, 1992 Vitamins containing folic acid
Li, 1994 Multivitamin, CNS
Mills, 1989 Multivitamin, CNS
Mulinare, 1988 Multivitamin, CNS
Nohr, 2014 Multivitamin, CNS
Scholl, 1997 Multivitamin, CNS
Shaw, 1995, 1997, 2000, 2006, 2010 Multivitamins containing folic acid, CNS
Smithells, 1983 Vitamins A 4000 IU, D 400 IU, B1 1.5 mg, B2 1.5 mg, B6 1 mg, nicotinamide 15 mg, C 40 mg, folic acid 0.36 mg, iron 75.6 mg, calcium phosphate 480 mg
Thompson, 2003 Vitamins containing folic acid, CNS
Tolarova, 1995 Vitamins A 6000 IU, B1 3 mg, B2 3 mg, B6 3 mg, C 150 mg, D3 300 IU, E 6 mg, nicotinamide 30 mg, calcium pantothenicum 3 mg, folic acid 10 mg. Most women also received iron 75 mg/day and extra vitamin B6 1 mg/day
Vahratian, 2004 Multivitamin, CNS
Wald, 1991 Vitamin A 4000 IU, D 400 U, B1 1.5 mg, B2 1.5 mg, B6 1 mg, C 40 mg, nicotinamide 15 mg. Half of the study population also received folic acid 4 mg
Werler, 1993, 1999 ≥2 water-soluble vitamins and ≥2 fat-soluble vitamins
Wilcox, 2007 Multivitamin containing folic acid
Yang Q, 1996 Multivitamin, CNS

Supplemental Table 3

Reference, year, country Study design, study period, participants, n Content of multivitamin supplement, control regimen used and GA (wks) at entry in the study in the intervention group (mean ± SD) a PTB (GA <37 wks), absolute values LBW (<2500 g) absolute values SGA (<10 percentile), absolute values Stillbirth absolute values Mortality, early neonatal (<7 d), late neonatal (7–28 d), perinatal (GA ≥ 28 wks to 7 d of life), neonatal (<28 d) Matching or adjustment Risk of bias (Cochrane)
Brough, 2010, England RCT, 2002–2004, n = 402 (S: n = 207) S: several micronutrients; US: placebo with iron oxide coating; GA: 12 (median) 77–87 (interquartile range) All: S: 2.5%; US: 2.3%; P = NS All: S: 7.3%; US: 4.6%; P = NS All: S: 16.8%; US: 17.8%; P = NS NA NA NA Unclear
Hininger, 2004, France RCT, study period: NA
n = 100 (S: n = 50)
S: several micronutrients; US: placebo; GA: 14 ± 2 NA S: 6.1%; US: 28.1%; P = 0.02; definition: <2700 g NA NA NA NA High
Kirke, 1992, Ireland RCT, block randomization, 1981–1987
n = 354 (S: n = 239)
S: multivitamins with or without folic acid; US: folic acid 360 μg; GA: preconceptional use NA NA NA S: 1.4%; US: 0%; P = NS; definition of stillbirth: NA NA NA Unclear

a See Supplemental Table 3 .

