Systematic Reviews ajog.

org

Multivitamin use and adverse birth outcomes in

high-income countries: a systematic review
and meta-analysis
Hanne T. Wolf, MD; Hanne K. Hegaard, PhD; Lene D. Huusom, MD;
Anja B. Pinborg, MD, PhD, DMSc

BACKGROUND: In high-income countries, a healthy diet is widely accessible. However, a change toward a poor-quality diet with a low
nutritional value in high-income countries has led to an inadequate vitamin intake during pregnancy.
OBJECTIVE: We conducted a systematic review and meta-analysis to evaluate the association between multivitamin use among women in
high-income countries and the risk of adverse birth outcomes (preterm birth [primary outcome], low birthweight, small for gestational age,
stillbirth, neonatal death, perinatal mortality, and congenital anomalies without further specification).
STUDY DESIGN: We searched electronic databases (MEDLINE, Embase, Cochrane, Scopus, and CINAHL) from inception to June 17, 2016,
using synonyms of pregnancy, study/trial type, and multivitamins. Eligible studies were all studies in high-income countries investigating
the association between multivitamin use (3 or more vitamins or minerals in tablets or capsules) and adverse birth outcomes. We evaluated
randomized, controlled trials using the Cochrane Collaboration tool. Observational studies were evaluated using the Newcastle-Ottawa
Scale. Meta-analyses were applied on raw data for outcomes with data for at least 2 studies and were conducted using RevMan
(version 5.3). Outcomes were pooled using the random-effect model. The quality of evidence was assessed using the Grades of Research,
Assessment, Development and Evaluation approach.
RESULTS: We identified 35 eligible studies including 98,926 women. None of the studies compared the use of folic acid and iron vs the use
of multivitamins. The use of multivitamin did not change the risk of the primary outcome, preterm birth (relative risk, 0.84 [95% confidence
interval, 0.69e1.03]). However, the risk of small for gestational age (relative risk, 0.77 [95% confidence interval, 0.63e0.93]), neural
tube defects (relative risk, 0.67 [95% confidence interval, 0.52e0.87]), cardiovascular defects (relative risk, 0.83 [95% confidence
interval, 0.70e0.98]), urine tract defects (relative risk, 0.60 [95% confidence interval, 0.46e0.78]), and limb deficiencies (relative risk,
0.68 [95% confidence interval, 0.52-0.89]) was decreased. Of the 35 identified studies, only 4 were randomized, controlled trials. The
degree of clinical evidence according to the Grades of Research, Assessment, Development, and Evaluation system was low or very low for
all outcomes except for recurrence of neural tube defects in which a moderate degree of clinical evidence was found.
CONCLUSION: Routine multivitamin use in high-income countries can be recommended but with caution because of the low quality of
evidence. Randomized, controlled trials or well-performed, large prospective cohort studies are needed.
Key words: adverse birth outcome, congenital birth defects, meta-analysis, multivitamin, pregnancy, systematic review

D uring pregnancy, an increased

need of micronutrient re-
quirements presents to meet the growing
From the Department of Obstetrics and
Gynaecology, Copenhagen University Hospital,
Hvidovre Hospital, Hvidovre (Drs Wolf, Huusom,
and Pinborg), and Research Unit, Department of
Women’s and Children’s Health, Juliane Marie
Center for Women, Children, and Reproduction,
Copenhagen University Hospital, Rigshospitalet
(Dr Hegaard), Copenhagen, Denmark.
Received Jan. 12, 2017; revised March 10,
2017; accepted March 23, 2017.
The authors report no conflict of interest.
Corresponding author: Hanne Trap Wolf, MD.
trapwolf@gmail.com
0002-9378/$36.00
ª 2017 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2017.03.029
demands of the fetoplacental unit. In
high-income countries (HIs), a healthy
diet is widely accessible. However, a
change toward a poor-quality diet with a
low nutritional value in HICs has led to
an inadequate vitamin and mineral
intake during pregnancy.1,2 In addition,
recent data show that micronutrient
intake and supplementation during
pregnancy in HICs is much lower than
recommended.3-5
A recent Cochrane review6 and several
meta-analyses7-10 have assessed the
possible association between multivi-
tamin use and the risk of adverse
pregnancy outcome. There seems to
be consensus that the risk of low
birthweight (LBW) and small-for-
gestational-age (SGA) is reduced with
multivitamin use and that the risk of
preterm birth (PTB) and mortality re-
mains unchanged.
The previous meta-analyses
mainly include study data from low-
and middle-income countries in
which conditions like famine, undernu-
trition, short interpregnancy intervals,
infectious diseases, and anemia are a
great challenge. Therefore, the results are
not directly applicable on populations
from HICs. A meta-analysis from 2006
on prenatal multivitamin use and the
risk of congenital anomalies showed a
decreased risk of several anomalies,11 but
additional studies have been published
since then; hence, an updated meta-
analysis is needed.
We aimed to perform a systematic
review and meta-analysis to investigate
the association between multivitamin

404 American Journal of Obstetrics & Gynecology OCTOBER 2017

ajog.org
use in pregnancy and the risk of adverse
birth outcomes including congenital
anomalies in HICs.
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 guidelines12 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 con-
tacted 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 Eco-
nomic Co-Operation and Development
with the World Bank.14 Eligible studies
should investigate the association be-
tween the multivitamin use (3 or more
vitamins or minerals in tablets or cap-
sules) 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 compari-
son 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 re-
ports, 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 (7e28 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 partic-
ipants, 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% confi-
dence 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 c2 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
OCTOBER 2017 American Journal of Obstetrics & Gynecology
Systematic Reviews
the observational studies was assessed
using the Newcastle-Ottawa Scale16
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 Evalua-
tion (GRADE)17 and was categorized
into 4 levels, from very low (4222)
to high (4444).
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 heterogene-
ity was assessed with the I2 statistic.
Also as recommended by the
Cochrane handbook, we considered an
I2 value of 0e40% to represent low
heterogeneity, 30e60% moderate het-
erogeneity, 50e90% substantial hetero-
geneity, and 75e100% 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
405
Systematic Reviews
assessment (Figure 1). Of these, 56 studies
were excluded for various reasons
(Supplemental Table 2). We identified 35
eligible studies including 98,926 women.
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 91418 and in the
cohort studies from 21119 to 22,285.20 The
number of studied cases in case-control
studies varied from 11221 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 818,19,23-28 of 35 studies
stated the exact content of the used sup-
plements, and of these, only 1 study used
folic acid compatible to the current daily
recommended intake24 (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 mul-
tivitamins. Supplemental Tables 4e7
summarize characteristics and results of
the included studies.
Preterm birth
The risk of PTB was assessed in 1 RCT24
and in 7 cohort studies.27,29-34 In the
RCT involving 402 women, an un-
changed risk of PTB was found.24 The
results of the cohort studies were con-
tradictory (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 sum-
mary RR involving 42,592 women with
2280 events was 0.84 (95% CI,
0.69e1.03), with a high degree of sta-
tistical heterogeneity (I2 ¼ 73%)
(Figure 2). All cohort studies had a low
risk of bias. The GRADE estimate for
406 American Journal of Obstetrics & Gynecology OCTOBER 2017
quality of evidence was very low
(4222).
Low birthweight
The risk of LBW after multivitamin use
was assessed in 1 RCT24 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 periconcep-
tional multivitamin use,33 but in 2 studies
the risk was not affected by periconcep-
tional 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, I2 ¼ 89%)
(Figure 2). The risk of bias was low in all
of the studies. The GRADE estimate for
quality of evidence was very low
(4222).
Small for gestational age
The risk of SGA in relation to multivi-
tamin use was assessed in 1 RCT24 and in
4 cohort studies.29-31,33 In the RCT an
unchanged risk of SGA was found using
an intention-to-treat analysis, but a sig-
nificant decrease in risk was seen when
using a per-protocol analysis.24 In 3 of the
cohort studies, the findings did not sup-
port the use of a multivitamin.29,30,33
However, in a large cohort study from
Denmark, Catov et al31 found a decreased
risk of SGA both for pre- and peri-
conceptional 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-anal-
ysis.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, I2 ¼ 43%) (Figure 2).
The GRADE estimate for quality of evi-
dence was very low (4222).
Stillbirth and mortality
A small RCT found a similar risk of
stillbirth in multivitamin users and
nonusers.35 Likewise, 2 cohort studies
ajog.org
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 5e6 weeks within the pre-
conceptional 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,
0.59e1.03, I2 ¼ 0%). The GRADE esti-
mate for quality of evidence was low
(4422).
No studies on multivitamin use and
the risk of perinatal and neonatal mor-
tality were found.
Congenital birth defects
Multiple congenital anomalies. The asso-
ciation 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
(4222).
Neural tube defect. Six observational
studies examined the association be-
tween multivitamin use and the occur-
rence of neural tube defects
(NTDs).27,36-40 The studies included
women with a periconceptional use of
multivitamin except for 1 study
including women with either pre-
conceptional 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, 0.52e0.87, I2 ¼
81%) (Figure 3). Removing the study
without data on periconceptional
multivitamin use38 did not alter the
estimated relative effect (RR, 0.59 [95%
CI, 0.36e0.96]). The GRADE estimate
for quality of evidence was very low
(4222).
The association between preconcep-
tional multivitamin use and the recur-
rence of NTDs was assessed in 1 RCT,35
while periconceptional multivitamin
ajog.org Systematic Reviews

