Preventive Medicine 114 (2018) 1–17

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Preventive Medicine
journal homepage: www.elsevier.com/locate/ypmed

Review Article

Folic acid supplementation during the preconception period: A systematic T

review and meta-analysis
K.I. Toivonena, E. Lacroixa, M. Flynna, P.E. Ronksleyb, K.A. Oinonenc, A. Metcalfeb,d,
⁎
T.S. Campbella,
a
Department of Psychology, University of Calgary, Calgary, AB, Canada
b
Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada
c
Department of Psychology, Lakehead University, Thunder Bay, ON, Canada
d
Department of Obstetrics and Gynecology, University of Calgary, Calgary, AB, Canada

A R T I C LE I N FO A B S T R A C T

Keywords: Guidelines recommend that women take folic acid supplements in the preconception period to prevent neural
Folic acid tube defects (NTDs) in their offspring. Estimates of adherence to this recommendation across different countries
Preconception care worldwide have not been synthesized. Medline, CINAHL, and EMBASE were systematically searched to identify
Review studies reporting the prevalence of preconception folic acid supplementation. Pooled prevalence estimates for
Meta-analysis
each country (where data were available) were calculated; and differences based on demographic, methodo-
logical, and study quality characteristics were examined. Of 3372 titles and abstracts screened, 722 full-texts
were reviewed and 105 articles that reported 106 estimates of preconception folic acid supplementation in 34
countries were included. Pooled prevalence estimates were 32–51% in North America, 9–78% in Europe,
21–46% in Asia, 4–34% in the Middle East, 32–39% in Australia/New Zealand, and 0% in Africa. No South
American studies were identified. Higher supplementation prevalence was observed in studies that had more
highly educated samples, were conducted in fertility clinics, and assessed folic acid use via self-report. Of note,
only 32% and 28% of studies reported timing of folic acid use and adherence to folic acid, respectively.
Preconception folic acid supplementation is highly variable worldwide and many women may not achieve
sufficient folate levels to prevent NTDs. To better understand non-adherence, recommendations for future re-
search include: more explicit reporting of methodology, more detailed assessment of folic acid use, assessment of
variables potentially relevant to folic acid use, and surveillance of folic acid use in a greater diversity of
countries, especially in the developing world.

1. Introduction
Neural tube defects (NTDs) result from failure of the neural tube to
close at approximately 3–4 weeks gestation, and can result in infant
mortality or long-term disability (Greene and Copp, 2014; Flores et al.,
2015). Most NTDs are preventable by sufficient intake of folate or its
synthetic form, folic acid (Greene and Copp, 2014; Czeizel et al., 2013).
Although the exact mechanisms are unclear, folate may play an im-
portant role in neural tube closure by regulating processes such as
nucleotide biosynthesis and methylation reactions (Greene and Copp,
2014). Evidence from observational studies indicated lower rates of
NTDs in offspring of women who supplemented with folic acid before
pregnancy (Mulinsky et al., 1989; Mulinare et al., 1988). Subsequently,
randomized controlled trials (RCTs) indicated meaningful reductions in
NTDs following folic acid supplementation (Wald and Sneddon, 1991;
Czeizel and Dudas, 1992). For example, a 72% protective effect of folic
acid was reported by a seven-country study (Wald and Sneddon, 1991).
Based on this evidence, the United States (US) government has re-
commended since 1992 that all women of childbearing age should
supplement with 0.4 mg of folic acid daily (MMWR., 1992; Crider et al.,
2011). The World Health Organization (WHO) similarly recommends
that all women attempting to become pregnant supplement with 0.4 mg
of folic acid daily (World Health Organization, 2017). Supplementation
is recommended before conception, rather than after confirmation of
pregnancy, because neural tube closure may occur before many women
are aware of their pregnancy (Greene and Copp, 2014; Government of
Canada, 2016).
Many countries (e.g., Canada, the US) have mandated fortification
of grain products with folic acid (Centers for Disease Control and
Prevention, 2010), resulting in increased levels of serum folate and

⁎
Corresponding author at: Administration Building, Department of Psychology, University of Calgary, 2500 University Drive NW, T2N 1N4, Canada.
E-mail address: campbet@ucalgary.ca (T.S. Campbell).