Supplemental Table 4

Reference, year, country Study design, study period, participants, n Content of multivitamin supplement, control regimen used a Timing of multivitamin use PTB (<37 wks), AOR/AHR/ARR (95% CI), or absolute values, % LBW (<2500 g), AOR (95% CI), or absolute values, % SGA (<10 percentile),
AOR/AHR (95% CI)
Stillbirth (definition according to author) AHR, (95% CI), or absolute values, % Mortality Matching or adjustment Risk of bias (NOS)
Alwan et al, 2010, 29 England Prospective cohort, 2003–2006, n = 1274 (S: n = 1043 in first trimester, n= 274 in second trimester, n= 139 in third trimester) S: Multivitamin; US: no vitamin use First trimester, second trimester, third trimester AOR, 1.3 (0.6–2.7), AOR, 1.8 (0.8–4.1), AOR, 3.4 (1.2–9.6) NA AOR, 1.3 (0.8–1.9); AOR, 1.1 (0.7–1.9); AOR, 0.9 (0.5–1.7) NA NA Salivary cotinine levels, self-reported alcohol intake, history of miscarriage, long-term chronic illness, IMD score, education, maternal vegetarian diet.
The outcome PTB was additionally adjusted for age, baby’s sex, and parity
Low
Catov et al, 2007, 30 United States Prospective cohort, 1997–2001, n = 1823 (S: n = 852) S: Multivitamin; US: no vitamin use Periconceptional PTB between GA 34 and 37 wks: AOR, 1.17 (0.77–1.79); PTB <GA 34 wks: AOR, 0.29 (0.13–0.64) NA SGA (fifth to <10th percentile); AOR, 1.12 (0.70–1.79); SGA (<fifth percentile);
AOR, 0.64 (0.40–1.03)
NA NA Race, age, education, GA at interview, household density, marital status, BMI, parity, smoking, moderate physical activity, >30 h of television watching per week, preeclampsia, transient hypertension, and family history of preeclampsia.
SGA was additionally adjusted for gestational age at delivery
Low
Catov et al, 2011, 31 Denmark Prospective cohort, 1997–2003, n = 33,288 (S: n= 21,785) S: Multivitamin; US: no vitamin use Periconceptional, postconceptional AHR, 0.89 (0.80–0.99); AHR, 0.92 (0.77–1.08) NA AHR, 0.83 (0.73–0.95); AHR, 0.68 (0.54–0.85) NA NA Age, parity, BMI, sociooccupational status, smoking Low
Czeizel et al, 2004, 27 Hungary Cohort (2 matched cohorts), 1993–1996, n = 6112 (S: n = 3056) S: Multivitamin; US: no vitamin use Periconceptional S: 5.6%; US: 5.2%; P = NS b S: 5.0%; US: 4.7%; P = NS b NA S: 0.2%; US: 0.3%; P = NS b ; definition: GA >28 wks and/or a fetus weighing >1000 g NA Age, socioeconomic status based on education and employment status, and residence of mother during pregnancy Low
Nohr et al, 2014, 20 Denmark Prospective cohort, 1996–2002, n = 33,678 (S: n = 22,285) S: Multivitamin
US: no vitamin use
Preconceptional (3–4 wk use); preconceptional (5–6 wk use); periconceptional; postconceptional (3–4 wk use); postconceptional (5–6 wk use) NA NA NA AHR, 0.53 (0.15–1.85); AHR, 1.83 (1.11–3.03); AHR, 1.06 (0.71–1.57); AHR, 0.88 (0.54–1.45); AHR, 0.55 (0.32–0.95); definition: GA ≥20 wks NA Age, parity, prepregnancy BMI, smoking, sociooccupational status, smoking, waiting time to pregnancy, infertility treatment, previous miscarriage Low
Scholl et al, 1997, 33 United States Prospective population-based cohort, 1985–1995, n = 1430 (S: n = 1148) S: Multivitamin; US: no vitamin use Periconceptional, first trimester, second trimester AOR, 0.55 (0.38–0.78); AOR, 0.56 (0.36–0.87); AOR, 0.54 (0.37–0.97) AOR, 0.59 (0.40–0.87); AOR, 0.63 (0.39–1.00); AOR, 0.57 (0.38–0.86) AOR, 1.07 (0.64–1.80); AOR, 1.22 (0.67–2.22); AOR, 1.00 (0.58–1.73) NA NA Age, parity, ethnicity, clinic pay status, inadequate weight gain, GA at entry, smoking, preconceptional BMI, prior PTB, first-trimester bleeding and nausea, caloric intake, preconceptional vitamin use.
Results for fist and second trimester not adjusted for GA at entry
Low
Shaw et al, 1997, 34 United States Retrospective cohort, 1987–1989, n = 734 (S: n = NA) S: Multivitamins containing folic acid; US: no vitamin use Periconceptional AOR, 0.72 (0.40–1.3) AOR, 1.2 (0.50–3.0) NA NA NA Race, age, smoking Low
Vahratian et al, 2004, 32 United States Prospective cohort, 1995–2000, n = 2010 (S: n = 1736) S: Multivitamin; US: no vitamin use Preconceptional, periconceptional ARR, 0.50 (0.20–1.25); ARR, 1.10 (0.73–1.65) NA NA NA NA Maternal health during pregnancy, vomiting during pregnancy, estimated energy intake, estimated iron and folate intake, parity, race, marital status Low

a See Supplemental Table 3

b Not calculated by the author of the trial.