use was assessed in 1 RCT and in 1

FIGURE 1
cohort study.18,41 One study had a high
risk of bias because of a missing
Flowchart of search results
response rate and missing adjust-
ments.41 The summary RR of recur-
rence of NTDs after pre- and
periconceptional multivitamin use
studied in RCTs and involving 1549
women with 28 events was 0.83 (95%
CI, 0.40e1.72, I2 ¼ 0%) (Figure 3). The
GRADE estimate for quality of evidence
was moderate (4442).

Orofacial defects. We could not find any

RCTs examining the association be-
tween periconceptional multivitamin
use and orofacial defects (cleft lip
with or without cleft palate),
but 7 observational studies were
found.27,42-47 One of these studies
found a significant decreased risk
restricted to postconceptional multivi-
tamin use,43 while another study found
a significant decreased risk after peri-
conceptional 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.42-44,46-48 The summary RR
involving 13,680 women with 1418
events was 0.88 (95% CI, 0.77e1.01,
I2 ¼ 23%) (Figure 3). Removing the only
study with a high risk of bias42 resulted
in a significant RR (0.86 [95% CI,
0.77e0.96) and a reduced statistical
heterogeneity (Supplemental Figure 1). Flow chart of search results and process for identification, selection, and inclusion of references in
The GRADE estimate for quality of evi- systematic review is shown.
dence was low (4422). Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017.
The association between periconcep-
tional multivitamin use and cleft palate
without cleft lip was assessed in the same
studies. The summary RR for cleft palate involving 2767 women with 110 events defects including septal defects, ste-
was 1.12 (95% CI, 0.94e1.33, I2 ¼ 0%) was 0.61 (95% CI, 0.22e1.64, I2 ¼ 55%) nosis, etc was used. All studies but
(Supplemental Figure 1). The GRADE (Supplemental Figure 1). The GRADE one49 had a low risk of bias.
estimate for quality of evidence was low estimate for quality of evidence was very The summary RR of these 6 studies
(4422). low (4222). involving 11,902 women with 1377
events was 0.83 (95% CI, 0.70e0.98,
Recurrence of cleft lip with or without Cardiovascular defects. Six observational I2 ¼ 56%) (Supplemental Figure 2).
cleft palate studies examined the association be- Excluding the study including only
In 2 cohort studies both with high risk of tween periconceptional multivitamin cases of tetralogy of Fallot and
bias, the association between peri- use and congenital cardiovascular de- d-transposition of the great arteries51
conceptional multivitamin use and the fects.22,27,46,49-51 One study included did not change the result. However,
recurrence of cleft lip with or without only cases with tetralogy of Fallot and excluding the study with the high
cleft palate was assessed.19,23 d-transposition of the great arteries,51 risk of bias49 resulted in a non-
Both studies provided data for while in the other studies, a very significant RR of 0.88 (95% CI,
the meta-analysis. The summary RR broad definition of cardiovascular 0.77e1.01). The GRADE estimate

OCTOBER 2017 American Journal of Obstetrics & Gynecology 407

Systematic Reviews ajog.org

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.

for quality of evidence was low
(4422).
Urinary tract defects. Three observational
studies all with a low risk of bias exam-
ined the association between peri-
conceptional 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, 0.46e0.78, I2 ¼ 0%)
(Supplemental Figure 3). The GRADE
estimate for quality of evidence was very
low (4222).
Limb deficiencies. Three observational
studies examined the association be-
tween periconceptional multivitamin
use and limb deficiencies.27,50,53 All
studies had a low risk of bias and sup-
plied data for the meta-analysis. The
summary RR including 8299 women
and 207 events was 0.68 (95% CI,
0.52e0.89, I2 ¼ 0%) (Supplemental
Figure 4). The GRADE estimate for
quality of evidence was very low
(4222).
Hydrocephalus. Two observational studies
examined the association between
periconceptional multivitamin use and
hydrocephalus and provided data for

408 American Journal of Obstetrics & Gynecology OCTOBER 2017

ajog.org
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 meta-analysis.27,49 The summary RR
using the random-effect model including
7719 women and 206 events was 0.74
(95% CI, 0.13e4.30, I2 ¼87%)
(Supplemental Figure 5). Removing a
study with a high risk of bias49 did not
affect the result. The GRADE estimate for
quality of evidence was very low
(4222).
Trisomy 21. Three observational studies
examined the association between peri-
conceptional multivitamin use and tri-
somy 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, 0.70e1.37, I2 ¼ 0%) (Supplemental
Figure 6). Removing the only study
with a high risk of bias28 did not affect
the result. The GRADE estimate for
quality of evidence was very low
(4222).
A summary of all results is presented
in the 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 un-
changed 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 de-
fects, 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
OCTOBER 2017 American Journal of Obstetrics & Gynecology
Systematic Reviews
which a moderate quality of clinical
evidence was found.
Strengths and limitations
We recognize several strengths and lim-
itations in relation to this systematic re-
view. This is a comprehensive
assessment of the evidence, incorpo-
rating both RCTs and observational
studies from HICs. Strengths also
include the strict use of Prospective,
Randomized Trial on Intensive Self-
Monitoring Blood Glucose Manage-
ment Added Value in Non-Insulin
Treated Type 2 Diabetes Mellitus Pa-
tients 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
409
Systematic Reviews ajog.org