https://doi.org/10.1016/j.ypmed.2018.05.023
Received 12 October 2017; Received in revised form 3 May 2018; Accepted 22 May 2018
Available online 23 May 2018
0091-7435/ © 2018 Elsevier Inc. All rights reserved.
K.I. Toivonen et al.
decreased incidence of NTDs (Crider et al., 2011; Canfield et al., 2005).
However, large scale studies of reproductive aged women suggest that
folic acid supplementation remains necessary even in countries with
mandatory grain fortification (e.g., 22% in Canada have sub-optimal
blood serum folate concentrations for NTD prevention (Colapinto et al.,
2011) and 22% in the US do not meet folate requirements from
diet alone (Bailey et al., 2010)). Ultimately, mandatory fortification has
not changed the recommendation for folic acid supplementation before
pregnancy (Crider et al., 2011; World Health Organization, 2017).
Despite recommendations, there is considerable room for improve-
ment in uptake of folic acid supplements. Among studies from countries
with ‘very high human development’ (designated by the United Nations'
human development index (United Nations Development Programme,
2015)), the prevalence of any preconception folic acid supplementation
varies considerably and can be < 10% (Toivonen et al., 2017). Even in
a population-based study of 35,351 US women planning a pregnancy
within the next year, only 54.3% reported taking folic acid supplements
daily (Chuang et al., 2011).
To better understand how preconception folic acid supplementation
rates compare to recommendations, there is a need to synthesize esti-
mates of supplementation and examine potential factors associated
with use. Ray et al. (2004) systematically reviewed preconceptional/
periconceptional folic acid use worldwide but did not provide estimates
by country or region. They observed a slight increase in use over time;
reported greater likelihood of use among women with higher educa-
tion, older age, non-immigrant status, partners, and planned pregnan-
cies; but characterized overall use as generally suboptimal. Peake et al.
(2013) published a systematic review and meta-analysis of peri-
conceptional folic acid use among women of different ethnicities within
the United Kingdom (UK), concluding that supplementation was nearly
three times as prevalent among Caucasians relative to non-Caucasians.
However, their meta-analytic estimates were based on only three stu-
dies for which adequate data were available (Peake et al., 2013). A
scoping review by Toivonen et al. (2017) examined several pre-
conception health behaviours, including folic acid use, however they
only included countries with “very high human development” and did
not synthesize prevalence estimates through meta-analysis. The present
systematic review and meta-analysis provides an update to the review
conducted by Ray et al. (2004), and is the first known study to provide
national prevalence estimates of any preconception folic acid use where
available. Potential sources of heterogeneity such as sample char-
acteristics, methodology, and country fortification policy were ex-
amined. Additionally, the impact of study quality indicators on sup-
plementation rates was investigated because low methodological
quality can impact internal validity and bias the results (Stroup et al.,
2000).
Because significant heterogeneity in supplementation estimates was
expected among different countries, a single global prevalence estimate
would not be meaningful. Therefore, the primary aim of this review was
to estimate preconception folic acid supplementation prevalence by
country. Secondary aims included: (1) examining supplementation
prevalence by country grain fortification policies; (2) determining
whether supplementation prevalence differed before and after im-
plementation of mandatory grain fortification, among countries with
mandatory fortification; and (3) examining supplementation prevalence
by participant characteristics (e.g., maternal age), methodological fac-
tors (e.g., self-reports vs interviews), and study quality factors (e.g.,
whether inclusion/exclusion criteria were explicitly reported). This
review defines the preconception period as any time before conception
(among studies of women who retrospectively reported while pregnant
or after a live birth), or the current time period (among women plan-
ning pregnancy within six months). Given the scarcity of data on ob-
jectively measured serum folate levels, and the inaccuracy of folate
levels estimated from self-reported diet, the outcome of interest was use
of folic acid supplementation as opposed to serum folate or estimated
folate intake from food.
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Preventive Medicine 114 (2018) 1–17
2. Methods
The present systematic review was performed according to a pre-
determined protocol (PROSPERO registration ID: CRD42016052774)
and in accordance with MOOSE (Meta-Analyses of Observational
Studies in Epidemiology) reporting guidelines (Stroup et al., 2000).
2.1. Search strategy
The databases Medline, CINAHL, and EMBASE were systematically
searched in October 2016. The search was limited to publication dates
after 1990 to align with introduction of the earliest recommendations
for folic acid supplementation (Crider et al., 2011). No language re-
strictions were used as part of the search; however, only articles that
included at minimum an abstract written in English, French, or
German, were considered for inclusion in the study selection phase.
Electronic databases were searched with two comprehensive themes
surrounding folic acid use (using the medical subject heading [MeSH]
term “Folic Acid” and keywords such as “folic acid”, “folate”, and
“multivitamin”) and the time period before conception (using the MeSH
term “Preconception Care” and keywords such as “preconception”,
“periconception”, and “pre-pregnancy”). Terms were combined using
the Boolean operator OR and themes were combined using AND (see
Appendix A for detailed search strategy). Both full text articles and
conference abstracts were considered for inclusion, and a sensitivity
analysis was conducted to examine whether full-text articles and ab-
stracts could be combined in analyses.
2.2. Study selection
In the first phase of screening, KT and EL independently examined
abstracts for eligibility using purposefully liberal inclusion/exclusion
criteria. At this stage, only abstracts that did not assess folic acid or any
multivitamin use, did not examine the preconception period, or did not
include original data were excluded. In the second phase of screening,
KT and EL examined records to determine whether they met inclusion
criteria. Records were excluded if: (1) they did not provide data on the
percentage of women who engaged in any folic acid supplementation
for the preconception period specifically (e.g., studies that described
the entire periconception period but did not provide preconception-
specific data; studies of women considering pregnancy in the next year,
rather than planning within six months), (2) they did not provide in-
formation about folic acid supplementation specifically (e.g., broadly
described multivitamin use without explicitly assessing folic acid use,
reported serum folate levels only), (3) they were experimental or case-
control studies, (4) they focused on populations of women with dia-
betes, epilepsy, or prior NTD-affected births (because these populations
have different folic acid recommendations and may be more closely
monitored by healthcare providers surrounding pregnancy), (5) if re-
ported data were insufficient to obtain a prevalence estimate, (6) ori-
ginal data was not reported (e.g., review articles), or (7) if full-texts or
abstracts were not written in English, French, or German. Any full-text
written in a language other than English, French, or German that had an
abstract written in English, French, or German was treated as an ab-
stract. Some records presented duplicate data (i.e., data which ap-
peared, based on sample name or participant characteristics, to be
drawn from the same participants, or a subset of the same participants).
When duplicate data were encountered (e.g., data drawn from a large
national database of participants) in a full-text article and a conference
abstract, only the full-text was retained. If duplicate data were en-
countered within the same article type the record with the largest
number of participants was retained. In cases where the number of
participants was identical, we retained whichever record provided
more detail. When articles reported separate information for a specific
subgroup that fit the inclusion criteria (e.g., a study of reproductive-
aged women, a portion of whom were planning pregnancy within the
K.I. Toivonen et al.
next six months), the information from that subgroup only was included
in the review. Interrater agreement for full-text inclusion (κ = 0.68)
was moderate (McHigh, 2012) and disagreements were resolved by
consensus between KT and EL.
2.3. Data extraction and quality assessment
KT, EL, and MF independently extracted data from all studies that
met inclusion criteria and consulted each other when studies reported
data ambiguously. The following study characteristics were extracted:
country, number of participants, date of data collection, demographics
(pregnancy status, proportion of pregnancies that were planned, age,
modal education level, gravidity, parity, body mass index, whether
preconception counselling was received, income, and ethnicity), pre-
valence of folic acid use, and whether the study was a full article or an
abstract. During the data extraction phase, the collection of ethnicity
data was halted due to inconsistent reporting, and a new immigration-
related variable assessing the proportion of the sample that was foreign-
born was collected instead. The following characteristics related to
study design were extracted: setting (e.g., hospital, community), data
collection method (i.e., self-report questionnaire, interview), reporting
period (i.e., retrospective, current), and sampling method (i.e., con-
secutive, random, other).
Studies were rated according to the following quality indicators: 1)
inclusion/exclusion criteria explicitly defined; 2) recruitment proce-
dure well-described; 3) setting well-described; 4) timing of folic acid
use explicitly noted (e.g., one month before conception), 5) dose of folic
acid explicitly noted, 6) adherence to folic acid explicitly described
(e.g., daily use); 7) health status well-described (i.e., reporting of
chronic illness aside from diabetes, epilepsy, and prior NTD-affected
births, which were exclusion criteria); 8) income reported; 9) education
reported in any manner; and 10) reasons for non-participation de-
scribed. Based on data from the Food Fortification Initiative (n.d.),
studies were coded based on whether they were conducted in a country
where grain fortification with folate is mandated, and if so, whether
data was collected prior to, during, or after the implementation of
fortification policy.
2.4. Data synthesis and analysis
All analyses were performed using the statistical software Stata/MP
v13.0 (Stata Corporation, College Station, United States). The propor-
tion of each sample who took folic acid in the preconception period, as
well as 95% confidence intervals (CI), were obtained from each study
using the “metaprop” command (specifically developed for prevalence
estimates) (Nyaga et al., 2014). In light of significant heterogeneity
anticipated both between and within countries, stratified random ef-
fects models were performed to obtain separate pooled estimates of the
prevalence of preconception folic acid supplementation for each
country. Weights for individual studies were calculated using the in-
verse variance method (Nyaga et al., 2014). Heterogeneity among in-
cluded studies was assessed with the I2 statistic. A series of stratified
meta-analyses and meta-regressions (applied to dichotomized vari-
ables) were performed to explore potential demographic, study char-
acteristic, and study quality factors contributing to heterogeneity. In an
attempt to mitigate extreme heterogeneity, these latter meta-analyses
and meta-regressions were only performed on countries considered to
have “very high human development” based on the United Nations
Human Development Index (United Nations Development Programme,
2015). In these analyses, continuous data were stratified based on
median split.
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Preventive Medicine 114 (2018) 1–17
3. Results
3.1. Study identification
Progress through stages of screening is summarized in a flow dia-
gram (Fig. 1). The initial search yielded 3372 citations and 722 were
included in full-text review. In total, 105 articles describing 106 pre-
valence estimates among different countries were included in the pre-
sent review and meta-analysis (one article described prevalence esti-
mates in two countries, thus they were treated as two separate
estimates). See Appendix B for references of included studies. Of the 34
countries represented, nine have implemented mandatory fortification
(Australia, Canada, Egypt, Iran, Oman, Saudi Arabia, Uganda, United
Arab Emirates, United States) and 26 are classified as having “very high
human development” (Australia, Belgium, Canada, Denmark, England,
France, Hungary, Iceland, Ireland, Israel, Italy, Japan, the Netherlands,
New Zealand, Norway, Poland, Portugal, Puerto Rico, Scotland, Saudi
Arabia, Scotland, Singapore, Spain, Sweden, United Arab Emirates,
United States).
3.2. Characteristics of included studies
An overview of the characteristics of 105 included studies (re-
porting 106 estimates) is presented in Table 1. Most (k = 88, 83%)
studies were full-text articles, and 18 (17%) were abstracts (12 con-
ference abstracts, and 6 English-language abstracts of full-texts pub-
lished in languages other than English, French, or German). The pub-
lication dates ranged from 1994 to 2016. Studies included as few as 13
to as many as over 900,000 participants. Nearly half (k = 51, 48%) of
studies reported the percent of women who planned pregnancy, 28
(26%) reported the percent who were primigravid, 45 (42%) reported
the percent who were primiparous, and 17 (16%) reported the percent
who were immigrants; all categories had considerable variability. Mean
age was reported by 57 (54%) studies and ranged from 25 to 35 years.
Mean body mass index was reported by 18 studies (17%) and ranged
from 21 (normal range) to 31 kg/m2 (obese range). Over half of studies
(k = 63, 59%) reported highest education in a way that could be coded:
modal level lower than secondary school (k = 7), modal level of sec-
ondary school completion (k = 25), and model level greater than sec-
ondary school (k = 31). Too few studies reported mean income or
percent of women who received preconception counselling for mean-
ingful analyses to be conducted with these variables. Most (k = 80;
75%) studies were cross-sectional; of the 26 (25%) cohort studies
(where folic acid use was examined at baseline), 17 reported attrition,
which ranged from 1.3% to 48.8%. Select characteristics for individual
studies are presented in Appendix C. Two studies were conducted in
fertility clinics. Since samples from fertility clinics may not be re-
presentative of the general population, these studies were not included
in meta-analytic estimates of folic acid use by country or by study
characteristics.
3.3. Study quality assessment
An overview of the quality of included studies is presented in
Table 1, while individual study quality ratings are listed in Appendix D.
The quality indicator most often reported was a description of the study
setting (reported by 99 studies; 93%), then education level (reported by
72; 67%), and inclusion/exclusion criteria (reported by 53; 50%). Note
that while 72 studies reported education in some way, only 63 reported
education in a way that could be coded for a meta-analysis stratified by
education level. The quality indicator least often reported was whether
reasons for non-participation were provided (reported by 8; 8%). Only
36 studies (34%) reported timing of folic acid use, 24 (22%) reported
dose, and 23 (21%) reported adherence.
K.I. Toivonen et al.
Fig. 1. Flow diagram of screening process. FA = folic acid, PC = preconception, SR = self-reported, NTD = neural tube defect.
3.4. Prevalence of preconception folic acid supplementation
The prevalence of preconception folic acid supplementation ranged
from 0% to 98% among the individual studies. Separate estimates for
each country are reported in Table 2. Fifteen countries were only re-
presented by a single study each and their prevalence estimates should
thus be interpreted with caution, particularly where sample sizes were
small (Button et al., 2013). The countries with the lowest prevalence
estimates (0%) were Nigeria and Uganda (represented by k = 2 and
k = 1 articles, respectively). The country with the highest prevalence
estimate was Belgium (78%), which was represented by one study with
a small, largely college-educated sample. Countries represented by the
largest numbers of studies, England (k = 10) and Australia (k = 10),
had more moderate pooled prevalence estimates of (36% and 32%,
respectively). The studies from fertility clinics were conducted in Eng-
land and Sweden and reported preconception folic acid use rates of 92%
and 59%, respectively.
By continent, the pooled prevalence estimates ranged from 32 to
51% in North America, 9–78% in Europe, 21–46% in Asia, 4–34% in the
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Preventive Medicine 114 (2018) 1–17
Middle East (including Turkey and Egypt), 32–39% in Australia/New
Zealand, and 0% in Africa (estimate based on two studies conducted in
Nigeria and a single study conducted in Uganda). No studies included in
the present review reported on prevalence in South America. For a vi-
sual representation of folic acid supplementation estimates globally, see
Fig. 2. As expected, there was significant heterogeneity among studies
in pooled estimates for every country, (I2 = 99.99%, p < .001). The
pooled prevalence estimates between full-text articles and abstracts did
not differ, and thus they were included together in subsequent analyses.
3.5. Prevalence of supplementation in relation to grain fortification status
Overall, there was no difference in pooled prevalence estimates
between countries with and without mandatory grain fortification.
There was only one country (Australia) for which data were available to
compare prevalence of folic acid use pre- and post-fortification. There
was no difference between pooled prevalence estimates before and after
grain fortification, which was introduced in 2009.
K.I. Toivonen et al. Preventive Medicine 114 (2018) 1–17

