Describing the Global Burden of Neural Tube Defects: A Systematic Literature Review

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RESEARCH ARTICLE
Describing the Prevalence of Neural Tube
Defects Worldwide: A Systematic Literature
Review
Ibrahim Zaganjor
1‡
*, Ahlia Sekkarie
1‡
, Becky L. Tsang
1
, Jennifer Williams
1
,
Hilda Razzaghi
1,2
, Joseph Mulinare
1,2
, Joseph E. Sniezek
1
, Michael J. Cannon
1
,
Jorge Rosenthal
1
1National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and
Prevention, Atlanta, Georgia, United States of America, 2Carter Consulting Inc., Atlanta, Georgia, United
States of America
‡These authors contributed equally to this work as co-first authors.
*wwa3@cdc.gov
Abstract
Background
Folate-sensitive neural tube defects (NTDs) are an important, preventable cause of morbid-
ity and mortality worldwide. There is a need to describe the current global burden of NTDs
and identify gaps in available NTD data.
Methods and Findings
We conducted a systematic review and searched multiple databases for NTD prevalence
estimates and abstracted data from peer-reviewed literature, birth defects surveillance reg-
istries, and reports published between January 1990 and July 2014 that had greater than
5,000 births and were not solely based on mortality data. We classified countries according
to World Health Organization (WHO) regions and World Bank income classifications. The
initial search yielded 11,614 results; after systematic review we identified 160 full text manu-
scripts and reports that met the inclusion criteria. Data came from 75 countries. Coverage
by WHO region varied in completeness (i.e., % of countries reporting) as follows: African
(17%), Eastern Mediterranean (57%), European (49%), Americas (43%), South-East Asian
(36%), and Western Pacific (33%). The reported NTD prevalence ranges and medians for
each region were: African (5.2–75.4; 11.7 per 10,000 births), Eastern Mediterranean (2.1–
124.1; 21.9 per 10,000 births), European (1.3–35.9; 9.0 per 10,000 births), Americas (3.3–
27.9; 11.5 per 10,000 births), South-East Asian (1.9–66.2; 15.8 per 10,000 births), and
Western Pacific (0.3–199.4; 6.9 per 10,000 births). The presence of a registry or surveil-
lance system for NTDs increased with country income level: low income (0%), lower-middle
income (25%), upper-middle income (70%), and high income (91%).
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 1/31
OPEN ACCESS
Citation: Zaganjor I, Sekkarie A, Tsang BL, Williams
J, Razzaghi H, Mulinare J, et al. (2016) Describing
the Prevalence of Neural Tube Defects Worldwide: A
Systematic Literature Review. PLoS ONE 11(4):
e0151586. doi:10.1371/journal.pone.0151586
Editor: Rogelio Cruz-Martinez, Hospital de
Especialidades del Niño y la Mujer de Queretaro,
MEXICO
Received: October 1, 2015
Accepted: February 29, 2016
Published: April 11, 2016
Copyright: This is an open access article, free of all
copyright, and may be freely reproduced, distributed,
transmitted, modified, built upon, or otherwise used
by anyone for any lawful purpose. The work is made
available under the Creative Commons CC0 public
domain dedication.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information files.
Funding: AS, IZ, and BLT were supported in part by
an appointment to the Research Participation
Program at the CDC administered by the Oak Ridge
Institute for Science and Education (ORISE). The
commercial company, Carter Consulting Inc.,
provided support in the form of salaries for authors
[HR, JM]. The funders had no role in study design,
data collection and analysis, decision to publish, or
preparation of the manuscript.

Conclusions
Many WHO member states (120/194) did not have any data on NTD prevalence. Where
data are collected, prevalence estimates vary widely. These findings highlight the need for
greater NTD surveillance efforts, especially in lower-income countries. NTDs are an impor-
tant public health problem that can be prevented with folic acid supplementation and fortifi-
cation of staple foods.
Introduction
Neural tube defects (NTDs), serious birth defects of the brain and spine, are a major, prevent-
able public health burden. Globally, it is estimated that approximately 300,000 babies are born
each year with NTDs [1], resulting in approximately 88,000 deaths and 8.6 million disability-
adjusted life years (DALYs) [2,3]. In low income countries, NTDs may account for 29% of
neonatal deaths due to observable birth defects [4]. As morbidity and mortality from infectious
diseases are decreasing worldwide, the contribution of birth defects to under-5 morbidity and
mortality will continue to increase proportionally [5].
Conclusive evidence from clinical trials has led to recommendations for adequate pericon-
ceptional folic acid intake to reduce the occurrence of a NTD-affected pregnancy [6]; as a
result, mandatory folic acid fortification (FAF) of staple cereal grains has been legislated in
many countries as recently reviewed [7,8]. Long-term surveillance of NTDs in countries that
have successfully implemented fortification, such as the United States, Canada, Costa Rica,
South Africa, and Chile, and data from a supplementation program in China suggest that folic
acid interventions can reduce NTD prevalence to as low as 5–6 per 10,000 pregnancies [8,9].
Because birth defects are a major cause of under-5 mortality, adequate surveillance data are
needed for prevention and evaluation purposes. This is particularly important for birth defects
that have well-established interventions. For example, depending on the baseline prevalence, it
is estimated that the majority of NTDs can be prevented with folic acid [4,10]. However,
national surveillance of NTDs and other birth defects remains limited worldwide. To promote
global birth defects surveillance efforts, in 2010 the World Health Assembly issued a resolution
urging member states “to develop and strengthen registration and surveillance systems for
birth defects”[11].
There have been recent efforts to model and estimate the worldwide burden of NTDs and
other major birth defects [1,12]. Some data are also available from systematic reviews, but
most of the reviews are specific to certain regions or income levels [13–15]. However, an accu-
rate estimate of the prevalence of NTDs in most countries is still unknown primarily due to
insufficient and fragmented data collection. To complement previous efforts, the goal of
our review is to describe the most current prevalence estimates of NTDs worldwide, while
highlighting key methodological differences and gaps in available data.
Methods
Search Strategy
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
guidelines (S1 Document)[16]. We searched the following bibliographic databases for English
and Spanish language literature published between January 1990 and July 2014: the Cochrane
Collaboration, CINAHL, Embase, POPLINE, PubMed, Global Health (CDC resource), Web of
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 2/31
Competing Interests: The commercial company,
Carter Consulting Inc., provided support in the form of
salaries for authors [HR, JM], but did not have any
additional role in the study design, data collection and
analysis, decision to publish, or preparation of the
manuscript.