Supplemental Table 5

Reference, year, country Study design, study period, participants, n Inclusion criteria Exclusion criteria Content of multivitamin supplement a Timing of multivitamin use Results
RR or absolute values, %
Matching or adjustment Risk of bias (Cochrane)
Kirke et al, 1992, Ireland 35 RCT, block randomization, 1981–1987, n = 354 (S: n = 239) Women with previous NTD affected pregnancy, nonpregnant and planned to have another child Women with impaired absorption from gastrointestinal tract S: multivitamins with or without folic acid; US: folic acid 360 μg Preconceptional Recurrence of NTD:
S: 0.6%; US: 0%; P = NS b
NA Moderate
Wald, 18 1991, United Kingdom, Hungary, Israel, France, Australia, Canada, Russia (previously USSR) RCT, 1983–1991, n = 1817 (S: n = 914) Women with previous NTD affected pregnancy and planned to have another child Women with epilepsy if treatment with folic acid adversely affected their treatment, women already taking vitamins S: multivitamins with or without folic acid; US: iron 120 mg and calcium phosphate 240 mg or folic acid 400 μg Periconceptional Recurrence of NTD:
RR, 0.80 (0.37–1.72)
NA Low

a See Supplemental Table 3

b Not calculated by the author of the trial.

Supplemental Table 6

Reference, year, country Study design, study period, definition, and participants, n Definition and controls, n Exclusion criteria Content of multivitamin supplement a Timing of multivitamin use Results, OR/AOR/RR/ARR
(95% CI) or absolute values, %
Adjustment Risk of bias (NOS)
Botto et al, 2000, 22 United States Case-control, 1968–1980 (information gathered in 1982–1983), n = 958 infants with nonsyndromic cardiac defects Random sample of infants without birth defects born in the same period, matched to the case group by hospital of birth, time of birth and race, n = 3029 Syndromic cases S: multivitamin; US: no vitamin use Periconceptional
Postconceptional
Congenital heart defects:
AOR, 0.76 (0.60–0.97)
AOR, 1.04 (0.87–1.24)
Period of birth, race, chronic disease; controls were matched to the case group by hospital of birth, birth period, and race Low
Botto et al, 2003, 49 United States Case-control, 1968–1980 (information gathered in 1982–1983), n = 170 infants with trisomy 21 Random sample of infants without birth defects born in the same period, matched to the case group by hospital of birth, time of birth and race, n = 2779 Syndromic cases S: multivitamin; US: no vitamin use Periconceptional Trisomy 21:
AOR, 0.8 (0.5–1.3)
Age, smoking, chronic illness, period of birth Low
Briggs, 1976, 23 United States Cohort, controlled, 1957–1976, n = 228 (women with previous pregnancy with orofacial clefting) Women with previous pregnancies with cleft lip with or without palate, n = 417 NA S: multivitamin; US: no vitamin use Periconceptional Recurrence of cleft lip with or without palate:
S: 4.4%; US: 4.8%; P = NS b
NA High
Correa, 2003, 49 United States Case-control, 1968–1980, n = 3278 infants with nonsyndromic birth defects that were reported to be associated with diabetes Random sample of infants without birth defects born in the same period, matched to the case group by hospital of birth, time of birth and race, n = 3029 Syndromic cases S: multivitamin; US: no vitamin use Periconceptional Cardiovascular defects: OR, 0.54 (0.37–0.79) b ; hydrocephalus: OR, 0.70 (0.43–1.15) NA High
Czeizel et al, 2004, 27 Hungary Cohort, controlled, 1993–1996, n = 3056 Women recruited at their first antenatal visit between eighth and 12th week of gestation, matched to the supplemented group by age, socioeconomic status, residence of mothers in the year of pregnancy, n = 3056 Delay in conception, current pregnancy, missing intake of supplement >7 d (these criteria were applied on the supplemented cohort) S: multivitamin containing folic acid; US: no vitamin use Periconceptional NTD: AOR, 0.11 (0.01–0.91); cardiovascular defects: AOR, 0.60 (0.38–0.96); cleft lip with or without palate: AOR, 1.63 (0.31–28.8); cleft palate: OR, 1.5 (0.17–18.0); urinary tract defects: AOR, 0.71 (0.33–1.50); limb deficiencies: OR, 0.33 (0.01–3.78); hydrocephalus: S: 0.3%; US: 0.1%, P = NS b ; trisomy 21: S: 0.3%; US: 0.3%, P = NS b Birth order, chronic maternal disorder, history of pregnancies with fetal death or congenital anomalies Low