TABLE
Summary of results
Studies in I2 (corresponding
Outcome Studies, n meta-analysis, n Participants, n Events, n P value) RR (95% CI) Grade
PTB 8 4 42,592 2280 73% (.01) 0.84 (0.69e1.03) Very low
LBW 5 2 7498 452 89% (.003) 0.79 (0.45e1.41) Very low
SGA 5 3 36,965 1413 43% (.17) 0.77 (0.63e0.93) Very low
Stillbirth 3 2 39,845 208 0% (.76) 0.78 (0.59e1.03) 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 (0.52e0.87) Very low
Recurrence of NTDs 3 2 1549 28 0% (.72) 0.83 (0.40e1.72) Moderate
Cleft lip with or without cleft palate 7 6 13,680 1418 23% (0.26) 0.88 (0.77e1.01) Low
Cleft palate 7 6 13,042 777 0% (0.51) 1.12 (0.94e1.33) Low
Recurrence of clefts 2 2 2767 110 55% (0.14) 0.61 (0.22e1.64) Very low
Cardiovascular defects 6 6 11,902 1377 56% (0.04) 0.83 (0.70e0.98) Low
Urinary tract defects 3 3 6880 230 0% (0.51) 0.60 (0.46e0.78) Very low
Limb deficiencies 3 3 8299 207 0% (0.44) 0.68 (0.52e0.89) Very low
Hydrocephalus 2 2 7719 206 87% (0.006) 0.74 (0.13e4.30) Very low
Trisomy 21 3 3 10,653 216 0% (0.61) 0.98 (0.70e1.37) Very low
CI, confidence interval; LBW, low birthweight; NA, not available; NTD, neural tube defect; PTB, preterm birth; RR, relative risk; SGA, small for gestational age.
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017.

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 study20
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 multivi-
tamin 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 defi-
nition 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 informa-
tion was missing in the studies
evaluated.
A limitation of this meta-analysis is
that we have pooled unadjusted esti-
mates, 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 pop-
ulations 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 rele-
vant to our results.
Interpretation
In line with meta-analyses including
studies from low- and middle-income
countries,6,7,9,10 we found an un-
changed risk of PTB. Also in line with the
previous results, we found that peri-
conceptional 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 al11 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

410 American Journal of Obstetrics & Gynecology OCTOBER 2017

ajog.org
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, uri-
nary 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 signifi-
cantly reduced, but the quality of evi-
dence 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 multi-
vitamin 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 Bhutta6
found in a Cochrane review
including studies from low- to
middle-income countries that multi-
vitamin 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/m2 or a height
155 cm
had a greater effect of multivitamin use
than women with a BMI <20 kg/m2 or a
height <155 cm. In HICs the vast ma-
jority of women have a BMI
20 kg/m2
and a height
155 cm,58-60 suggesting
that this population might have a posi-
tive effect of multivitamin use compared
with iron and folic acid alone.
Conclusion
Because there seems to be a protective
effect of periconceptional multivi-
tamin 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 un-
certainty 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. - 14. The World Bank. OECD members. Available
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ajog.org Systematic Reviews

SUPPLEMENTAL TABLE 1
Search strategy
Database Search strategy Date Hits
Medline (((((“Pregnant Women” [Mesh]) or “Pregnancy”[Mesh] June 17, 2016 5850
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
Embase (“Pregnant Women” OR Pregnancy OR pregnant* OR June 17, 2016 408
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
CINAHL ((MH “Expectant Mothers”) OR (MH “Pregnancy”) OR June 17, 2016 15
“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
Cochrane ((Mesh descriptor: [micronutrients] explode all trees) June 17, 2016 958
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
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017. (continued)

OCTOBER 2017 American Journal of Obstetrics & Gynecology 412.e1

Systematic Reviews ajog.org

SUPPLEMENTAL TABLE 1
Search strategy (continued)
Database Search strategy Date Hits
SCOPUS ((ALL (concurrent study OR follow up OR random OR June 17, 2016 2229
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”))
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017.

SUPPLEMENTAL TABLE 2
List of excluded studies in the systematic review (n[ 56)
Author, year Reason for exclusion
1
Chen et al, 2015 Not correct intervention
2
Aronsson et al, 2013 Not correct intervention
3
Carmichael et al, 2013 Not correct intervention
Leung et al, 20134 Not relevant study outcome
5
Wallenstein et al, 2013 Not correct intervention
6
Haider and Bhutta, 2012 Review and all relevant studies included
7
Ramakrishnan et al, 2012 Review and all relevant studies included
8
Ramakrishnan et al, 2012 Review and all relevant studies included
Carmichael et al, 20129 Not correct intervention
10
Dunlop et al, 2012 Not correct intervention
11
Siegfried et al, 2012 Review and all relevant studies included
12
Roy et al, 2012 Not relevant study outcome
13
Avalos et al, 2011 Not relevant study outcome
Czeizel, 201114 Review and all relevant studies included
15
Meltzer et al, 2011 Not correct intervention
16
Haider et al, 2011 Review and all relevant studies included
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017. (continued)

412.e2 American Journal of Obstetrics & Gynecology OCTOBER 2017

ajog.org Systematic Reviews

SUPPLEMENTAL TABLE 2
List of excluded studies in the systematic review (n[ 56) (continued)
Author, year Reason for exclusion
17
Czeizel and Bánhidy, 2011 Review and all relevant studies included
18
Christian, 2010 Review and all relevant studies included
19
Allen and Peerson, 2009 Not relevant study outcome
20
Burris et al, 2010 Not relevant study outcome
Watson and McDonald, 201021 Not correct intervention
22
Shah et al, 2009 Review and all relevant studies included
23
Czeizel, 2009 Review and all relevant studies included
24
Smedts et al, 2008 Not correct (unsure) intervention. Data not available from authors.
25
Bitsko and Sachdev, 2007 Not correct intervention
Bille et al, 200726 Not correct intervention
27
Goh et al, 2006 Review and all relevant studies included
28
Shah et al, 2004 Review and all relevant studies included
29
Lagiou et al, 2005 Not relevant study outcome
30
Yuskiv et al, 2005 Includes less than 100 cases
Lammer et al, 200431 Double data
32
Czeizel and Medveczky, 2003 Double data
33
Merialdi et al, 2003 Review and all relevant studies included
34
Shaw et al, 2002 Double data
35
Lumley et al, 2011 Article withdrawn
Black, 200136 Review and all relevant studies included
37
Mathews et al, 1999 Not correct intervention
38
Velie et al, 1999 Not correct intervention
39
Shaw et al, 2010 Double data
40
Khoury et al, 1996 Double data
Czeizel et al, 199441 Not correct intervention
42
Czeizel et al, 1993 Not correct intervention
43
Bower and Stanley, 1992 Includes less than100 cases
44
Czeizel and Dudás, 1992 Not correct intervention
Milunsky et al, 198945 Not correct intervention
46
Sheppard et al, 1989 Not correct intervention
47
Hill et al, 1988 Not correct intervention
48
Wild et al, 1986 Double data
49
Simpson and Robertson, 1985 Commentary
Czeizel and Rodé, 198450 Study protocol
51
Seller and Nevin, 1984 Double data
52
Chalmer and Nevin, 1982 Commentary
53
Viegas et al, 1982 Not correct intervention
54
Smithells et al, 1981 Double data
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017. (continued)