Science, and several World Health Organization (WHO) library resources (African Index Medi-
cus, Index Medicus for the Eastern Mediterranean Region, Spanish Health Sciences Bibliographic
Index, Index Medicus for the South-East Asian Region, Latin American and Caribbean Health
Sciences Literature, and the World Health Organization Library Information System). We
adapted the search terms to each database and included keywords for neural tube defects, congen-
ital anomalies, epidemiology, registries, and hospitals. We also identified international birth defect
registries and searched the databases/reports of the European Surveillance of Congenital Anoma-
lies (EUROCAT), the International Clearinghouse for Birth Defects Surveillance and Research
(ICBDSR), and other reports. Finally, we included additional studies and reports from hand
searching reference lists of systematic reviews.
Inclusion/Exclusion Criteria and Algorithm Review
We included case-control and cross-sectional studies and reports with either a reported preva-
lence of NTDs (defined as anencephaly/spina bifida/encephalocele), or numerator (number of
reported NTD cases) and denominator data (number of births in the study population). Many
studies reported on NTDs without explaining how they defined them; we included these stud-
ies in order to increase coverage.
We excluded the following: 1) case reports and supplementation trials; 2) studies that only
included anencephaly and/or encephalocele; 3) studies that only counted non-NTDs per our
definition, such as amniotic band sequence, chromosomal abnormalities, or spina bifida
occulta; 4) studies with a denominator of fewer than 5,000 total births given the high degree of
uncertainty of NTD prevalence in such a small sample size; 5) studies that reported prevalence
in graphs without point estimates; 6) studies that only used mortality data; 7) studies with data
based only on prenatal diagnosis; 8) and studies whose data were collected prior to 1990. We
also excluded studies that reported data after a contamination event that may have caused an
increase in NTD prevalence estimates.
We developed an algorithm to ensure that the most current and relevant data for each coun-
try were included in our review. If multiple studies were available for the same region or coun-
try but at different time periods, we included the study with the most recent data. In instances
where multiple studies existed for one country from different geographic locations, all studies
from that country were included, except if nationally representative data were available. In
these cases, only the nationally representative study was used. However, if one study reported
nationwide data that were not nationally representative, we still included studies from individ-
ual regions.
Data Abstraction and Risk-of-Bias (RoB) Assessment
We abstracted data on the number of cases (numerator), the birth cohort (denominator), and
calculated prevalence into a standard table. Three authors reviewed the abstracted data from
the original reports and corrected errors in both abstraction and the original reports. To verify
the reported prevalence estimates and to exclude syndromes, chromosomal abnormalities, iso-
lated hydrocephalus, and spina bifida occulta cases, we re-calculated the prevalence of anen-
cephaly, spina bifida, and encephalocele. We also calculated a sum of reported NTDs, which
included spina bifida and/or anencephaly and encephalocele, depending on what NTDs the
authors of the original study assessed. In addition to prevalence, we also abstracted the follow-
ing information for each study: years included, geographic location, inclusion/exclusion crite-
ria, study design (population-based vs. hospital-based), and whether the data were gathered
from a birth defects registry/surveillance system. We did not distinguish between registries and
surveillance systems in this review.
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 3/31

We developed and pre-piloted a risk-of-bias (RoB) tool to assess the quality of each study’s
methodology. A study’s RoB score was based on the following components: study design, case
ascertainment methods, case definition, representativeness, and limitations. The lower the RoB
score, the less the study was considered to be prone to bias. Two authors reviewed each study
independently and their scores were averaged for a single RoB score (possible score range: 0.0–
18.0). We placed final RoB scores into quartiles: low (0.0–5.4), moderately low (5.5–7.9), mod-
erately high (8.0–10.9), or high (11.0–18.0). We assigned the lowest RoB scores to studies that:
were based on surveillance systems or registries; were population-based; were representative
(as defined by the original authors to accurately describe their population of interest); included
an NTD case definition; defined inclusion and exclusion criteria (e.g., gestational age, birth
weight, birth outcome); and had case reporting from multiple sources.
Analysis
As part of our analyses, we stratified countries by WHO regions, World Bank income levels
(low, lower-middle, upper-middle, high), presence of a surveillance system/registry, and RoB
quartiles [17,18]. For publications that did not provide NTD prevalence, we calculated the
sum of reported NTDs and individual NTD type-specific prevalence estimates. In addition, if it
was not provided by the reference, we calculated the 95% confidence interval for each preva-
lence using the Poisson distribution if the number of cases was below 30, and using the bino-
mial distribution if the number of cases was greater than or equal to 30. We calculated the
range and median reported NTD prevalence for each WHO region.
We used ArcGIS 10.2.1 (ESRI, Redlands, California) to create maps illustrating NTD preva-
lence distributions and registry/surveillance coverage. On the maps, NTD prevalence was clas-
sified into quintiles based on all reported prevalence estimates. If there were national data, the
entire country was filled-in. In Europe, if regional data were available, this geographical level
was also filled-in. In instances where multiple prevalence estimates were available at the
national level, the prevalence reported by the study/report with the least RoB was selected.
Graphical representations of data were created using SigmaPlot 12.5 (Systat Software, San Jose,
California).
Results
PRISMA
The literature search yielded 11,614 results, of which 3,948 were duplicates. Two authors
reviewed and screened the 7,666 unique titles and abstracts for inclusion and exclusion criteria.
After this initial screening, we excluded 6,549 abstracts and conducted the first wave of full-
text review for the remaining 1,117 citations, in which 600 more were excluded. We then evalu-
ated the remaining 517 citations and an additional 66 hand-searched sources from reports
such as ICBDSR and author contacts to ensure the most relevant sources (i.e., most up-to-date
data) were included. We identified 160 unique studies and reports published between January
1990 and July 2014 that met our inclusion criteria in the final stage of review (Fig 1).
The results represent data from 75 countries. Among the 194 WHO member states, the per-
cent reporting within each region is as follows: African (8/47; 17%), Eastern Mediterranean
(12/21; 57%), European (26/53; 49%), Americas (15/35; 43%), South-East Asian (4/11; 36%)
and Western Pacific (9/27; 33%). Of the countries in our review, 46% have high, 31% have
upper-middle, 16% have lower-middle, and 7% have low income status as defined by the
World Bank.
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 4/31

Of the 160 studies, 2% reported spina bifida alone, 10% spina bifida and anencephaly, 1%
spina bifida and encephalocele, and 81% reported all 3 conditions (either stratified or not). Six
percent of studies did not provide a clear definition of how they defined NTDs.