Table 1 Table 2
Methodological, demographic, and quality characteristics of the 105 included Stratified meta-analysis of preconception folic acid supplementation by nation.
studies (including 106 estimates).
Nation k Total N Supplementation prevalence
Characteristics
Pooled % 95%CI
Countries (n) 34
Article type (n) LL UL
Full-texts 88
Abstracts 18 Australia 10 5643 32 26 39
Publication dates range 1994–2016 Belgium 1 148 78 70 84
Participants (n) range 13–902,270 Canada 4 9014 51 32 70
Preconception folic acid use (%) range 0–98 China 6 1,094,012 46 43 50
Modal education (n) Denmark 4 10,341 45 41 50
< 12 years 7 Egypt 1 660 9 7 11
12 years 25 England 10 122,293 36 29 43
> 12 years 31 France 1 12,646 15 14 15
Planned pregnancy (%) range 6.5–100 Hungary 2 454 19 15 22
Mean age (years) range 25–34.7 Iceland 1 113 9 5 16
Primigravid (%) range 0–100 Iran 3 994 25 20 29
Primiparous (%) range 0–100 Ireland 8 20,813 39 24 53
Foreign-born (%) range 2–100 Israel 1 1860 34 32 36
Mean body mass index (kg/m2) range 21–31.2 Italy 5 7696 19 6 32
Inclusion/exclusion criteria clearly defined n (%) 53 (50) Japan 1 1076 35 32 38
Method well-described n (%) 34 (32.1) Lebanon 1 5280 14 13 15
Setting well-described n (%) 99 (93.4) Netherlands 9 21,435 60 47 72
Timing of folic acid use explicitly stated n (%) 36 (34) New Zealand 2 6265 39 37 40
Dose of folic acid explicitly stated n (%) 24 (22.6) Nigeria 2 822 0 0 0
Adherence to folic acid described n (%) 23 (21.7) Norway 2 138,248 55 55 56
Health status well-described n (%) 16 (15.1) Oman 1 139 8 4 14
Income described n (%) 21 (19.8) Poland 1 677 34 31 38
Education described n (%) 72 (67.9) Portugal 1 249 18 14 24
Reasons for non-participation described n (%) 8 (7.5) Puerto Rico 1 479 32 28 36
Saudi Arabia 1 254 21 17 27
Scotland 2 701 21 18 24
Singapore 1 861 21 19 24
Spain 5 3983 25 9 42
3.6. Stratified analyses to examine demographic, methodological, and Sri Lanka 2 749 21 19 24
quality-related sources of heterogeneity Sweden 4 9204 20 0 39
Turkey 2 530 4 3 6
Uganda 1 394 0 0 1
3.6.1. Demographic sources of heterogeneity United Arab Emirates 1 277 8 5 12
Demographic, methodological, and quality-related characteristics United States 7 37,740 49 44 54
were examined as additional potential sources of heterogeneity among
studies. Table 3 outlines analyses of countries with “very high human Note. k = Number of studies included in meta-analytic prevalence estimate;
development” stratified by demographic characteristics. Meta-regres- CI = confidence interval. Studies from fertility clinics excluded.
sion analysis showed that studies with a modal education higher than
secondary school (45%, 95%CI = 36–55%) had higher supplementa- to folic acid, health status, income, education, or reasons for non-par-
tion estimates than those with a modal education of secondary school ticipation.
completion (32%, 95%CI = 24–41%, p = .03; only one study had a
modal education of less than secondary school completion and was thus 4. Discussion
excluded from this analysis). There were no effects of age, pregnancy
planning, gravidity, parity, proportion of the sample that was foreign The lowest pooled estimates (0%) were observed in Uganda and
born, or country national grain fortification policy. Nigeria (represented by one and two studies, respectively). The
Ugandan government has published guidelines on maternal nutrition
3.6.2. Methodological sources of heterogeneity that recommend preconception folic acid intake (Ministry of Health,
Table 3 also outlines analyses stratified by methodological char- 2010), and women typically receive folic acid upon their first antenatal
acteristics. There were higher supplementation estimates among studies visit in both countries (Lawal and Adeleye, 2014; Bannink et al., 2015),
that employed self-report questionnaires (40%, 95%CI = 31–50%) though the first antenatal visit is often after the end of the first trimester
compared to those that conducted in-person interviews (28%, (Lawal and Adeleye, 2014). Factors such as food insecurity, insufficient
95%CI = 22–34%, p = .01). Based on an examination of confidence or poor access to health services, lack of health education, and high
intervals, telehealth studies (43%, 95%CI = 40–45%) had higher sup- rates of unplanned pregnancy may contribute to lower prevalence of
plementation estimates than those conducted in hospitals/clinics (34%, preconception folic acid use (Ministry of Health, 2010; Bannink et al.,
95%CI = 30–39%). Studies conducted in fertility clinics (76%, 2015). During the time of data collection, Uganda had mandatory flour
95%CI = 73–79%) had higher supplementation estimates than those fortification of folic acid whereas Nigeria did not, which is likely re-
conducted in any other setting. There was no effect of reporting period flected in the prevalence of NTDs in Uganda and Nigeria: 14 and 27 per
(retrospective or current), whether sampling was random, or whether 10,000, respectively (Food Fortification Initiative, n.d.).
sampling was consecutive. Belgium had the highest prevalence of folic acid use (78%), how-
ever, this estimate was based on a single study with 148 participants
3.6.3. Quality-related sources of heterogeneity (Pauwels et al., 2016). Further, the sample was highly educated and
Table 3 additionally outlines analyses stratified by study quality consisted of only Caucasian women, which may overestimate folic acid
items. There were no differences in pooled prevalence estimates based use in Belgium given prior associations of folic acid supplementation
on whether the following factors were defined or described: recruit- with higher education (Miller et al., 2011; Xing et al., 2012; Khodr
ment method, setting, timing of folic use, dose of folic acid, adherence et al., 2014; Tort et al., 2013) and Caucasian ethnicity (Peake et al.,