OCTOBER 2017 American Journal of Obstetrics & Gynecology 412.e3

Systematic Reviews ajog.org

SUPPLEMENTAL TABLE 2
List of excluded studies in the systematic review (n[ 56) (continued)
Author, year Reason for exclusion
55
Jacobson, 1980 Not correct intervention
56
Conway, 1958 Includes less than 100 cases
1
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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; 5 Wallenstein MB, Shaw GM, Yang W, Carmichael SL. Periconceptional nutrient intakes and risks of orofacial clefts in California. Pediatr Res 2013;74:457-65; 6 Haider
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maternal diet and dietary supplement intake in pregnant New Zealand women with infant birthweight. Eur J Clin Nutr 2010;64:184-93; 22 Shah PS, Ohlsson A, Knowledge Synthesis Group on De-
terminants of Low Birth Weight and Preterm Births. Effects of prenatal multimicronutrient supplementation on pregnancy outcomes: a meta-analysis. CMAJ 2009;180:E99-108; 23 Czeizel AE. Peri-
conceptional 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; 27 Goh YI, Bollano E, Einarson TR, Koren G. Prenatal
multivitamin supplementation and rates of congenital anomalies: a meta-analysis. J Obstet Gynaecol Can 2006;28:680-9; 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; 31 Lammer EJ, Shaw GM, Iovannisci DM, Finnell RH. Periconceptional multivitamin
intake during early pregnancy, genetic variation of acetyl-N-transferase 1 (NAT1), and risk for orofacial clefts. Birth Defects Res A Clin Mol Teratol 2004;70:846-52; 32 Czeizel AE, Medveczky E.
Periconceptional multivitamin supplementation and multimalformed offspring. Obstet Gynecol 2003;102:1255-61; 33 Merialdi M, Carroli G, Villar J, et al. Nutritional interventions during pregnancy for the
prevention or treatment of impaired fetal growth: an overview of randomized controlled trials. J Nutr 2003;133(5 Suppl 2):1626S-31S; 34 Shaw GM, Lammer EJ, Zhu H, Baker MW, Neri E, Finnell RH.
Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spina bifida. Am J Med Genet 2002;108:1-6; 35 Lumley J, Watson L, Watson M, Bower C.
WITHDRAWN: periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects. Cochrane database Syst Rev 2011:CD001056; 36 Black RE. Micronutrients in
pregnancy. Br J Nutr 2001;85(Suppl 2):S193-7; 37 Mathews F, Yudkin P, Neil A. Influence of maternal nutrition on outcome of pregnancy: prospective cohort study. BMJ 1999;319:339-43; 38 Velie EM,
Block G, Shaw GM, Samuels SJ, Schaffer DM, Kulldorff M. Maternal supplemental and dietary zinc intake and the occurrence of neural tube defects in California. Am J Epidemiol 1999;150:605-16;
39
Shaw GM, Carmichael SL, Yang W, Lammer EJ. Periconceptional nutrient intakes and risks of conotruncal heart defects. Birth Defects Res A Clin Mol Teratol 2010;88:144-51; 40 Khoury MJ, Shaw GM,
Moore CA, Lammer EJ, Mulinare J. Does periconceptional multivitamin use reduce the risk of neural tube defects associated with other birth defects? Data from two population-based case-control studies.
Am J Med Genet 1996;61:30-6; 41 Czeizel AE, Dudás I, Métneki J. Pregnancy outcomes in a randomised controlled trial of periconceptional multivitamin supplementation. Final report. Arch Gynecol Obstet
1994;255:131-9; 42 Czeizel AE. Prevention of congenital abnormalities by periconceptional multivitamin supplementation. BMJ 1993;306:1645-8; 43 Bower C, Stanley FJ. Periconceptional vitamin
supplementation and neural tube defects; evidence from a case-control study in Western Australia and a review of recent publications. J Epidemiol Community Health 1992;46:157-61; 44 Czeizel AE,
Dudás I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832-5; 45 Milunsky A, Jick H, Jick SS, et al. Multivitamin/folic acid
supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 1989;262:2847-52; 46 Sheppard S, Nevin NC, Seller MJ, et al. Neural tube defect recurrence after “partial”
vitamin supplementation. J Med Genet 1989;26:326-9; 47 Hill L, Murphy M, McDowall M, Paul AH. Maternal drug histories and congenital malformations: limb reduction defects and oral clefts. J Epidemiol
Community Health 1988;42:1-7; 48 Wild J, Read AP, Sheppard S, et al. Recurrent neural tube defects, risk factors and vitamins. Arch Dis Child 1986;61:440-4; 49 Simpson D, Robertson E. Vitamins and
neural tube defects. Med J Aust 1985;142:706; 50 Czeizel A, Rodé K. Trial to prevent first occurrence of neural tube defects by periconceptional multivitamin supplementation. Lancet (London, England)
1984;2:40; 51 Seller MJ, Nevin NC. Periconceptional vitamin supplementation and the prevention of neural tube defects in south-east England and Northern Ireland. J Med Genet 1984;21:325-30;
52
Chalmers TC, Sacks H. Vitamin supplements to prevent neural tube defects. Lancet (London, England) 1982;1:748; 53 Viegas OA, Scott PH, Cole TJ, Mansfield HN, Wharton P, Wharton BA. Dietary
protein energy supplementation of pregnant Asian mothers at Sorrento, Birmingham. I: unselective during second and third trimesters. Br Med J (Clin Res Ed) 1982;285:589-92; 54 Smithells RW,
Sheppard S, Schorah CJ, et al. Apparent prevention of neural tube defects by periconceptional vitamin supplementation. Arch Dis Child 1981;56:911-8; 55 Jacobson HN. A randomized controlled trial of
prenatal nutritional supplementation. Pediatrics 1980;65:835-6; 56 Conway H. Effect of supplemental vitamin therapy on the limitation of incidence of cleft lip and cleft palate in humans. Plast Reconstr
Surg Transplant Bull 1958;22:450-3.
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SUPPLEMENTAL TABLE 3
Composition of the multivitamin used in the studies
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 mg, niacinamide
100 mg, C 300 mg, calcium pantothenate 20 mg
Brough, 2010 b-carotene 3 mg, thiamin 3 mg, riboflavin 2 mg, niacin 20 mg,
B6 10 mg, B12 6 mg, C 70 mg, D 5 mg , E 20 mg, K 70 mg, folic
acid 400 mg, Fe 20 mg, Zn 15 mg, Mg 150 mg, iodine 140 mg,
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 mg, 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, b-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 mg, cobalamin 1 mg, 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, Multivitamins containing folic acid, CNS
2000, 2006, 2010
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
CNS, content not stated.
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412.e6 American Journal of Obstetrics & Gynecology OCTOBER 2017