Prevalence of Neural Tube Defects
This systematic review demonstrates great variability in reported NTD prevalence estimates
globally (range: 0.3–199.4 per 10,000 births) (Table 1)[19–124]. Of note, both the lowest and
highest point estimates in this global range came from studies conducted in different regions of
China; Beijing [113]andLuliang[112], respectively. However, even after excluding these esti-
mates, the global range is still quite variable (range: 1.2–124.1 per 10,000 births) (Table 1)[122,
48]. Fig 2 also illustrates that NTD prevalence estimates throughout the world are high, with
approximately 80% of reported prevalence estimates above 6.0 per 10,000 births (i.e., the approx-
imate rate that should be attainable through adequate periconceptional folic acid intake) [8].
Fig 1. PRISMA Flowchart.
doi:10.1371/journal.pone.0151586.g001
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 5/31

Table 1. Neural Tube Defect (NTD) Prevalence Estimates by World Health Organization (WHO) Region*.
Country World Bank
Classification
Location Author Year(s) Included Prevalence Rate per 10,000 Births
Anencephaly Spina bifida Encephalocele Sum of Reported
NTDs
¥
Prevalence 95%
CI
Prevalence 95%
CI
Prevalence 95%
CI
Prevalence 95% CI
AFRICA
Algeria Upper-middle Setif Houcher, et al.[19] 2004–2006 32.2 (25.6,
38.8)
42.8
[f]
(35.2,
50.4)
0.3 (0.0,
2.0)
75.4 (65.4,
85.4)
Cameroon Lower-middle Yaounde Njamnshi AK, et al.[20] January 1997-
December 2006
18.6 (14.9,
22.3)
Democratic
Republic of
Congo
Low Nyankunde, Oriental Province Ahuka OL, et al.[21] January 1993–
August 2001
1.1 (0.0,
6.3)
6.8 (2.5,
14.8)
2.3 (0.3,
8.2)
10.2 (4.7,
19.4)
Ghana Lower-middle Accra Anyebuno M, et al.[22] January 1991–
December 1992
8.4 (4.8,
13.6)
3.1 (1.2,
6.8)
11.5 (7.2,
17.4)
Malawi Low Blantyre Msamati BC, et al.[23] 1998–1999 6.3 (3.6,
10.2)
6.3 (3.6,
10.2)
Nigeria Lower-middle Cross River and Akwa Ibom
States
Ekanem TB, et al.[24] 1980–2003 1.6 (1.0,
2.4)
3.7 (2.7,
4.8)
5.2 (4.0,
6.5)
Nigeria Lower-middle Jos Airede KI [25] June 1987–June
1990
3.3 (0.4,
12.1)
41.8 (27.1,
61.7)
13.4 (5.8,
26.4)
58.6
[a]
(39.3,
78.0)
South Africa Upper-middle Eastern Cape, Kwazulu Natal,
Mpumalanga, and Free State
Provinces
Sayed AR, et al.[26] October 2004–June
2005
3.7 (2.2,
5.9)
5.4 (3.5,
8.0)
9.8 (6.9,
12.7)
South Africa Upper-middle Sovenga, Northern Transvaal Venter PA, et al.[27] June 1989–
December 1992
17.1 (9.1,
29.2)
15.8 (8.1,
27.5)
2.6 (0.3,
9.5)
35.4 (23.4,
51.6)
South Africa Upper-middle Cape Town Viljoen DL, et al. [28] 1973–1992 11.7 (10.8,
12.6)
Tanzania Low Dar es Salaam Kinasha AD and Manji
K[29]
2000–2002 1.2 (0.3,
3.0)
26.1 (20.7,
31.5)
2.9 (1.4,
5.4)
30.2 (24.4,
36.0)
EASTERN MEDITERRANEAN
Egypt Lower-middle Upper Egypt Mohammed YA, et al.
[30]
March 2007–
October 2007
2.0 (0.1,
11.1)
10.0 (3.3,
23.3)
4.0 (0.5,
14.5)
16.0
[b]
(6.9,
31.5)
Iran Upper-middle Yasuj, South West Iran Ebrahimi S, et al.[31] March 2008–
February 2011
38.1 (24.9,
51.3)
Iran Upper-middle Ahvaz Behrooz AG and
Gorjizadeh MH [32]
March 2002–March
2004
24.9 (16.4,
33.4)
15.1 (9.2,
23.3)
2.3 (0.5,
6.6)
42.2 (31.2,
53.3)
Iran Upper-middle Gorgan, Golestan Abdollahi Z, et al.[33] December 2007–
December 2008
21.9 N/A
Iran Upper-middle Tehran Delshad S, et al.[34] March 2005-March
2007
8.5 (6.2,
10.8)
1.6 (0.8,
3.0)
10.1 (7.6,
12.7)
Iran Upper-middle Birjand Afshar M, et al.[35] April 1997–
December 2001
15.5 (10.1,
22.7)
8.9 (5.0,
14.7)
1.8 (0.4,
5.2)
29.8 (21.6,
38.0)
Iran Upper-middle Urmia Rad IA, et al.[36] January 2001–
June 2005
55.2 (43.0,
67.5)
24.8 (16.6,
33.0)
2.8 (0.8,
7.3)
82.9 (67.9,
97.8)
Iran Upper-middle Hamadan Province Farhud DD, et al.[37] 1991–1997 15.6 (8.1,
25.9)
7.0 (2.6,
15.2)
50.1 (35.2,
65.0)
Iran Upper-middle Tabriz ICBDSR 2011 Report
[38]
2009 4.7 (2.4,
8.5)
0.9 (0.1,
3.1)
0.9 (0.1,
3.1)
6.5 (3.6,
10.7)
Iraq Upper-middle Al-Ramadi, Al-Anbar
Governate