5
K.I. Toivonen et al.
Fig. 2. Preconception folic acid supplementation prevalence estimates by country, studies from fertility clinics excluded.
2013). The Flemish Minister of Welfare, Public Health and Family
formally launched a website specifically promoting preconception care
in 2015 (Delbaere et al., 2016), though this was after Pauwels et al.'s
study was conducted and thus would not have contributed to the high
rate of preconception folic acid intake they reported. Future studies
conducted in Belgium with larger and more representative samples will
help determine how Belgium's preconception folic acid supplementa-
tion compares to that of other counties.
Preconception folic acid supplementation estimates did not differ
between countries with and without mandatory grain fortification.
Further, estimates did not differ in Australia before or after the im-
plementation of mandatory fortification. While theoretically, countries
without mandatory fortification might report higher estimates of folic
acid supplementation to reflect a compensatory mechanism to protect
against NTDs, this does not appear to be the case. For example, studies
conducted in North America reported relatively higher supplementa-
tion estimates in addition to mandatory fortification. This is consistent
with research suggesting mandatory fortification is insufficient
(Mulinsky et al., 1989; Mulinare et al., 1988), and the recommenda-
tions that women take supplements even in countries with mandatory
fortification (Crider et al., 2011; World Health Organization, 2017).
The relationship between grain fortification and folic acid supple-
mentation is likely complicated by many factors such as economic de-
velopment, political and cultural views, and because countries from
several regions (e.g., Africa) were not well-represented in the present
review. Ultimately, the lack of a demonstrated relationship between
country grain fortification status and supplementation prevalence fur-
ther emphasizes the importance of understanding and promoting pre-
conception folic acid supplementation, particularly in areas where
mandatory fortification has not been implemented and pregnancies
may be particularly vulnerable to NTDs.
In the present review, folic acid supplementation estimates were
higher among studies with more highly educated samples. This finding
is consistent with the review by Ray et al. (2004) and several studies
published since 2004 (Miller et al., 2011; Xing et al., 2012; Khodr et al.,
2014; Tort et al., 2013), which have similarly reported higher levels of
education to be associated with higher supplementation rates. Several
factors may help explain this association, including greater access to
health care, increased health literacy, higher income, increased interest
in preventative health care, and increased exposure to folic acid cam-
paigns targeting colleges or universities (Miller et al., 2011; Tort et al.,
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Preventive Medicine 114 (2018) 1–17
2013). In the present study, folic acid supplementation estimates were
also higher among studies that employed self-report questionnaires to
assess folic acid than among studies that used in-person interviews; the
reasons for this discrepancy are unclear. Finally, studies in the present
review that were conducted at fertility clinics or used telehealth data
reported higher supplementation estimates than studies conducted at
hospitals or clinics. The greater frequency of supplementation in studies
conducted at fertility clinics may reflect preconception counselling
(which is typically a standard component of care in this setting) or
higher rates of pregnancy planning, given prior associations between
pregnancy planning and preconception folic acid supplementation
(Xing et al., 2012; Lantz et al., 2010; Richard-Tremblay et al., 2011).
Supplementation estimates did not relate to any of the study quality
items assessed in the present review. Of note, fewer than a quarter of
studies reported dose of folic acid or adherence to folic acid.
Results from the present review indicate sparse information re-
garding folic acid supplementation in many parts of the world, parti-
cularly in the continents of South America and Africa, and in countries
with large populations such as India and Russia. The language restric-
tions used in the search strategy may have contributed to these gaps,
particularly in South America, as South American databases such as
Latin American and Caribbean Literature in Health Sciences (LILACS)
(Barreto and Barata, 2008) were not searched. Because available data
indicate a high prevalence of NTDs in Africa (5.2–75.4 per 10,000
births), South America (1.4–27.9 per 10,000 births), India (7.5–66.2
per 10,000 births), and Russia (7.6–21.1 per 10,000 births) relative to
Canada and the United States (4.6 and 5.3 per 10,000 births) (Zaganjor
et al., 2016), it is particularly important to characterize and better
understand patterns of preconception folic acid use in these regions.
4.1. Strengths and limitations
The present review has several key strengths. First, potential sources
of heterogeneity were considered a priori to characterize heterogeneous
data, as recommended by the MOOSE guidelines (Stroup et al., 2000).
Second, the search strategy was designed to be overly inclusive to in-
crease confidence in the comprehensiveness of the search (e.g., we re-
trieved 86 studies published since Ray et al. (2004)). Finally, inclusion
of conference abstracts allowed more grey literature and data from
countries that are not primarily English-speaking to be included in the
analyses, potentially diminishing the ‘file-drawer’ effect. A major
K.I. Toivonen et al. Preventive Medicine 114 (2018) 1–17