SUPPLEMENTAL TABLE 4
Study characteristics of included RCTs (perinatal adverse outcomes)
Content of multivitamin Mortality, early
supplement, control neonatal (<7 d), late
regimen used and GA PTB (GA neonatal (7e28 d),
Study design, (wks) at entry in the <37 wks), SGA (<10 Stillbirth perinatal (GA ‡ 28
Reference, year, study period, study in the intervention absolute LBW (<2500 g) percentile), absolute wks to 7 d of life), Matching or Risk of bias
country participants, n group (mean – SD)a values absolute values absolute values values neonatal (<28 d) adjustment (Cochrane)
Brough, 2010, RCT, 2002e2004, S: several micronutrients; All: S: 2.5%; All: S: 7.3%; All: S: 16.8%; NA NA NA Unclear
England n ¼ 402 US: placebo with US: 2.3%; US: 4.6%; US: 17.8%;
(S: n ¼ 207) iron oxide coating; P ¼ NS P ¼ NS P ¼ NS
GA: 12 (median)
77e87 (interquartile
range)
Hininger, 2004, RCT, study S: several micronutrients; NA S: 6.1%; US: NA NA NA NA High
France period: NA US: placebo; GA: 14  2 28.1%;
n ¼ 100 P ¼ 0.02; definition:
(S: n ¼ 50) <2700 g
Kirke, 1992, RCT, block S: multivitamins with or NA NA NA S: 1.4%; NA NA Unclear
Ireland randomization, without folic acid; US: folic US: 0%;
1981e1987 acid 360 mg; GA: P ¼ NS;
n ¼ 354 preconceptional use definition of
(S: n ¼ 239) stillbirth: NA
GA, gestational age; LBW, low birthweight; NA, not applicable; NS, nonsignificant; PTB, preterm birth; RCT, randomized controlled trial; S, supplemented; SGA, small for gestational age; US, unsupplemented.
a
See Supplemental Table 3.
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SUPPLEMENTAL TABLE 5
Study characteristics of included observational studies (perinatal adverse outcomes)
Content of PTB (<37 wks), LBW (<2500
multivitamin AOR/AHR/ARR g), AOR (95% SGA (<10 Stillbirth (definition
Study design, supplement, (95% CI), or CI), or percentile), according to author) Risk of
Reference, year, study period, control regimen Timing of absolute values, absolute AOR/AHR (95% AHR, (95% CI), or Matching or bias
country participants, n useda multivitamin use % values, % CI) absolute values, % Mortality adjustment (NOS)
Alwan et al, Prospective S: Multivitamin; First trimester, AOR, 1.3 NA AOR, 1.3 NA NA Salivary cotinine Low
2010,29 England cohort, US: no vitamin second trimester, (0.6e2.7), AOR, (0.8e1.9); AOR, levels, self-reported
2003e2006, use third trimester 1.8 (0.8e4.1), 1.1 (0.7e1.9); alcohol intake, history
n ¼ 1274 (S: AOR, 3.4 AOR, 0.9 of miscarriage,
n ¼ 1043 in first (1.2e9.6) (0.5e1.7) long-term chronic
trimester, illness, IMD score,
n¼ 274 in second education, maternal
trimester, n¼ 139 vegetarian diet.
in third trimester) The outcome PTB
was additionally
adjusted for age,
baby’s sex, and parity
Catov et al, Prospective S: Multivitamin; Periconceptional PTB between GA NA SGA (fifth to NA NA Race, age, education, Low
2007,30 United cohort, US: no vitamin 34 and 37 wks: <10th GA at interview,
States 1997e2001, use AOR, 1.17 percentile); AOR, household density,
n ¼ 1823 (S: (0.77e1.79); PTB 1.12 (0.70 marital status, BMI,
n ¼ 852) <GA 34 wks: e1.79); SGA parity, smoking,
AOR, 0.29 (<fifth moderate physical
activity, >30 h of
OCTOBER 2017 American Journal of Obstetrics & Gynecology

(0.13e0.64) percentile);
AOR, 0.64 television watching
(0.40e1.03) per week,
preeclampsia,
transient
hypertension, and
family history of
preeclampsia.
SGA was additionally
adjusted for
gestational age at

Systematic Reviews
delivery
Catov et al, Prospective S: Multivitamin; Periconceptional, AHR, 0.89 NA AHR, 0.83 NA NA Age, parity, BMI, Low
2011,31 Denmark cohort, US: no vitamin postconceptional (0.80e0.99); (0.73e0.95); sociooccupational
1997e2003, use AHR, 0.92 AHR, 0.68 status, smoking
n ¼ 33,288 (0.77e1.08) (0.54e0.85)
(S: n¼ 21,785)
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017. (continued)
412.e7
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412.e8 American Journal of Obstetrics & Gynecology OCTOBER 2017

SUPPLEMENTAL TABLE 5
Study characteristics of included observational studies (perinatal adverse outcomes) (continued)
Content of PTB (<37 wks), LBW (<2500
multivitamin AOR/AHR/ARR g), AOR (95% SGA (<10 Stillbirth (definition
Study design, supplement, (95% CI), or CI), or percentile), according to author) Risk of
Reference, year, study period, control regimen Timing of absolute values, absolute AOR/AHR (95% AHR, (95% CI), or Matching or bias
country participants, n useda multivitamin use % values, % CI) absolute values, % Mortality adjustment (NOS)
Czeizel et al, Cohort (2 S: Multivitamin; Periconceptional S: 5.6%; US: S: 5.0%; US: NA S: 0.2%; US: 0.3%; NA Age, socioeconomic Low
2004,27 Hungary matched cohorts), US: no vitamin 5.2%; P ¼ NSb 4.7%; P ¼ P ¼ NSb; definition: status based on
1993e1996, use NSb GA >28 wks and/or a education and
n ¼ 6112 fetus weighing employment status,
(S: n ¼ 3056) >1000 g and residence of
mother during
pregnancy
Nohr et al, Prospective S: Multivitamin Preconceptional NA NA NA AHR, 0.53 NA Age, parity, Low
2014,20 Denmark cohort, US: no vitamin (3e4 wk use); (0.15e1.85); AHR, prepregnancy BMI,
1996e2002, use preconceptional 1.83 (1.11e3.03); smoking,
n ¼ 33,678 (5e6 wk use); AHR, 1.06 sociooccupational
(S: n ¼ 22,285) periconceptional; (0.71e1.57); AHR, status, smoking,
postconceptional 0.88 (0.54e1.45); waiting time to
(3e4 wk use); AHR, 0.55 pregnancy, infertility
postconceptional (0.32e0.95); treatment, previous
(5e6 wk use) definition: GA
20 miscarriage
wks
Scholl et al, Prospective S: Multivitamin; Periconceptional, AOR, 0.55 AOR, 0.59 AOR, 1.07 NA NA Age, parity, ethnicity, Low
1997,33 United population-based US: no vitamin first trimester, (0.38e0.78); (0.40e0.87); (0.64e1.80); clinic pay status,
States cohort, use second trimester AOR, 0.56 AOR, 0.63 AOR, 1.22 inadequate weight
1985e1995, (0.36e0.87); (0.39e1.00); (0.67e2.22); gain, GA at entry,
n ¼ 1430 AOR, 0.54 AOR, 0.57 AOR, 1.00 smoking,
(S: n ¼ 1148) (0.37e0.97) (0.38e0.86) (0.58e1.73) 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
Shaw et al, Retrospective S: Multivitamins Periconceptional AOR, 0.72 AOR, 1.2 NA NA NA Race, age, smoking Low
1997,34 United cohort, containing folic (0.40e1.3) (0.50e3.0)
States 1987e1989, acid; US: no