Al-Ani ZR, et al.[39] October 2010 –
October 2011
3.5 (0.4,
12.6)
15.7 (7.2,
29.8)
8.7 (2.8,
20.3)
27.9
[a]
(15.9,
45.2)
Iraq Upper-middle Basrah Al-Sadoon I, et al.[40] 1990 2.5 (0.5,
7.2)
7.4 (3.4,
14.1)
9.9 (5.1,
17.2)
(Continued)
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 6/31

Table 1. (Continued)
Country World Bank
Classification
Location Author Year(s) Included Prevalence Rate per 10,000 Births
Anencephaly Spina bifida Encephalocele Sum of Reported
NTDs
¥
Prevalence 95%
CI
Prevalence 95%
CI
Prevalence 95%
CI
Prevalence 95% CI
Jordan Upper-middle North Jordan Amarin ZO and
Obeidat AZ [41]
2005–2006 9.5 (5.5,
15.5)
Jordan Upper-middle Amman Aqrabawi HE [42] April 2002 –April
2003
0.0 (0.0,
7.3)
59.0 (37.9,
80.0)
3.9 (0.5,
14.2)
62.9
[a]
(41.2,
84.6)
Jordan Upper-middle Amman Masri AT [43] 1993–2002 3.5
[c]
(1.7,
6.5)
7.1
[c]
(4.3,
10.9)
0.4
[c]
(0.0,
2.0)
11.0
[c]
(7.1,
14.8)
Jordan Upper-middle Irbid Province Daoud AS, et al.[44] January 1991–
December 1993
3.7 (2.4,
5.0)
10.0 (7.9,
12.1)
2.6 (1.7,
4.0)
16.4 (13.7,
19.1)
Kuwait Upper-middle Al-Jahara Region Madi SA, et al.[45] January 2000–
December 2001
3.9 (0.8,
11.3)
2.6 (0.3,
9.3)
6.5 (2.1,
15.1)
Libya Upper-middle Benghazi Singh R and Al-Sudani
O[46]
1995 7.4 (3.8,
13.0)
0.6 (0.0,
3.4)
8.0 (4.3,
13.7)
Oman High National Alasfoor D and
ElSayed MK [47]
2010 6.8 N/A 23.2 N/A
Pakistan Lower-middle Swat Khattak ST, et al.[48] Januray 2007–
December 2007
113.3 (85.5,
141.1)
7.2 (2.0,
18.4)
124.1
[d]
(95.0,
153.2)
Pakistan Lower-middle Peshawar Qazi G [49] Januray 2009–
December 2009
47.2 (30.3,
70.2)
21.6 (10.8,
38.7)
68.8 (46.1,
91.6)
Pakistan Lower-middle Karachi Perveen F and Tyyab
S[50]
January 2000–
October 2005
29.4 (17.2,
47.1)
15.6 (7.1,
29.6)
5.2 (1.1,
15.2)
50.2 (33.6,
72.1)
Pakistan Lower-middle Lahore Najmi RS [51] November 1994–
October 1996;
August 1997–
March 1998
29.6 (19.5,
39.7)
17.0 (10.3,
26.6)
2.7 (0.6,
7.9)
49.3 (36.3,
62.3)
Pakistan Lower-middle Karachi Jooma R [52] 2002 19.8 (11.6,
30.0)
15.7 (8.5,
25.0)
3.1 (0.6,
8.9)
38.6 (26.4,
50.9)
Qatar High Doha Bener A, et al.[53] January 1985–
December 2009
3.6 (2.9,
4.3)
7.3 (6.4,
8.4)
10.9 (9.7,
12.2)
Saudi Arabia High Al-Khobar Al-Jama F, et al.[54] January 1992–
December 1997
22.4 (14.8,
30.0)
25.7 (17.5,
33.9)
5.4 (2.3,
10.7)
53.5 (41.7,
65.3)
Saudi Arabia High Asir Region Asindi A and Al-Shehri
A.[55]
January 1995–
December 1998
0.4 (0.1,
1.1)
5.6 (4.0,
7.2)
1.6
[a]
(0.8,
2.7)
7.5
[a]
(5.6,
9.4)
Saudi Arabia High Jeddah Safdar OY, et al.[56] 2001–2005 7.6 N/A
Saudi Arabia High Al-Madinah Al-Munawarah Murshid WR [57] April 1996–March
1997
10.9 (6.5,
17.2)
10.9 (6.5,
17.2)
Saudi Arabia High Riyadh Hakami WS and
Majeed-Saidan MA
[58]
January 2001–
December 2010
4.5 (3.2,
5.9)
Sudan Lower-middle Omdurman Elsheikh GEA and
Ibrahim SA [59]
February 2003–
January 2004
12.5 (7.4,
17.6)
16.3 (10.5,
22.1)
4.9 (2.2,
9.3)
33.7
[a]
(25.3,
42.1)
United Arab
Emirates
High National Al Hosani H, et al.[60] January 1999–
December 2001
2.1
[f]
(1.4,
2.8)
EUROPE
Austria High Styria EUROCAT [61] 2003–2009 1.7 (0.9,
2.9)
4.6 (3.1,
6.4)
1.5 (0.8,
2.7)
7.7 (5.8,
10.0)
Belgium High Antwerp EUROCAT [61] 2003–2012 2.6 (2.0,
3.5)
4.5 (3.6,
5.5)
0.8 (0.5,
1.4)
8.0 (6.8,
9.3)
(Continued)
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 7/31

Table 1. (Continued)
Country World Bank
Classification
Location Author Year(s) Included Prevalence Rate per 10,000 Births
Anencephaly Spina bifida Encephalocele Sum of Reported
NTDs
¥
Prevalence 95%
CI
Prevalence 95%
CI
Prevalence 95%
CI
Prevalence 95% CI
Belgium High Hainaut EUROCAT [61] 2003–2012 3.2 (2.3,
4.4)
4.1 (3.1,
5.4)
1.2 (0.7,
2.0)
8.5 (7.0,
10.3)
Bulgaria Upper-middle Plevin Region Kovacheva K, et al.[62] 1988–2006 20.2 (16.2,
24.2)
Croatia High Zagreb EUROCAT [61] 2003–2012 2.0 (1.1,
3.3)
1.4 (0.7,
2.6)
1.1 (0.5,
2.2)
4.5 (3.1,
6.4)
Czech
Republic