Table 3
Stratified meta-analyses of preconception folic acid supplementation by sample, method, and quality characteristics among studies from highly developed countriesa.
Supplementation prevalence Meta-regression

% 95%CI

LL UL t p

Sample characteristics
Mean aget ≥30 (k = 24) 42 30 54 1.86 .07
< 30 (k = 22) 30 18 43
Population Pregnant (k = 64) 38 31 46 – –
Recent birth (k = 13) 30 21 39
Planning (k = 6) 30 6 53
Pregnancy intention ≥71% Planned (k = 18) 39 18 59 1.59 .12
< 71% Planned (k = 25) 31 26 36
Previous pregnancies ≥40% Primigravid (k = 12) 32 22 43 −1.51 .15
< 40% Primigravid (k = 10) 46 30 62
Previous children ≥50% Primiparous (k = 21) 37 28 46 −0.77 .45
< 50% Primiparous (k = 18) 42 31 54
Birthplace ≥20% Foreign born (k = 9) 39 34 44 −0.18 .86
< 20% Foreign born (k = 7) 40 26 54
Modal education⁎ > Secondary school (k = 26) 45 36 55 2.29 .03
=Secondary school (k = 20) 32 24 41
National grain fortification status Mandatory (k = 23) 39 32 45 0.59 .56
No policy (k = 62) 36 29 43

Method characteristics
Setting Hospital/clinic (n = 61) 34 30 39 – –
Midwife centre (k = 8) 36 18 54
Community (k = 6) 47 36 58
Fertility clinic (k = 2) 76 73 79
Telehealth (k = 3) 43 40 45
Reporting period Retrospective (k = 80) 37 31 43 0.84 .40
Current (k = 6) 30 6 53
⁎
Data collection method Self-report (k = 49) 40 31 50 2.61 .01
In-person interview (k = 26) 28 22 34
Random sampling used Yes (k = 7) 36 6 66 0.10 .92
No/unclear (k = 78) 37 31 43
Consecutive sampling used Yes (k = 19) 31 22 39 1.56 .12
No/unclear (k = 66) 38 32 45

Quality characteristics
Inclusion/exclusion criteria defined Yes (k = 43) 37 30 44 0.10 .92
No (k = 42) 36 27 45
Recruitment method well-described Yes (k = 26) 33 23 43 1.23 .22
No (k = 59) 38 31 46
Setting well-described Yes (k = 80) 36 30 43 0.59 .56
No (k = 5) 39 32 47
Folic acid timing described Yes (k = 28) 41 31 51 1.44 .16
No (k = 57) 34 29 40
Folic acid dose reported Yes (k = 23) 36 30 42 0.24 .81
No (k = 62) 37 28 46
Folic acid adherence reported Yes (k = 20) 42 31 53 1.48 .14
No (k = 65) 35 30 40
Health status described Yes (k = 15) 31 21 41 1.22 .23
No (k = 70) 38 31 45
Income described Yes (k = 14) 36 30 43 0.01 .99
No (k = 71) 37 30 43
Education described Yes (k = 55) 39 31 47 1.56 .12
No (k = 30) 32 25 39
Reasons for non-participation described Yes (k = 6) 38 31 44 1.60 .11
No (k = 79) 23 17 30

Note. k = Number of studies included in meta-analytic prevalence estimate; CI = confidence interval; LL = lower limit; UL = upper limit. Studies from fertility
clinics excluded except in the case of analyses stratified by setting.
a
Based on random effects modeling, very highly developed nations only.
⁎
p < .05.
t
p < .10 (nonsignificant trend).

limitation of the present review was the extreme heterogeneity ob-
served among prevalence estimates, even within individual countries.
Thus, the generalizability of the prevalence estimates (particularly
those based on a small number of studies) is limited. Second, many of
the additional variables examined as potential sources of heterogeneity
were not reported by all studies, although this may reflect word and
space constraints (particularly in abstracts). As a consequence, several
of the stratified analyses could only be conducted on fewer than half of
the included studies. Combined with extreme heterogeneity, this may
have led to insufficient statistical power to detect statistically sig-
nificant relationships. Third, many countries, such as those within Asia,
Africa, and Central and South America, were not well represented,
which may be due in part to the lack of non-English-language databases
searched in the present review. Fourth, as most studies did not assess