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n ¼ 734 (S: vitamin use
n ¼ NA)
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017. (continued)
 ajog.org
SUPPLEMENTAL TABLE 5
Study characteristics of included observational studies (perinatal adverse outcomes) (continued)
Content of PTB (<37 wks), LBW (<2500
multivitamin AOR/AHR/ARR g), AOR (95% SGA (<10 Stillbirth (definition
Study design, supplement, (95% CI), or CI), or percentile), according to author) Risk of
Reference, year, study period, control regimen Timing of absolute values, absolute AOR/AHR (95% AHR, (95% CI), or Matching or bias
country participants, n useda multivitamin use % values, % CI) absolute values, % Mortality adjustment (NOS)
Vahratian et al, Prospective S: Multivitamin; Preconceptional, ARR, 0.50 NA NA NA NA Maternal health Low
2004,32 United cohort, US: no vitamin periconceptional (0.20e1.25); during pregnancy,
States 1995e2000, use ARR, 1.10 vomiting during
n ¼ 2010 (S: (0.73e1.65) pregnancy, estimated
n ¼ 1736) energy intake,
estimated iron and
folate intake, parity,
race, marital status
AHR, adjusted hazard ratio; AOR, adjusted odds ratio; BMI, body mass index; GA, gestational age; LBW, low birthweight; NA, not applicable; NOS, Newcastle Ottawa Score; NS, nonsigfnificant; PTB, preterm birth; RR, relative risk; S, supplemented with multivitamin;
SGA, small for gestational age; US, unsupplemented.
a
See Supplemental Table 3; b Not calculated by the author of the trial.
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017.
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Systematic Reviews
412.e9
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SUPPLEMENTAL TABLE 6
Study characteristics of included RCTs (birth defects)
Results
Study design, study Timing of RR or
Reference, year, period, participants, Content of multivitamin multivitamin absolute Matching or Risk of bias
country n Inclusion criteria Exclusion criteria supplementa use values, % adjustment (Cochrane)
Kirke et al, 1992, RCT, block Women with previous Women with impaired S: multivitamins with or Preconceptional Recurrence NA Moderate
Ireland35 randomization, NTD affected pregnancy, absorption from without folic acid; US: folic of NTD:
1981e1987, n ¼ 354 nonpregnant and planned gastrointestinal tract acid 360 mg S: 0.6%; US:
(S: n ¼ 239) to have another child 0%; P ¼ NSb
Wald,18 1991, United RCT, 1983e1991, Women with previous Women with epilepsy if S: multivitamins with Periconceptional Recurrence NA Low
Kingdom, Hungary, Israel, n ¼ 1817 (S: n ¼ 914) NTD affected pregnancy treatment with folic acid or without folic acid; of NTD:
France, Australia, Canada, and planned to adversely affected their US: iron 120 mg and RR, 0.80
Russia (previously USSR) have another child treatment, women calcium phosphate 240 mg (0.37e1.72)
already taking vitamins or folic acid 400 mg
NA, not applicable; NS, nonsignificant; NTD, neural tube defects; RCT, randomized, controlled trial; RR, relative risk; S, supplemented; US, unsupplemented.
a
See Supplemental Table 3; b Not calculated by the author of the trial.
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SUPPLEMENTAL TABLE 7
Study characteristics of included observational studies (birth defects)
Results,
Study design, study Content of OR/AOR/RR/ARR Risk of
Reference, period, definition, Definition and multivitamin Timing of (95% CI) or bias
year, country and participants, n controls, n Exclusion criteria supplementa multivitamin use absolute values, % Adjustment (NOS)
Botto et al, Case-control, Random sample of Syndromic cases S: multivitamin; Periconceptional Congenital heart Period of birth, race, Low
2000,22 United 1968e1980 infants without birth US: no vitamin use Postconceptional defects: chronic disease;
States (information gathered defects born in the AOR, 0.76 (0.60e0.97) controls were matched
in 1982e1983), same period, matched AOR, 1.04 (0.87e1.24) to the case group by
n ¼ 958 infants with to the case group by hospital of birth, birth
nonsyndromic cardiac hospital of birth, time period, and race
defects of birth and race,
n ¼ 3029
Botto et al, Case-control, Random sample of Syndromic cases S: multivitamin; Periconceptional Trisomy 21: Age, smoking, chronic Low
2003,49 United 1968e1980 infants without birth US: no vitamin use AOR, 0.8 (0.5e1.3) illness, period of birth
States (information gathered defects born in the
in 1982e1983), same period, matched
n ¼ 170 infants with to the case group by
OCTOBER 2017 American Journal of Obstetrics & Gynecology

trisomy 21 hospital of birth, time

of birth and race,
n ¼ 2779
Briggs, 1976,23 Cohort, controlled, Women with previous NA S: multivitamin; Periconceptional Recurrence of cleft lip NA High
United States 1957e1976, n ¼ 228 pregnancies with cleft US: no vitamin use with or without palate:
(women with previous lip with or without S: 4.4%; US: 4.8%; P ¼
pregnancy with palate, n ¼ 417 NSb
orofacial clefting)
Correa, 2003,49 Case-control, Random sample of Syndromic cases S: multivitamin; Periconceptional Cardiovascular NA High
United States 1968e1980, n ¼ 3278 infants without birth US: no vitamin use defects: OR, 0.54

Systematic Reviews
infants with defects born in the (0.37e0.79)b;
nonsyndromic birth same period, matched hydrocephalus: OR,
defects that were to the case group by 0.70 (0.43e1.15)
reported to be hospital of birth, time
associated with of birth and race,
diabetes n ¼ 3029
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017. (continued)
412.e11
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412.e12 American Journal of Obstetrics & Gynecology OCTOBER 2017

SUPPLEMENTAL TABLE 7
Study characteristics of included observational studies (birth defects) (continued)
Results,
Study design, study Content of OR/AOR/RR/ARR Risk of
Reference, period, definition, Definition and multivitamin Timing of (95% CI) or bias
year, country and participants, n controls, n Exclusion criteria supplementa multivitamin use absolute values, % Adjustment (NOS)
Czeizel et al, Cohort, controlled, Women recruited at Delay in conception, S: multivitamin Periconceptional NTD: AOR, 0.11 Birth order, chronic Low
2004,27 Hungary 1993e1996, n ¼ 3056 their first antenatal visit current pregnancy, containing folic acid; (0.01e0.91); maternal disorder,
between eighth and missing intake of US: no vitamin use cardiovascular defects: history of pregnancies
12th week of gestation, supplement >7 AOR, 0.60 with fetal death or
matched to the d (these criteria were (0.38e0.96); cleft lip congenital anomalies
supplemented group applied on the with or without palate:
by age, socioeconomic supplemented cohort) AOR, 1.63 (0.31
status, residence of e28.8); cleft palate:
mothers in the year of OR, 1.5 (0.17e18.0);
pregnancy, n ¼ 3056 urinary tract defects:
AOR, 0.71 (0.33
e1.50); limb
deficiencies: OR, 0.33
(0.01e3.78);
hydrocephalus: S:
0.3%; US: 0.1%,
P ¼ NSb; trisomy 21: S:
0.3%; US: 0.3%,
P ¼ NSb
Czeizel and Case-control, Three groups of Inherited disorders or S: multivitamin First trimester Trisomy 21: NA High
Puhó, 2005,28 1980e1996, n ¼ 781 controls: chromosomal anomaly containing folic acid; OR, 1.1 (0.4e2.8)
Hungary (1) sample of matched US: no vitamin use (control group 1); OR,
control infants born 1.8 (0.9e3.3) (control
with other congenital group 2); OR, 1.1
anomalies, n ¼ 781; (0.6e2.0) (control
(2) infants born with group 3)
congenital anomalies,
n ¼ 22,843; (3) infants
born without
congenital anomalies,
n ¼ 38,151
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017. (continued)