Czeizel and Puhó, 2005, 28 Hungary Case-control, 1980–1996, n = 781 Three groups of controls:
(1) sample of matched control infants born with other congenital anomalies, n = 781; (2) infants born with congenital anomalies, n = 22,843; (3) infants born without congenital anomalies, n = 38,151
Inherited disorders or chromosomal anomaly S: multivitamin containing folic acid; US: no vitamin use First trimester Trisomy 21:
OR, 1.1 (0.4–2.8) (control group 1); OR, 1.8 (0.9–3.3) (control group 2); OR, 1.1 (0.6–2.0) (control group 3)
NA High
Hayes et al, 1996, 42 United States Case-control, 1988–1991, n = 303 infants with orofacial clefts Random sample of infants with other birth defects born in the same period, n = 1167 Inherited disorders or chromosomal anomaly S: multivitamin containing folic acid; US: no vitamin use Periconceptional Cleft lip with or without palate: RR, 1.3 (0.8–2.1); cleft palate: RR, 0.9 (0.5–1.6) Smoking status, alcohol use, race, education, income, maternal age, paternal age, previous miscarriage, parity, and gravidity (however, the authors of the study present only the unadjusted results because no significant differences were found when adjusting) High
Itikala et al, 2001, 43 United States Case-control, 1968–1980, n = 309 infants with orofacial clefts Random sample of infants without birth defects born in the same period, matched to the case group by hospital of birth, time of birth and race, n = 3029 Syndromic cases, cases with holoprosencephaly, hemifacial macrosomia, and amniotic band sequence S: multivitamin; US: no vitamin use Periconceptional Postconceptional
Periconceptional Postconceptional
Cleft lip with or without palate:
AOR, 0.63 (0.37–1.06); AOR, 0.52 (0.34–0.80); cleft palate:
AOR, 0.75 (0.35–1.62); AOR, 0.81 (0.44–1.52)
Age, education, sex of baby, smoking, flu, chronic disease, and family history Low
Li et al, 1995, 52 United States Case-control, 1990–1991, n = 118 infants with CUTA Random sample among singletons born in the same period with no birth defects except for CUTA, n = 369 Chromosome abnormality S: multivitamin; US: nothing or use of only 1 type of vitamin After first trimester, first trimester, but not before periconceptional Urinary tract deficiencies:
AOR, 0.31 (0.09–1.02); AOR, 0.16 (0.06–0.46); AOR, 0.14 (0.05–0.41)
Maternal and paternal age, marital status, race, education, income, presence of maternal and paternal birth defects, county of residence, birth year, nausea and vomiting throughout pregnancy, use of alcohol, smoking and illicit drugs, parity, gravidity, prior miscarriages, and induced abortions and stillbirths Low
Mills et al, 1989, 36 United States Case-control, 1985–1987, n = 571 infants with NTDs Two groups of controls:
(1) sample of live-born without major abnormalities, n = 573; (2) sample of infants born with abnormality or stillborn, n = 546.
Both groups matched to the case group by race, GA at diagnosis, date of diagnosis, and geographic area
Women with unknown use of vitamins S: multivitamin containing ≥4 vitamins; US: no vitamin use Periconceptional NTD:
AOR, 0.97 (0.82–1.13) (control group 1); AOR, 0.93 (0.79–1.09) (control group 2)
Multivitamin use, employment status, maternal education, family income, trimester of first prenatal care, and race or ethnical group Low
Mulinare et al, 1988, 37 United States Case-control, 1968–1980, n = 347 infants with NTDs Random sample without birth defects born in the same period, n = 2829 Women with unknown use of vitamins S: multivitamin; US: no vitamin use Periconceptional NTD:
AOR, 0.41 (0.26–0.66)
Age, education level, alcohol use, history of miscarriages, smoking, chronic illnesses, use of spermicides before the index birth Low
Shaw et al, 1995, 38 United States (1) Case-control, 1987–1989, n = 731 infants with orofacial clefts Random sample of liveborn nonmalformed infants living in the same counties as cases, n =734 Infants with chromosome anomaly, infants of mothers not speaking English or Spanish S: multivitamin containing folic acid; US: vitamin A or no vitamin use Periconceptional Cleft lip with or without palate:
OR (when no alcohol use), 0.61 (0.40–0.91);
OR (when alcohol use ≥1 time/wk), 0.16 (0.05–0.55)
Age, race, education, gravidity, smoking status, alcohol use (however, no significant differences were found and why the results are not presented as adjusted) Low
Shaw et al, 1995, 45 United States (2) Case-control, 1987–1988, n = 207 (conotruncal malformations), n = 178 (limb deficiencies) Random sample of liveborn nonmalformed infants living in the same counties as cases, n = 481 Infants with chromosome anomaly, infants of mothers not speaking English or Spanish S: multivitamin containing folic acid; US: no vitamin use Periconceptional AOR (conotruncal malformations):
0.53 (0.34–0.85); AOR (limb deficiencies), 0.70 (0.43–1.10)
Age, race, education, gravidity, smoking status, alcohol use Low
Shaw et al, 1995, 50 United States
(3)
Case-control, 1989–1991, n = 624 children with NTDs Random sample of liveborn nonmalformed infants, n = 612 Infants of mothers not speaking English or Spanish S: multivitamin containing folic acid; US: no vitamin use Preconceptional
first trimester
NTD:
OR, 0.65 (0.45–0.94); OR, 0.60 (0.46–0.79)
Age, race, education, gravidity, smoking status, alcohol use Low
Shaw et al, 2000, 21 United States Case-control, 1993–1996, n = 112 infants with ≥2 congenital abnormalities Random sample of liveborn nonmalformed infants born in the same time period and area as cases, n = 195 Infants with chromosome anomaly, infants of mothers not speaking English or Spanish S: multivitamin containing folic acid; US: no vitamin use Periconceptional
Postconceptional
Multiple congenital anomalies:
AOR, 2.9 (0.8–10.3); OR, 1.7 (0.9–3.3)
Age, race, education, gravidity, smoking status, alcohol use, BMI (however, no significant differences were found and why the results for postconceptional use of vitamins are not presented as adjusted) Low
Shaw et al, 2006, 44 USnited States Case-control, 1997–2000, n = 704 children with orofacial clefts, n = 404 children with cleft palate Random sample of liveborn nonmalformed infants, n =2594 Infants with chromosome anomaly, infants with clefts believed to be secondary to other defects S: multivitamin containing folic acid; US: no vitamin use Periconceptional Cleft lip with or without cleft palate: AOR, 1.01 (0.82–1.24); cleft palate: AOR, 1.02 (0.77–1.34) Age, race, education Low
Shaw et al, 2010, 51 United States Case-control, 1999–2004, n = 140 infants with dTGA d-transposition of great arteries (dTGA = 163 infants with TOF Random sample of liveborn nonmalformed infants born in the same area as cases, n = 698 Type 1 or 2 diabetes S: multivitamin containing folic acid; US: no vitamin use Periconceptional dTGA: AOR, 0.9 (0.6–1.3); TOF: AOR, 0.9 (0.6–1.4) Age, race, education Low
Smithells et al, 1983, 26 United Kingdom Cohort, controlled (2 cohorts, same study protocol, combined data); start date, NA. Recruitment closed 1982, n = 454 (women with previous pregnancy with NTDs) Women with previous pregnancies with NTDs, n = 519 Ectopic pregnancy, uncertain last menstrual period, uncertain vitamin intake/timing of intake S: multivitamin containing folic acid; US: no vitamin use Periconceptional Recurrence of NTDs:
S: 0.7%; US: 4.7%; P = .0001 b
Some centers matched the control group on age, number of previous NTD births, and estimated date of conception High
Thompson et al, 2003, 39 United States Case-control , 1992–1997, n = 179 infants with NTDs Randomly selected sample of live-born without NTDs, n = 288 Multiple pregnancy, women taking anticonvulsant medication S: multivitamin containing folic acid; US: no vitamin use Periconceptional NTD:
AOR, 0.55 (0.25–1.22)
Age, race, passive smoking, BMI, dietary folate Low
Tolarova et al, 1995, 19 Czech Republic Cohort, controlled, 1930–1962 (adults with nonsyndromic orofacial clefting), n = 88, and 1970–1982 (women with nonsyndromic orofacial clefting), n = 133 Women who did not want to participate or who started supplementation after the embryonic period; United States, n= 1901 Family history of clefting S: several micronutrients;