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K.I. Toivonen et al. Preventive Medicine 114 (2018) 1–17

adherence to folic acid, it is difficult to determine to what degree the
prevalence estimates reported in the present review reflect folic acid
use in accordance with recommendations. Fifth, since the six full-texts
written in languages other than English, French, or German were
treated as abstracts, details of their methodology not presented in the
abstracts were missed. Sixth, limiting the stratified meta-analyses to
studies from countries with “very high human development” limits the
generalizability of findings to other countries. Finally, because study-
level differences were examined rather than individual level differ-
ences, relationships that may exist at the individual level would not
have emerged from the present meta-analysis.
4.2. Future directions
Future studies should be more explicit in reporting methodology
and sample characteristics, and report more details regarding patterns
of folic acid use. Specifically, studies should report specific time frame
of folic acid supplementation assessed (e.g., in number of weeks or
months before conception), dose of folic acid taken, and adherence
(e.g., daily use), as well as whether adherence changed over time.
Studies surveying folic acid use should also collect and report in-
formation about potentially relevant variables that could influence
their prevalence estimates, such as education. Given that no studies
reported complete supplementation (even among those where all
women planned their pregnancy or were seeking fertility treatment),
future studies should continue to explore barriers to use of pre-
conception folic acid. Finally, studies need to survey folic acid use in a
broader array of countries and regions, and examine whether pre-
valence estimates differ by demographic or methodological character-
istics among countries that are not considered to have “very high
human development”. Understanding factors that influence pre-
conception folic acid use may help inform the design and im-
plementation of future interventions to increase use in accordance with
recommendations.
5. Conclusion
The present systematic review reported variable pooled prevalence
estimates for preconception folic acid supplementation among different
countries worldwide for which data were available. Estimates were
highest among countries within North America (32–51%) and Europe
(9–78%), and lowest in parts of Africa (0%). In light of scarce or non-
existent data available in many regions and entire continents, there is a
need for more widespread monitoring of preconception folic acid sup-
plementation. Detailed reporting of dose, timing, and adherence should
be emphasized, given that 34% of studies, or fewer, reported each of
these indicators. Studies should also provide more detailed information
about factors that might affect interpretation of folic acid supple-
mentation prevalence, such as proportion of planned pregnancies or
inclusion/exclusion criteria (each reported by half of studies in the
present review). The incomplete reporting of several factors used in our
stratified meta-analyses remains a major limitation of the present study.
Additionally, research to help better understand factors that influence
preconception folic acid supplementation is an important step to help
inform efforts to increase uptake of this important health behaviour.
Acknowledgements
K. Toivonen is supported by a Canadian Institutes of Health
Research Doctoral Award.
Conflicts of interest
The authors have no conflicts of interest to disclose.

Appendix A. Medline search strategy

1. exp Folic Acid/

2. folic acid.tw.
3. folate.tw.
4. vitamin*.tw.
5. multivitamin*.tw.
6. folacin.tw.
7. 1 or 2 or 3 or 4 or 5 or 6
8. exp Preconception Care/
9. preconception.tw.
10. pre-conception.tw.
11. periconception.tw.
12. peri-conception.tw.
13. (before adj2 conception).tw.
14. (prior adj2 conception).tw.
15. (plan* adj2 preg*).tw.
16. prepregnancy.tw.
17. pre-pregnancy.tw.
18. 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17
19. 7 and 18
20. limit 19 to animals
21. limit 19 to (animals and humans)
22. 20 not 21
23. 19 not 22
24. 23
25. limit 24 to yr = “1990–current”

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Appendix B. References of all included studies

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27. Fabre, E., Bermejo, R., Doval, J. L., Perez-Campos, E., Martinez-Salmean, J., & Lete, I. (2014). Cross-sectional study of vitamin and folic acid
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Appendix C. Select characteristics of all included studies

Author Year Country N Age Education Primigravid Primiparous Foreign born Folic acid
(M) (%) (%) (%) (%)

Aden et al. 2007 Sweden 50 30 . . 62 . 0.01

Al Darzi et al. 2014 Egypt 660 . 2 . . . 8.79
Al-Hossani et al. 2010 UAE 277 . 3 . 32.1 . 7.94

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Al-Riyami et al. 2011 Oman 139 28 2 31.7 39.6 12.9 7.91

Amitai et al. 2008 Israel 1860 28.5 2 . . . 33.98
Asgharnia et al. 2009 Iran 224 . . . . . 22.77
Backhausen et al. 2014 Denmark 258 . . . 58 77 44.19
Bannick et al. 2015 Uganda 394 29 1 . . . 0.01
Basgul et al. 2007 Turkey 359 29.9 3 . 40 . 3.34
Baykan et al. 2011 Turkey 171 . 1 . . 71.9 12.28
Blas-Robledo et al. 2011 Spain 371 32.1 . . 50.4 . 47.98
Bower et al. 1997 Australia 121 . . . . 62.6 30.58
Bukowski et al. 2009 USA 34,480 30 3 . 45 . 55.75
Callaway et al. 2009 Australia 412 31.4 2 . 43 65 56.31
Cawley et al. 2016 Ireland 856 30.7 3 . 39.3 62.9 43.81
Chen et al. 2016 China 902,270 . . . . . 53.36
Cheng et al. 2016 Singapore 861 30.5 2 . 44.9 56 21.37
Cueto et al. 2012 Denmark 5383 28 2 . 66.7 100 41.67
Cunningham et al. 2012 USA 189 . . . . . 47.09
Czeizel et al. 1994 Hungary 105 26.8 2 . 88.7 . 6.67
Dante et al. 2015 Italy 2301 33 2 . 52.9 . 0.91
de la Vega et al. 2002 Puerto Rico 479 27 . . . 35.1 31.52
De Santis et al. 2013 Italy 500 33.5 2 45.8 54.8 100 43.40
Ding et al. 2015 China 12,309 29.1 3 . 100 71 58.79
Dobson et al. 2006 NZ 104 29.3 . . 48 64 38.46
Eindhoven et al. 2014 Netherlands 146 34.7 3 39 65.7 . 97.95
Fabre et al. 2014 Spain 1020 . . . . 25 28.63
Farah et al. 2013 Ireland 288 30.8 . . 37.2 71.2 54.86
Forster et al. 2009 Australia 588 32 3 . 53.3 . 28.57
Frayne et al. 2015 Australia 284 . . . . 15.49
Goldberg 2006 USA 327 . 2 39.1 60.9 42.5 44.04
Han et al. 2009 Canada 6349 28.7 3 . . . 58.67
Henry and Crowther 2000 Australia 140 29.9 2 26.4 . 66.4 31.43
Howell et al. 2001 England 249 26.4 . 49.1 . 56.9 16.87
Hoyo et al. 2011 USA 539 . 2 . . . 50.65
Inskip et al. 2009 England 238 28.9 2 . . . 44.12
Joelsson et al. 2016 Sweden 448 30.2 3 . . 100 59.38
Karlsdottir et al. 2002 Iceland 113 . . . . 62.9 8.85
Koning et al. 2015 Netherlands 135 32.1 3 37.1 64 . 80.00
Langley-Evans and Langley- 2002 England 301 27.9 . 49 . . 42.86
Evans
Lantz et al. 2010 Canada 454 29.3 3 41.9 . 67.6 64.10
Lawal and Adeleye 2014 Nigeria 602 29.3 1 32.9 . 2.49
Leirgul 2015 Norway 53,072 . 2 . . . 29.08
Lewis et al. 1997 England 662 28.2 . 46.7 . 67.8 32.93
Liang et al. 2011 China 453 . . . . 100 29.58
Lindsay et al. 2014 Ireland 52 32 . . 26.9 . 15.38
Livock et al. 2016 Australia 2146 . . . . . 39.75
Maats and Crowther 2002 Australia 211 . . . . . 33.18
Malek et al. 2016 Australia 857 31 3 . 47 74 26.95
Mannien et al. 2014 Netherlands 5975 . 3 . 45.7 . 55.53
Martinussen et al. 2012 USA 1499 . 3 . 44.7 . 51.23
Mashayeki et al. 2011 Iran 400 26.5 2 45.8 50 . 22.50
Masih et al. 2015 Canada 353 31.7 3 39.9 53.8 . 52.12
Mastroiacovo et al. 2014 Italy 2212 33 2 . . 64.5 23.51
Mathews et al. 1998 England 963 25.3 2 . . . 31.46
McGovern et al. 1997 Scotland 487 29 . 51 . 58 20.94
McKeating et al. 2015 Ireland 7953 31.2 . . 38.7 60.2 43.10
McNally and Bourke 2012 Ireland 10,891 31.6 . . . . 64.00
McWalter et al. 2015 Saudi 254 . 3 26.5 . . 21.26
Arabia
Morin et al. 2002 Canada 1858 . 3 34 . 84.5 27.50
Morris et al. 2013 England 117,260 . . . . . 26.00
Morton et al. 2013 NZ 6161 . . . . . 38.70
Mullane and O'Riordan 2011 Ireland 190 . . . . . 63.16
Murphy et al. 2002 Spain 93 29.4 . . . 100 0.01
Navarrete-Munoz et al. 2015 Spain 2332 . 2 . 56.7 83.3 22.81
Neill et al. 1999 England 1000 . . . . 77.3 43.30
Nilsen et al. 2016 Italy 2189 33 2 . 56.9 63.6 23.53