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SUPPLEMENTAL TABLE 7
Study characteristics of included observational studies (birth defects) (continued)
Results,
Study design, study Content of OR/AOR/RR/ARR Risk of
Reference, period, definition, Definition and multivitamin Timing of (95% CI) or bias
year, country and participants, n controls, n Exclusion criteria supplementa multivitamin use absolute values, % Adjustment (NOS)
Hayes et al, Case-control, Random sample of Inherited disorders or S: multivitamin Periconceptional Cleft lip with or without Smoking status, High
1996,42 United 1988e1991, n ¼ 303 infants with other birth chromosomal anomaly containing folic acid; palate: RR, 1.3 alcohol use, race,
States infants with orofacial defects born in the US: no vitamin use (0.8e2.1); cleft palate: education, income,
clefts same period, n ¼ 1167 RR, 0.9 (0.5e1.6) 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)
Itikala et al, Case-control, Random sample of Syndromic cases, S: multivitamin; Periconceptional Cleft lip with or without Age, education, sex of Low
2001,43 United 1968e1980, n ¼ 309 infants without birth cases with US: no vitamin use Postconceptional palate: baby, smoking, flu,
States infants with orofacial defects born in the holoprosencephaly, Periconceptional AOR, 0.63 chronic disease, and
clefts same period, matched hemifacial Postconceptional (0.37e1.06); AOR, family history
to the case group by macrosomia, and 0.52 (0.34e0.80); cleft
hospital of birth, time amniotic band palate:
OCTOBER 2017 American Journal of Obstetrics & Gynecology

of birth and race, sequence AOR, 0.75

n ¼ 3029 (0.35e1.62); AOR,
0.81 (0.44e1.52)
Li et al, 1995,52 Case-control, Random sample Chromosome S: multivitamin; US: After first trimester, Urinary tract Maternal and paternal Low
United States 1990e1991, n ¼ 118 among singletons born abnormality nothing or use of only 1 first trimester, but not deficiencies: age, marital status,
infants with CUTA in the same period with type of vitamin before AOR, 0.31 race, education,
no birth defects except periconceptional (0.09e1.02); AOR, income, presence of
for CUTA, n ¼ 369 0.16 (0.06e0.46); maternal and paternal
AOR, 0.14 (0.05e0.41) birth defects, county of
residence, birth year,

Systematic Reviews
nausea and vomiting
throughout pregnancy,
use of alcohol,
smoking and illicit
drugs, parity, gravidity,
prior miscarriages, and
induced abortions and
stillbirths
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017. (continued)
412.e13
 Systematic Reviews
412.e14 American Journal of Obstetrics & Gynecology OCTOBER 2017

SUPPLEMENTAL TABLE 7
Study characteristics of included observational studies (birth defects) (continued)
Results,
Study design, study Content of OR/AOR/RR/ARR Risk of
Reference, period, definition, Definition and multivitamin Timing of (95% CI) or bias
year, country and participants, n controls, n Exclusion criteria supplementa multivitamin use absolute values, % Adjustment (NOS)
Mills et al, Case-control, Two groups of controls: Women with unknown S: multivitamin Periconceptional NTD: Multivitamin use, Low
1989,36 United 1985e1987, n ¼ 571 (1) sample of live-born use of vitamins containing
4 AOR, 0.97 (0.82e1.13) employment status,
States infants with NTDs without major vitamins; US: no (control group 1); AOR, maternal education,
abnormalities, n ¼ vitamin use 0.93 (0.79e1.09) family income,
573; (2) sample of (control group 2) trimester of first
infants born with prenatal care, and race
abnormality or or ethnical group
stillborn, n ¼ 546.
Both groups matched
to the case group by
race, GA at diagnosis,
date of diagnosis, and
geographic area
Mulinare et al, Case-control, Random sample Women with unknown S: multivitamin; Periconceptional NTD: Age, education level, Low
1988,37 United 1968e1980, n ¼ 347 without birth defects use of vitamins US: no vitamin use AOR, 0.41 (0.26e0.66) alcohol use, history of
States infants with NTDs born in the same miscarriages,
period, n ¼ 2829 smoking, chronic
illnesses, use of
spermicides before the
index birth
Shaw et al, Case-control, Random sample of Infants with S: multivitamin Periconceptional Cleft lip with or without Age, race, education, Low
1995,38 United 1987e1989, n ¼ 731 liveborn nonmalformed chromosome anomaly, containing folic acid; palate: gravidity, smoking
States (1) infants with orofacial infants living in the infants of mothers not US: vitamin A or no OR (when no alcohol status, alcohol use
clefts same counties as speaking English or vitamin use use), 0.61 (however, no
cases, n ¼734 Spanish (0.40e0.91); significant differences
OR (when alcohol use were found and why

1 time/wk), 0.16 the results are not
(0.05e0.55) presented as adjusted)
Shaw et al, Case-control, Random sample of Infants with S: multivitamin Periconceptional AOR (conotruncal Age, race, education, Low
1995,45 United 1987e1988, n ¼ 207 liveborn nonmalformed chromosome anomaly, containing folic acid; malformations): gravidity, smoking
States (2) (conotruncal infants living in the infants of mothers not US: no vitamin use 0.53 (0.34e0.85); AOR status, alcohol use
malformations), same counties as speaking English or (limb deficiencies),
n ¼ 178 (limb cases, n ¼ 481 Spanish 0.70 (0.43e1.10)
deficiencies)
Shaw et al, Case-control, Random sample of Infants of mothers not S: multivitamin Preconceptional NTD: Age, race, education, Low
1995,50 United 1989e1991, n ¼ 624 liveborn nonmalformed speaking English or containing folic acid; first trimester OR, 0.65 (0.45e0.94); gravidity, smoking
States children with NTDs infants, n ¼ 612 Spanish US: no vitamin use OR, 0.60 (0.46e0.79) status, alcohol use

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(3)
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017. (continued)
 ajog.org
SUPPLEMENTAL TABLE 7
Study characteristics of included observational studies (birth defects) (continued)
Results,
Study design, study Content of OR/AOR/RR/ARR Risk of
Reference, period, definition, Definition and multivitamin Timing of (95% CI) or bias
year, country and participants, n controls, n Exclusion criteria supplementa multivitamin use absolute values, % Adjustment (NOS)
Shaw et al, Case-control, Random sample of Infants with S: multivitamin Periconceptional Multiple congenital Age, race, education, Low
2000,21 United 1993e1996, n ¼ 112 liveborn nonmalformed chromosome anomaly, containing folic acid; Postconceptional anomalies: gravidity, smoking
States infants with
2 infants born in the infants of mothers not US: no vitamin use AOR, 2.9 (0.8e10.3); status, alcohol use,
congenital same time period and speaking English or OR, 1.7 (0.9e3.3) BMI (however, no
abnormalities area as cases, n ¼ 195 Spanish significant differences
were found and why
the results for
postconceptional use
of vitamins are not
presented as adjusted)
Shaw et al, Case-control, Random sample of Infants with S: multivitamin Periconceptional Cleft lip with or without Age, race, education Low
2006,44 USnited 1997e2000, n ¼ 704 liveborn nonmalformed chromosome anomaly, containing folic acid; cleft palate: AOR, 1.01
States children with orofacial infants, n ¼2594 infants with clefts US: no vitamin use (0.82e1.24); cleft
clefts, n ¼ 404 believed to be palate: AOR, 1.02
children with cleft secondary to other (0.77e1.34)
palate defects
Shaw et al, Case-control, Random sample of Type 1 or 2 diabetes S: multivitamin Periconceptional dTGA: AOR, 0.9 Age, race, education Low
2010,51 United 1999e2004, n ¼ 140 liveborn nonmalformed containing folic acid; (0.6e1.3); TOF: AOR,
OCTOBER 2017 American Journal of Obstetrics & Gynecology