US: no vitamin use
Periconceptional Recurrence of cleft lip with or without cleft palate:
S: 4.22%; US: 1.42%; P = .03
NA High
Werler et al, 1993, 40 United States Case-control, 1988–1991, n = 436 infants with NTDs Infants with major congenital anomalies except for NTDs and oral clefts, n = 2615 Chromosome anomaly, known monogenetic disease, infants with an NTD-affected sibling S: multivitamin containing folic acid; US: no vitamin use Periconceptional NTD: 0.6 (0.4–0.8) Age, education, race, religion, ethnic group, income, birth status (liveborn/stillborn, therapeutic abortion), gravidity, parity, duration between pregnancies, level of planning of pregnancy, number of gynecological and obstetric visits, routine use of seatbelt, routine exercise, recreational drug use, smoking, diabetes, medication, calendar time, geographic region Low
Werler et al, 1999, 46 United States Case-control, 1993–1996, n = 114 (orofacial defects), n = 157 (conotruncal defects), and n = 271 (urinary tract defects) Two groups of controls:
(1) sample of live-born without abnormalities, n = 521 (control, 1); (2) sample of infants born with major abnormality other than NTDs (control, 2), n = 442
Infants with NTD, chromosome anomaly, known monogenetic disease S: ≥2 water-soluble vitamins and ≥2 fat-soluble vitamins; US: no vitamin use Periconceptional
Postconceptional
Periconceptional
Postconceptional
Periconceptional
Postconceptional
Urinary tract defects:
AOR (control 1), 0.6 (0.3–1.0); AOR, (control 1) 0.4 (0.3–0.8); cleft lip with or without cleft palate:
AOR (control 1), 0.7 (0.4–1.3); AOR (control 1), 0.8 (0.5–1.5); conotruncal defects:
AOR (control 1), 1.0 (0.6–1.6); AOR (control 1), 1.0 (0.6–1.7)
(results for control group 2 are not different from the above and therefore not shown)
Age, educational level, race, planned pregnancy, nausea and vomiting, place of living Low
Wilcox et al, 2007, 47 Norway Case-control, 1996–2001, n = 573 infants with orofacial clefting Randomly selected live-born infants, n = 763 Lack of ability to speak Norwegian, dead infants S: multivitamin containing folic acid; US: no vitamin use Periconceptional Cleft lip with or without cleft palate:
AOR, 0.75 (0.50–1.11)
Age, education, alcohol use, folic acid supplement, dietary folate, smoking status, other birth defects Low
Yang, 1997, 53 United States Case-control, 1968–1980, n = 117 infants with nonsyndromic limb deficiency Random sample of infants without birth defects born in the same period, matched to the case group by hospital of birth, time of birth and race, n = 3029 Syndromic cases S: multivitamin; US: no vitamin use Periconceptional
Postconceptional
Limb deficiencies:
OR, 0.47 (0.23–0.97); OR, 0.77 (0.41–1.46)
Age, race, birth periods, educational level, chronic illness, smoking and alcohol use during first trimester
(however, no significant differences were found and why the results are not presented as adjusted)
Low

a See Supplemental Table 3

b Not calculated by the author of the trial.

Supplemental Table 7

fx1
 

Supplemental Figure 1
Forest plot of the effect estimates for clefts
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017 .

fx2
 

Supplemental Figure 2
Forest plot of the effect estimates for cardiovascular defects
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017 .

fx3
 

Supplemental Figure 3
Forest plot of the effect estimates for urinary tract deficiencies
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017 .

fx4
 

Supplemental Figure 4
Forest plot of the effect estimates for limb deficiencies
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017 .

fx5
 

Supplemental Figure 5
Forest plot of the effect estimates for hydrocephalus
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017 .

fx6
 

Supplemental Figure 6
Forest plot of the effect estimates for trisomy 21
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017 .

 

The authors report no conflict of interest.

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