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O'Leary et al. 2001 Ireland 288 26.5 . 42.4 . 38.5 18.06

Paulik et al. 2009 Hungary 349 29.9 2 . 56.4 83.7 31.52
Pauwels et al. 2016 Belgium 148 30.63 3 . 48 . 77.70
Pinto et al. 2008 Portugal 249 29 1 . 62.7 56.6 18.47
Poels et al. 2015 Netherlands 283 . . . . . 56.54
Primavera et al. 2007 Italy 494 . . . . . 5.26
Rabiu et al. 2012 Nigeria 220 30.3 3 30 . . 0.01
Rasmussen et al. 2010 Denmark 84 30 3 56 . 85.7 51.19
Rey et al. 2008 Spain 167 . . . . . 28.14
Rezaei et al. 2013 Iran 370 28 2 65.4 . 70 29.46
Robbins et al. 2006 USA 13 . 2 . . 6.5 46.15
Rousian et al. 2010 Netherlands 54 . . . . . 77.78
Sato et al. 2013 Japan 1076 32.2 3 . . . 34.67
Sayers et al. 1997 Ireland 295 27.4 . 41 . 44.4 5.76
Sen et al. 2009 England 300 28 3 41 . 63 44.67
Shand et al. 2016 Australia 589 . 3 . 54.9 . 37.18
Sikkens et al. 2011 Netherlands 4234 32 . . 58 . 39.89
Sillender 2000 England 162 27 . 44.4 . 51.9 27.16
Stepanuk et al. 2002 USA 693 . 3 35.8 . . 41.99
Stephenson et al. 2014 England 1158 . 3 . 59 73 51.04
Stern et al. 2015 Sweden 3390 29.5 3 31 46 74 29.41
Suliga 2015 Poland 677 . 3 . . . 34.27
Suren et al. 2013 Norway 85,176 3 . 44.6 79.9 71.67
Tamim et al. 2008 Lebanon 5280 29.2 3 33 39.2 69.8 14.00
Timmermans et al. 2008 Netherlands 6940 . 2 . 56.8 69.9 37.35
Tort et al. 2013 France 12,646 . 3 . 43.7 . 14.80
Tyden et al. 2011 Sweden 270 30.8 3 . . 74.8 20.74
Tyden et al. 2015 Sweden 5494 . . . . 74 29.00
Tyden et al. 2015 Denmark 4616 . . . . 75 48.01
van Eijsden et al. 2008 Netherlands 3153 . 2 0 0 . 34.60
Wang et al. 2015 China 172,206 24.98 1 . . . 52.77
Waters et al. 2013 England 141 . . . . . 92.20
Wickramasinghe et al. 2013 Sri Lanka 524 . . . . . 45.99
Wickremasinghe et al. 2003 Sri Lanka 225 . 2 . 55.5 81.3 6.67
Wilton and Foureur 2010 Australia 295 . . 100 100 67.7 23.39
Wu et al. 2013 Scotland 214 . . . . . 20.09
You et al. 2015 China 1012 . 1 . . . 13.44
Zetstra et al. 2012 Netherlands 515 . . . 46.7 75.5 60.58
Zheng et al. 2016 China 5762 . 1 . . . 64.60

Appendix D. Quality indicators of all included studies

Study Inclusion/ Method Setting Folic acid Folic acid Folic acid Health Income Education Reasons for
exclusion described described timing dose adherence status described described non-
criteria described described described described participation
defined described

Aden (2007) 0 0 1 0 0 0 0 0 0 1
Al-Darzi (2014) 1 1 1 0 0 0 0 0 1 0
Al-Hossani 0 1 1 0 1 1 0 0 1 0
(2010)
Al-Riyami (2011) 1 0 1 1 0 0 0 0 1 0
Amitai (2008) 1 1 1 0 0 1 0 0 1 0
Asgharnia 0 0 1 1 0 0 0 0 0 0
(2009)
Backhausen 0 1 1 1 0 0 1 0 1 0
(2014)
Bannink (2015) 0 1 1 0 0 0 0 0 1 0
Basgul (2007) 0 0 1 1 0 0 0 1 1 0
Baykan (2011) 0 1 1 1 1 1 0 1 1 0
Blas-Robledo 0 0 1 0 0 0 0 0 0 0
(2013)
Bower (1997) 0 0 1 0 0 0 0 0 1 0
Bukowski (2009) 1 0 1 1 0 0 0 0 1 0