High National EUROCAT [61] 2003–2010 2.4 (2.1,
2.8)
3.9 (3.5,
4.3)
1.3 (1.0,
1.5)
7.6 (7.0,
8.2)
Denmark High National Pasternak B, et al.[63] 1997–2011 5.5 (4.1,
6.8)
Denmark High Odense EUROCAT [61] 2003–2012 4.1 (2.5,
6.2)
5.8 (3.9,
8.3)
1.5 (0.7,
3.1)
11.4 (8.7,
14.7)
Finland High National EUROCAT [61] 2003–2011 3.2 (2.7,
3.7)
4.0 (3.5,
4.6)
1.9 (1.5,
2.3)
9.0 (8.3,
9.9)
France High Bas-Rhin Stoll C, et al.[64] 1979–2008 4.3
[a]
(3.7,
4.9)
4.8
[a]
(4.1,
5.5)
1.2
[a]
(0.9,
1.5)
10.3
[a]
(9.3,
11.3)
France High Auvergne EUROCAT [61] 2002 2.2 (0.4,
6.6)
3.0 (0.8,
7.7)
3.0 (0.8,
7.7)
8.2 (4.1,
14.7)
France High French West Indies EUROCAT [61] 2009–2012 3.3 (1.8,
5.6)
4.0 (2.3,
6.5)
1.2 (0.4,
2.8)
8.5 (6.0,
11.8)
France High Ile de la Reunion EUROCAT [61] 2003–2012 7.3 (6.0,
8.8)
9.1 (7.6,
10.8)
2.0 (1.3,
2.9)
18.4 (16.3,
20.7)
France High Paris EUROCAT [61] 2003–2012 4.7 (3.9,
5.6)
5.1 (4.3,
6.1)
1.8 (1.3,
2.4)
11.6 (10.3,
13.0)
Germany High Northern Rhine Region Klusmann A, et al.[65] January 1996
-December 2003
1.9 (1.6,
2.2)
4.4 (3.9,
4.9)
0.8 (0.6,
1.0)
7.1 (6.5,
7.7)
Germany High Mainz EUROCAT [61] 2003–2011 3.8 (1.9,
6.9)
6.6 (4.0,
10.4)
3.5 (1.7,
6.4)
14.0 (10.0,
19.0)
Germany High Saxony-Anhalt EUROCAT [61] 2003–2012 2.0 (1.4,
2.8)
5.6 (4.6,
6.9)
1.4 (0.9,
2.1)
9.0 (7.6,
10.5)
Hungary Upper-middle National ICBDSR 2011 Report
[38]
2005–2009 2.0 (1.6,
2.4)
4.4 (3.8,
5.0)
0.6 (0.4,
0.9)
7.0 (6.3,
7.7)
Ireland High National McDonnell R, et al.[66] 2009–2011 4.7 (3.8,
5.6)
5.1 (4.2,
6.0)
0.7 (0.4,
1.1)
10.4 (9.1,
11.8)
Ireland High Cork & Kerry EUROCAT [61] 2003–2012 4.9 (3.6,
6.5)
5.4 (4.0,
7.0)
1.0 (0.5,
1.9)
11.3 (9.2,
13.6)
Ireland High Dublin EUROCAT [61] 2003–2012 2.2 (1.7,
2.9)
3.0 (2.4,
3.8)
0.7 (0.4,
1.1)
5.9 (5.0,
7.0)
Ireland High South East Ireland EUROCAT [61] 2003–2012 3.3 (2.1,
4.9)
5.0 (3.6,
6.9)
0.3 (0.0,
1.0)
8.6 (6.6,
11.0)
Israel High National Zlotogora J, et al.[67] 2002–2004
Jews 4.9 N/A 2.7 N/A 8.1 N/A
Arabs and Druze 8.2 N/A 6.2 N/A 16.7 N/A
Israel High Multi-Regional ICBDSR 2011 Report
[38]
2005–2009 1.3 (0.8,
1.8)
2.9 (2.2,
3.6)
0.5 (0.2,
0.9)
4.6 (3.7,
5.5)
Italy High Emilia Romagna EUROCAT [61] 2003–2012 2.2 (1.7,
2.7)
2.7 (2.2,
3.3)
0.7 (0.5,
1.0)
5.6 (4.9,
6.4)
(Continued)
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 8/31

Table 1. (Continued)
Country World Bank
Classification
Location Author Year(s) Included Prevalence Rate per 10,000 Births
Anencephaly Spina bifida Encephalocele Sum of Reported
NTDs
¥
Prevalence 95%
CI
Prevalence 95%
CI
Prevalence 95%
CI
Prevalence 95% CI
Italy High Sicily EUROCAT [61] 2003–2004 0.5 (0.1,
1.8)
1.5 (0.5,
3.3)
0.0 (0.0,
0.9)
2.0 (0.9,
3.9)
Italy High Tuscany EUROCAT [61] 2003–2012 1.9 (1.5,
2.5)
3.1 (2.5,
3.8)
0.7 (0.4,
1.1)
5.7 (4.9,
6.6)
Italy High Campania ICBDSR 2011 Report
[38]
2005–2009 3.6 (2.9,
4.2)
3.1 (2.5,
3.8)
1.0 (0.6,
1.3)
7.7 (6.7,
8.7)
Italy High Lombardy ICBDSR 2011 Report
[38]
2009 2.0 (0.2,
7.1)
2.0 (0.2,
7.1)
1.0 (0.0,
5.5)
4.9 (1.6,
11.5)
Italy High North East Italy ICBDSR 2011 Report
[38]
2005–2009 1.5 (1.0,
2.0)
2.5 (1.9,
3.1)
0.5 (0.2,
0.8)
4.5 (3.7,
5.3)
Malta High National EUROCAT [61] 2003–2011 2.2 (0.9,
4.3)
6.3 (4.0,
9.5)
1.6 (0.6,
3.6)
10.2 (7.2,
14.0)
Netherlands High Northern Netherlands EUROCAT [61] 2003–2012 2.6 (1.9,
3.5)
4.6 (3.7,
5.7)
0.6 (0.3,
1.0)
7.7 (6.5,
9.1)
Norway High National EUROCAT [61] 2003–2012 3.5 (3.0,
4.0)
4.7 (4.1,
5.2)
0.9 (0.7,
1.2)
9.1 (8.4,
9.9)
Poland High National EUROCAT [61] 2003–2010 0.8 (0.7,
0.9)
4.5 (4.3,
4.8)
0.6 (0.5,
0.7)
5.9 (5.7,
6.2)
Poland High Wielkopolska EUROCAT [61] 2003–2010 1.2 (0.8,
1.7)
6.3 (5.5,
7.3)
1.0 (0.7,
1.4)
8.5 (7.5,
9.6)
Portugal High South Portugal EUROCAT [61] 2003–2011 1.2 (0.8,
1.9)
1.8 (1.2,
2.5)
0.2 (0.1,
0.6)
3.2 (2.4,
4.2)
Russia High Arkhangelskaja Oblast Petrova JG and
Vaktskjold A [68]
1995–2004 10.7 (9.0,
12.4)
10.4 (8.7,
12.1)
21.1 (18.7,
23.5)
Russia High Moscow ICBDSR 2011 Report