States infants with dTGA d- infants born in the US: no vitamin use 0.9 (0.6e1.4)
transposition of great same area as cases,
arteries (dTGA ¼ 163 n ¼ 698
infants with TOF
Smithells et al, Cohort, controlled Women with previous Ectopic pregnancy, S: multivitamin Periconceptional Recurrence of NTDs: Some centers matched High
1983,26 United (2 cohorts, same study pregnancies with uncertain last containing folic acid; S: 0.7%; US: 4.7%; the control group on
Kingdom protocol, combined NTDs, n ¼ 519 menstrual period, US: no vitamin use P ¼ .0001b age, number of
data); start date, NA. uncertain vitamin previous NTD births,
Recruitment closed intake/timing of intake and estimated date of
1982, n ¼ 454 (women conception

Systematic Reviews
with previous
pregnancy with NTDs)
Thompson et al, Case-control , Randomly selected Multiple pregnancy, S: multivitamin Periconceptional NTD: Age, race, passive Low
2003,39 United 1992e1997, n ¼ 179 sample of live-born women taking containing folic acid; AOR, 0.55 (0.25e1.22) smoking, BMI, dietary
States infants with NTDs without NTDs, n ¼ 288 anticonvulsant US: no vitamin use folate
medication
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017. (continued)
412.e15
 Systematic Reviews
412.e16 American Journal of Obstetrics & Gynecology OCTOBER 2017

SUPPLEMENTAL TABLE 7
Study characteristics of included observational studies (birth defects) (continued)
Results,
Study design, study Content of OR/AOR/RR/ARR Risk of
Reference, period, definition, Definition and multivitamin Timing of (95% CI) or bias
year, country and participants, n controls, n Exclusion criteria supplementa multivitamin use absolute values, % Adjustment (NOS)
Tolarova et al, Cohort, controlled, Women who did not Family history of S: several Periconceptional Recurrence of cleft lip NA High
1995,19 Czech 1930e1962 (adults want to participate or clefting micronutrients; with or without cleft
Republic with nonsyndromic who started US: no vitamin use palate:
orofacial clefting), supplementation after S: 4.22%; US: 1.42%;
n ¼ 88, and the embryonic period; P ¼ .03
1970e1982 (women United States, n¼
with nonsyndromic 1901
orofacial clefting),
n ¼ 133
Werler et al, Case-control, Infants with major Chromosome anomaly, S: multivitamin Periconceptional NTD: 0.6 (0.4e0.8) Age, education, race, Low
1993,40 United 1988e1991, n ¼ 436 congenital anomalies known monogenetic containing folic acid; religion, ethnic group,
States infants with NTDs except for NTDs and disease, infants with US: no vitamin use income, birth status
oral clefts, n ¼ 2615 an NTD-affected (liveborn/stillborn,
sibling 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
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017. (continued)

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SUPPLEMENTAL TABLE 7
Study characteristics of included observational studies (birth defects) (continued)
Study design, study
Reference, period, definition, Definition and
year, country and participants, n controls, n
Werler et al, Case-control,
1999,46 United 1993e1996, n ¼ 114
States (orofacial defects),
n ¼ 157 (conotruncal
defects), and n ¼ 271
(urinary tract defects)
OCTOBER 2017 American Journal of Obstetrics & Gynecology
Two groups of controls:
(1) sample of live-born
without abnormalities,
n ¼ 521 (control, 1); (2)
sample of infants born
with major abnormality
other than NTDs
(control, 2), n ¼ 442
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Results,
Content of OR/AOR/RR/ARR Risk of
multivitamin Timing of (95% CI) or bias
Exclusion criteria supplementa multivitamin use absolute values, % Adjustment (NOS)
Infants with NTD, S:
2 water-soluble Periconceptional Urinary tract defects: Age, educational level, Low
chromosome anomaly, vitamins and Postconceptional AOR (control 1), 0.6 race, planned
known monogenetic
2 fat-soluble Periconceptional (0.3e1.0); AOR, pregnancy, nausea and
disease vitamins; US: no Postconceptional (control 1) 0.4 vomiting, place of
vitamin use Periconceptional (0.3e0.8); cleft lip with living
Postconceptional or without cleft palate:
AOR (control 1), 0.7
(0.4e1.3); AOR
(control 1), 0.8
(0.5e1.5); conotruncal
defects:
AOR (control 1), 1.0
(0.6e1.6); AOR
(control 1), 1.0
(0.6e1.7)
(results for control
group 2 are not
different from the
above and therefore

not shown)
Wilcox et al, Case-control, Randomly selected Lack of ability to speak S: multivitamin Periconceptional Cleft lip with or without Age, education, alcohol Low
2007,47 Norway 1996e2001, n ¼ 573 live-born infants, n ¼ Norwegian, dead containing folic acid; cleft palate: use, folic acid
infants with orofacial 763 infants US: no vitamin use AOR, 0.75 (0.50e1.11) supplement, dietary
clefting folate, smoking status,
other birth defects
Yang, 1997,53 Case-control, 1968 Random sample of Syndromic cases S: multivitamin; Periconceptional Limb deficiencies: Age, race, birth Low
United States e1980, n ¼ 117 infants without birth US: no vitamin use Postconceptional OR, 0.47 (0.23e0.97); periods, educational
infants with defects born in the OR, 0.77 (0.41e1.46) level, chronic illness,
nonsyndromic limb same period, matched smoking and alcohol

Systematic Reviews
deficiency to the case group by use during first
hospital of birth, time trimester
of birth and race, n ¼ (however, no
3029 significant differences
were found and why
the results are not
presented as adjusted)
(A)OR, (adjusted) odds ratio; (A)RR, (adjusted) relative risk; BMI, body mass index; CI, confidence interval; CUTA, congenital urinary tract anomalies; dTGA, d-transposition of great arteries; GA, gestational age; NA, not applicable; NOS, Newcastle-Ottawa Scale; NTD,
neural tube defect; S, supplemented; TOF, tetralogy of Fallot; US, unsupplemented.
412.e17

a
See Supplemental Table 3; b Not calculated by the author of the trial.
Wolf. Multivitamin use and birth outcomes in high-income countries. Am J Obstet Gynecol 2017.
Systematic Reviews ajog.org

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.

412.e18 American Journal of Obstetrics & Gynecology OCTOBER 2017

ajog.org Systematic Reviews

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.

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.

OCTOBER 2017 American Journal of Obstetrics & Gynecology 412.e19

Systematic Reviews ajog.org

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.

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.

412.e20 American Journal of Obstetrics & Gynecology OCTOBER 2017

ajog.org Systematic Reviews

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.

OCTOBER 2017 American Journal of Obstetrics & Gynecology 412.e21