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Callaway (2009) 0 1 1 0 0 0 0 0 1 0
Cawley (2016) 1 0 1 1 1 1 0 1 1 0
Chen (2016) 0 0 0 1 0 0 0 0 0 0
Cheng (2016) 1 0 1 0 0 0 1 1 1 0
Cueto (2012) 1 1 1 0 0 1 1 1 1 0
Cunningham 0 0 1 0 0 0 0 0 0 0
(2012)
Czeizel (1994) 0 0 1 0 0 0 0 0 1 0
Dante (2015) 1 1 1 0 1 0 1 0 1 1
de la Vega 0 0 1 0 0 0 0 0 0 0
(2002)
De Santis (2013) 1 0 1 0 1 0 0 0 1 0
Ding (2015) 1 0 1 1 0 0 0 1 1 0
Dobson (2006) 1 0 1 0 0 0 0 0 0 1
Eindhoven 1 0 1 0 0 0 0 0 1 0
(2014)
Fabre (2014) 0 0 0 0 0 0 0 0 0 0
Farah (2013) 1 0 1 0 0 0 0 0 0 0
Forster (2009) 1 0 1 1 1 0 0 1 1 0
Frayne (2015) 0 0 1 0 0 0 1 0 0 0
Goldberg (2006) 0 1 1 0 0 0 0 0 1 0
Han (2009) 1 1 1 1 0 0 0 1 1 0
Henry (2000) 1 0 1 1 0 0 0 0 1 0
Howell (1997) 0 0 1 0 0 0 0 0 1 0
Hoyo (2011) 1 0 1 0 1 0 1 0 1 0
Ingskip (2009) 1 0 1 1 1 1 0 0 1 0
Joelsson (2016) 1 0 1 0 0 0 0 1 1 1
Karlsdottir 1 1 1 0 0 0 0 0 0 0
(2002)
Koning (2015) 1 0 1 1 1 1 0 0 1 0
Langley-Evans 1 1 1 0 1 1 0 0 0 0
(2002)
Lantz (2010) 1 0 1 1 0 0 0 0 1 0
Lawal (2014) 0 1 1 0 0 0 0 0 1 0
Leirgul (2015) 1 0 1 0 1 0 0 1 1 0
Lewis (1997) 1 1 1 0 0 0 0 0 0 0
Liang (2011) 1 0 0 0 0 1 0 0 1 0
Lindsay (2014) 1 0 1 0 0 0 0 0 1 0
Livock (2016) 1 0 1 1 0 0 0 1 1 0
Maats (2002) 1 0 1 1 0 0 0 0 1 0
Malek (2016) 1 0 1 1 1 1 0 1 1 0
Mannien (2014) 1 1 1 0 0 1 1 0 1 0
Martinussen 1 0 1 1 1 1 0 1 1 0
(2012)
Mashayekhi 1 1 1 1 0 0 0 0 1 1
(2011)
Masih (2015) 1 0 1 1 1 1 0 1 1 1
Mastroiacovo 1 1 1 1 0 0 1 0 1 0
(2014)
Mathews (1998) 1 1 1 0 1 1 0 0 1 0
McGovern 1 0 1 0 0 0 0 0 0 0
(1997)
McKeating 1 1 1 0 1 0 0 0 0 0
(2015)
McNally (2012) 0 1 1 0 0 0 0 0 0 0
McWalter (2015) 0 1 1 1 1 0 0 0 1 0
Morin (2002) 0 0 1 0 1 1 1 1 1 0
Morris (2013) 0 0 0 0 1 0 0 0 0 0
Morton (2013) 0 0 0 0 0 0 0 0 0 0
Mullane (2011) 0 0 1 0 0 0 0 0 0 0
Murphy (2002) 1 0 1 0 0 0 0 0 0 0
Navarrete- 1 0 1 0 1 1 0 0 1 0
Munoz
(2015)
Neill (1999) 0 0 1 0 0 0 0 0 0 0
Nilsen (2016) 1 0 1 1 0 1 1 0 1 1

15
K.I. Toivonen et al. Preventive Medicine 114 (2018) 1–17

O'Leary (2001) 1 1 1 0 1 0 0 0 0 1
Paulik (2009) 0 0 1 0 0 0 1 0 1 0
Pauwels (2016) 1 0 1 1 1 1 0 0 1 1
Pinto (2009) 1 1 1 1 1 0 0 1 1 1
Poels (2015) 0 0 1 0 0 0 0 0 1 0
Primavera 0 0 1 1 0 0 0 0 0 0
(2007)
Rabiu (2012) 0 0 1 0 0 0 0 0 1 0
Rasmussen 0 0 1 0 0 0 0 0 1 0
(2010)
Rey (2008) 0 0 1 0 0 0 0 0 0 0
Rezaei (2013) 0 0 1 0 0 0 0 0 1 0
Robbins (2006) 0 1 1 0 0 1 0 1 1 0
Rousian (2010) 0 0 0 0 0 0 0 0 0 0
Sato (2013) 0 0 1 0 0 1 0 0 1 0
Sayers (1997) 0 0 1 0 0 0 0 0 0 0
Sen (2016) 0 1 1 1 0 0 0 0 1 0
Shand (2016) 1 0 1 1 0 0 1 0 1 0
Sikkens (2011) 0 0 1 0 0 0 0 0 0 0
Sillender (2000) 0 1 1 0 0 0 0 0 0 1
Stepanuk (2002) 0 0 1 1 0 0 0 0 1 0
Stephenson 0 0 1 0 0 0 1 0 1 0
(2014)
Stern (2016) 0 1 1 1 0 1 1 1 1 1
Suliga (2015) 0 0 1 0 0 0 0 0 1 0
Suren (2013) 0 0 1 1 0 1 0 0 1 0
Tamim (2009) 1 1 1 0 0 0 0 1 1 0
Timmermans 0 0 0 0 1 0 0 0 1 0
(2008)
Tort (2013) 1 1 1 1 0 0 1 0 1 0
Tyden (2011) 1 1 1 0 0 0 0 0 1 0
Tyden (2015) 0 0 1 0 0 0 0 0 0 0
Tyden (2015) 0 0 1 0 0 0 0 0 0 0
Van Eijsden 1 0 1 0 0 0 0 0 1 0
(2008)
Wang (2015) 1 0 1 0 0 0 1 0 1 0
Waters (2013) 0 0 1 0 0 0 0 0 0 0
Wickramasinghe 0 1 1 0 0 0 0 0 0 0
(2003)
Wickramasinghe 0 0 1 0 0 0 0 1 1 0
(2013)
Wilton (2010) 1 1 1 1 0 0 0 0 0 0
Wu (2013) 0 0 1 0 0 0 0 0 0 0
You (2015) 1 1 1 1 0 0 0 1 1 0
Zetstra (2012) 0 0 1 1 0 0 0 0 1 0
Zheng (2015) 1 0 1 0 0 1 0 0 1 0

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