[38]
2005–2009 2.9 (2.3,
3.5)
3.7 (3.0,
4.4)
1.1 (0.7,
1.4)
7.6 (6.6,
8.6)
Slovak
Republic
High Multi-Regional ICBDSR 2011 Report
[38]
2005–2009 0.9 (0.6,
1.3)
2.2 (1.7,
2.8)
0.7 (0.4,
1.0)
3.8 (3.1,
4.5)
Spain High Barcelona EUROCAT [61] 2003–2007 4.9 (3.4,
6.8)
3.3 (2.1,
4.9)
0.8 (0.3,
1.8)
9.0 (7.0,
11.4)
Spain High Basque Country EUROCAT [61] 2003–2011 5.2 (4.2,
6.3)
4.1 (3.2,
5.2)
0.7 (0.4,
1.2)
10.0 (8.6,
11.5)
Spain High National EUROCAT [61] 2003–2012 0.3 (0.2,
0.5)
0.9 (0.6,
1.1)
0.2 (0.1,
0.3)
1.3 (1.0,
1.6)
Spain High Valencia Region EUROCAT [61] 2007–2011 2.4 (1.9,
3.1)
2.4 (1.9,
3.1)
1.5 (1.1,
2.1)
6.4 (5.5,
7.4)
Sweden High National EUROCAT [61] 2007–2011 2.8 (2.4,
3.3)
3.8 (3.3,
4.3)
1.0 (0.7,
1.3)
7.5 (6.8,
8.3)
Switzerland High National Poretti A, et al.[69] January 2001–
December 2007
1.8
[a, b]
(1.0,
2.6)
7.8
[a]
(6.1,
9.5)
1.1
[a]
(0.6,
2.0)
10.7
[a]
(8.7,
12.6)
Switzerland High Vaud EUROCAT [61] 2003–2012 3.5 (2.3,
5.2)
4.5 (3.1,
6.2)
2.4 (1.4,
3.7)
10.4 (8.2,
12.9)
Turkey Upper-middle Afyonkarahisar Onrat ST, et al.[70] July 2003–
December 2004
13.9 (7.2,
24.3)
19.7 (11.5,
31.5)
2.3 (0.3,
8.4)
35.9 (23.3,
48.5)
Turkey Upper-middle Izmir Mandiracioglu A, et al.
[71]
January 2000–
December 2000
14.3
[a, b]
(10.4,
18.2)
(Continued)
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 9/31

Table 1. (Continued)
Country World Bank
Classification
Location Author Year(s) Included Prevalence Rate per 10,000 Births
Anencephaly Spina bifida Encephalocele Sum of Reported
NTDs
¥
Prevalence 95%
CI
Prevalence 95%
CI
Prevalence 95%
CI
Prevalence 95% CI
Turkey Upper-middle Multi-Regional Tuncbilek E, et al.[72] July 1993–June
1994
11.0 (7.0,
16.3)
13.2 (8.4,
18.0)
5.9 (3.2,
10.2)
30.1 (22.9,
37.4)
Turkey Upper-middle Ankara Himmetoglu O, et al.
[73]
1988–1995 34.9 (22.6,
46.6)
Ukraine Lower-middle Rivne and Khmelnytsky
Provinces
[g]
EUROCAT [61] 2005–2011 7.0 (5.9,
8.2)
9.0 (7.8,
10.4)
1.7 (1.2,
2.4)
17.7 (16.0,
19.6)
United
Kingdom
High East Midlands and South
Yorkshire
EUROCAT [61] 2003–2012 4.9 (4.4,
5.5)
5.3 (4.8,
5.9)
1.0 (0.8,
1.3)
11.3 (10.5,
12.1)
United
Kingdom
High Glasgow EUROCAT [61] 1990–2000 6.8 (5.4,
8.4)
7.8 (6.3,
9.6)
2.4 (1.6,
3.4)
16.9 (14.7,
19.4)
United
Kingdom
High Merseyside and Chesire EUROCAT [61] 1995–1999 5.4 (4.2,
6.7)
6.5 (5.2,
8.0)
1.1 (0.6,
1.8)
12.9 (11.1,
15.0)
United
Kingdom
High North West Thames EUROCAT [61] 2003–2004 5.0 (3.7,
6.6)
4.7 (3.4,
6.3)
1.2 (0.6,
2.1)
10.9 (8.9,
13.2)
United
Kingdom
High Northern England EUROCAT [61] 2003–2012 5.8 (5.0,
6.6)
6.5 (5.6,
7.4)
1.6 (1.2,
2.1)
13.8 (12.6,
15.1)
United
Kingdom
High South West England EUROCAT [61] 2005–2012 4.2 (3.6,
4.9)
5.2 (4.5,
6.0)
1.2 (0.9,
1.6)
10.7 (9.7,
11.7)
United
Kingdom
High Thames Valley EUROCAT [61] 2003–2012 4.9 (4.1,
5.8)
4.8 (4.0,
5.8)
1.1 (0.7,
1.6)
10.8 (9.6,
12.1)
United
Kingdom
High Wales EUROCAT [61] 2003–2012 5.1 (4.4,
5.9)
6.4 (5.6,
7.3)
2.0 (1.5,
2.5)
13.5 (12.3,
14.8)
United
Kingdom
High Wessex EUROCAT [61] 2003–2012 5.9 (5.1,
6.9)
4.8 (4.0,
5.7)
1.0 (0.6,
1.4)
11.7 (10.5,
13.0)
AMERICAS
Argentina Upper-middle National Groisman B, et al.[74] November 2009–
June 2012
3.6 (2.9,
4.3)
6.4 (5.5,
7.7)
1.9 (1.5,
2.5)
11.9 (10.7,
13.2)
Argentina Upper-middle Multi-Regional Lopez-Camelo JS,
et al.[75]
2005–2007 3.7 (2.7,
4.6)
6.6 (5.3,
7.9)
2.0 (1.3,
2.8)
12.2 (10.5,
14.0)
Brazil Upper-middle National Orioli IM, et al.[76] 2006 1.4 (1.3,
1.5)
1.4 (1.3,
1.5)
Brazil Upper-middle Multi-Regional Lopez-Camelo JS,
et al. [75]
July 2005–
December 2007
6.9 (5.2,
8.6)
14.2 (11.8,
16.6)
3.2 (2.1,
4.4)
24.3 (21.2,
27.5)
Canada High National ICBDSR 2011 Report
[38]
2005–2009 1.0 (0.9,
1.2)
3.0 (2.7,
3.2)
0.7 (0.6,
0.8)
4.6 (4.3,
5.0)
Chile High Bio Bio, Los Lagos, Los Rios,
Maule, Santiago Metropolitan,
O'Higgins, Tarapaca, and
Valparaiso Regions
Nazer J and Cifuentes
L[77]
2001–2010 3.7 (3.0,
4.4)
4.5 (3.7,
5.3)
1.7 (1.2,
2.1)
9.6 (8.5,
10.7)
Chile High Multi-Regional Lopez-Camelo JS,
et al.[75]
2001–2007 3.7 (2.9,
4.4)
4.6 (3.8,
5.5)
1.8 (1.3,
2.3)
10.1 (8.8,
11.3)
Colombia Upper-middle Cali Pachajoa H, et al.[78] March 2004–
October 2008
6.4 (3.9,
9.7)
7.3 (4.7,
10.8)
3.0 (1.5,
5.6)
16.7 (12.3,
21.1)
Colombia Upper-middle Bogota, Ubate, and Manizales Zarante I, et al.[79] April 2001–January
2008
11.0 (8.2,
13.8)
Colombia Upper-middle Bogota ICBDSR 2011 Report
[38]
2009 1.6 (0.5,
3.8)
2.0 (0.7,
4.3)
0.0 (0.0,
1.2)
3.6 (1.8,
6.5)
(Continued)
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 10 / 31

Table 1. (Continued)
Country World Bank
Classification
Location Author Year(s) Included Prevalence Rate per 10,000 Births
Anencephaly Spina bifida Encephalocele Sum of Reported
NTDs
¥
Prevalence 95%
CI
Prevalence 95%
CI
Prevalence 95%
CI
Prevalence 95% CI
Colombia Upper-middle Baraya, Garzon, Neiva, and
Palermo
Ostos H, et al.[80] 1998 9.6 (3.9,
19.8)
9.6 (3.9,
19.8)
1.4 (0.0,
7.7)
20.6 (11.5,
34.0)
Costa Rica Upper-middle National de la Paz Barboza-
Arguello M, et al.[81]
2003–2012 4.8 (4.3,
5.3)
Cuba Upper-middle National ICBDSR 2011 Report
[38]
2005–2009 3.8 (3.3,
4.3)
4.4 (3.9,
5.0)
1.7 (1.4,
2.1)
10.0 (9.2,
10.8)
Ecuador Upper-middle Multi-Regional Gonzalez-Andrade F
and Lopez-Pulles R
[82]
2001–2007 0.3 (0.3,
0.4)
2.5 (2.3,
2.7)
0.5 (0.4,
0.6)
3.3 (3.1,
3.5)
Guatemala Lower-middle National Acevedo CR, et al.[83] 2001–2003 2.3 (1.7,
2.9)
22.7 (20.8,
24.6)
3.0 (2.3,
3.7)
27.9 (25.8,
30.0)
Honduras Lower-middle Tegucigalpa Hernandez R and
Alvarenga R [84]
July 1998–
September 2000
11.9 (8.2,
15.5)
Mexico Upper-middle Monterrey, Nuevo Leon Hernandez-Herrera
RJ, et al.[85]
1995–1999 6.5 (5.1,
7.9)
8.2 (6.6,
9.7)
1.3 (0.8,
2.1)
16.0 (13.9,
18.2)
Mexico Upper-middle Guadalajara Alfaro N, et al.[86] 1988–1999 9.5 (8.0,
10.9)
10.3 (8.8,
11.8)
19.7 (17.6,
21.8)
Mexico Upper-middle National Navarrete Hernandez
E, et al.[87]
2009–2010 2.1 (1.9,
2.2)
1.2 (1.1,
1.3)
3.3 (3.1,
3.5)
Mexico Upper-middle National ICBDSR 2011 Report
[38]
2005–2009 4.6 (3.3,
5.9)
5.8 (4.3,
7.2)
1.6 (0.9,
2.5)
11.9 (9.8,
14.1)
Peru Upper-middle Lima Sanabria Rojas HA,
et al.[88]
2006–2010 1.9 (1.1,
3.1)
6.1
[a]
(4.5,
7.8)
0.1 (0, 0.6) 8.2
[a]
(6.3,
10.0)
Uruguay Upper-middle Montevideo Castilla EE, et al.[89] 1999–2001 17.5 (11.9,
23.1)
United States High National Canfield MA, et al.[90] 1999–2007 1.3 (1.2,
1.4)
3.2 (3.1,
3.3)
0.8 (0.7,
0.8)
5.3 (5.1,
5.4)
Venezuela Upper-middle Maracaibo, Coro, and Ciudad
Bolivar
Castilla EE, et al.[89] 2000–2001 14.9 (11.0,
18.8)
SOUTH-EAST ASIA
Bangladesh Low Dhaka Dey AC, et al.[91] August 2006–July
2007
13.8 (9.2,
20.0)
India Lower-middle Kolkata Sarkar S, et al.[92] September 2011–
August 2012
1.6 (0.2,
5.6)
14.0 (8.3,
22.1)
2.3 (0.5,
6.8)
17.8 (11.3,
26.8)
India Lower-middle Delhi Sood M, et al.[93] January 1988–
August 1990
39.0 (26.3,
51.8)
26.0 (16.7,
38.7)
1.1 (0.0,
6.0)
66.2 (49.7,
82.8)
India Lower-middle Lucknow Sharma AK, et al.[94] 1982–1991 19.2 (16.8,
21.6)
19.6
[e]
(17.2,
22.0)
38.8
[d]
(35.4,
42.2)
India Lower-middle Pondicherry Mahadevan B and
Bhat BV [95]
July 1998–June
2004
18.0 (14.5,
21.6)
31.0 (26.3,
35.7)
7.0 (4.8,
9.2)
55.5
[a]
(49.3,
61.8)
India Lower-middle Duragpur Duttachoudhury A and
Pal SK [96]
January 1991
-December 1993
5.5 (1.5,
14.1)
5.5 (1.5,
14.1)
11.0 (4.8,
21.8)
India Lower-middle Erode Ponne S and Lakshmi
UK [97]
2000–2004 10.7 (6.6,
12.7)
14.7 (12.3,
17.2)
1.9 (1.1,
2.8)
27.4 (24.1,
30.7)
India Lower-middle Himachal Pradesh Shimla Grover N [98] January 1991–
December 1995
20.8 (12.9,
31.8)
16.8 (9.8,
27.0)
6.9 (2.8,
14.3)
44.6 (31.6,
57.5)
(Continued)
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 11 / 31

Table 1. (Continued)
Country World Bank
Classification
Location Author Year(s) Included Prevalence Rate per 10,000 Births
Anencephaly Spina bifida Encephalocele Sum of Reported
NTDs
¥
Prevalence 95%
CI
Prevalence 95%
CI
Prevalence 95%
CI
Prevalence 95% CI
India Lower-middle Multi-Regional ICBDSR 2011 Report
[38]
2005–2009 12.3 (11.4,
13.1)
11.0 (10.2,
11.8)
3.6 (3.1,
4.0)
26.8 (25.6,
28.1)
India Lower-middle Sevagram, Wardha Taksande A, et al.[99] January 2005–July
2007
5.3 (1.7,
12.4)
2.1 (0.3,
7.7)
7.5 (3.0,
15.4)
Nepal Low Thapathali Malla BK [100] 2004 5.3 (2.4,
10.1)
4.7 (2.0,
9.3)
1.8 (0.4,
5.2)
11.8 (7.2,
18.2)
Thailand Upper-middle Songkhla, Phatthalung, and
Trang Provinces
Jaruratanasirikul S,
et al.[101]
January 2001–
December 2012
0.8 (0.4,
1.4)
0.7 (0.4,
1.3)
0.3 (0.1,
0.8)
1.9 (1.3,
2.7)
Thailand Upper-middle Chiang Mai Kitisomprayoonkul N
and Tongsong T [102]
June 1989–May
2000
5.6 (3.9,
7.4)
0.6 (0.2,
1.5)
0.4 (0.1,
1.3)
6.6 (4.7,
8.6)
Thailand Upper-middle Bangkok Wasant P and
Sathienkijkanchai A
[103]
1990–1999 2.6 (1.8,
3.4)
3.2 (2.4,
4.1)
0.8 (0.5,
1.4)
6.7
[b, d]
(5.5,
7.9)
WESTERN PACIFIC
Australia High South Australia Flood L, et al.[104] 2010 19.5 (13.4,
25.6)
Australia High Victoria, West Australia,
South Australia, New South
Wales, Queensland States
Macaldowie A and
Hilder L [105]
2006–2008 8.8 (8.2,
9.4)
China Upper-middle Hainan Province Fan L, et al.[106] 2010 5.8 (3.9,
7.7)
China Upper-middle Shenzhen City Yang M, et al.[107] 2003–2009 5.7 (4.6,
6.8)
China Upper-middle National Li X, et al.[108] 2006–2008 5.9 (5.6,
6.2)
6.0 (5.7,
6.3)
2.2 (2.0,
2.3)
14.0 (13.4,
14.5)
Northern China 6.8 (6.4,
7.3)
9.2 (8.6,
9.8)
2.7 (2.4,
3.0)
18.7 (17.9,
19.5)
Southern China 5.0 (4.6,
5.4)
3.1 (2.8,
3.4)
1.7 (1.5,
1.9)
9.7 (9.1,
10.3)
China Upper-middle Inner Mongolia Zhang X, et al.[109] 2005–2008 6.9 (4.8,
9.0)
10.6 (8.1,
13.2)
2.7 (1.4,
4.0)
20.3
[f]
(16.8,
23.8)
China Upper-middle National Dai L, et al. [110] 2009 6.5 (6.1,
6.9)
China Upper-middle Zhejiang Province Zhang XH, et al.[111] 2007–2009 6.3 (5.7,
7.0)
3.6 (3.1,
4.1)
1.4 (1.1,
1.7)
11.3 (10.4,
12.2)
China Upper-middle Luliang Prefecture, Shanxi
Province
Chen G, et al.[112] 2004–2005 82.6 (60.5,
104.7)
38.9 (25.2,
57.5)
26.5 (15.4,
42.4)
199.4
[d]
(165.2,
233.6)
China Upper-middle Beijing Li Y, et al.[113] January 2003–
March 2009
0.0 (0.0,
0.6)
0.3 (0.0,
1.2)
0.3 (0.0,
1.2)
China Upper-middle Guizhou Province Liu J, et al. [114] Januray 1996–
December 2004
4.2 (2.9,
5.5)
5.9 (4.4,
7.4)
0.7 (0.3,
1.4)
12.2
[d]
(10.0,
14.4)
China Upper-middle Gansu Province Cheng N, et al.[115] January 2001–
January 2002
66.5 (46.9,
86.1)
China High Taiwan Chen BY, et al.[116] 2002 1.1 (0.7,
1.6)
1.1 (0.7,
1.6)
0.4 (0.2,
0.7)
2.5 (1.9,
3.1)
Japan High Osaka City Imaizumi Y, et al.[117] 1981–1990 7.1 (4.2,
11.4)
1.3 (0.3,
3.7)
8.4 (5.1,
12.9)
(Continued)
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 12 / 31

Table 1. (Continued)
Country World Bank
Classification
Location Author Year(s) Included Prevalence Rate per 10,000 Births
Anencephaly Spina bifida Encephalocele Sum of Reported
NTDs
¥
Prevalence 95%
CI
Prevalence 95%
CI
Prevalence 95%
CI
Prevalence 95% CI
Japan High Ishikawa Prefecture Seto T, et al.[118] 1981–2000 0.8 (0.2,
1.3)
0.9 (0.3,
1.5)
1.0 (0.3,
1.6)
2.6 (1.7,
3.9)
Japan High National ICBDSR 2011 Report
[38]
2005–2009 0.9 (0.6,
1.2)
5.2 (4.5,
5.9)
0.8 (0.5,
1.1)
6.9 (6.1,
7.7)
South Korea High National Kim MA, et al.[119] 2005–2006 0.2 (0.1,
0.3)
2.6 (2.2,
2.9)
0.3 (0.2,
0.4)
3.1 (2.7,
3.5)
Malaysia Upper-middle National Boo NY, et al.[120] 2009 2.1 (1.5,
2.6)
1.6 (1.1,
2.1)
0.8 (0.5,
1.2)
5.4 (4.5,
6.2)
New Zealand High National ICBDSR 2011 Report
[38]
2005–2009 0.4 (0.2,
0.6)
2.1 (1.6,
2.6)
0.5 (0.3,
0.8)
3.0 (2.4,
3.6)
Papua New
Guinea
Lower-middle Port Moresby Dryden R [121] 1985–1986 3.0 (0.6,
8.8)
4.0 (1.1,
10.2)
7.0 (2.6,
14.4)
Singapore High National Shi LM, et al.[122] 1994–1998 0.5
[b]
(0.3,
0.9)
0.7 (0.4,
1.1)
1.2
[b]
(0.8,
1.8)
Vietnam Lower-middle Binh Thuan Province Hoang T, et al.[123] 2010 3.6 (1.2,
8.4)
0.0 (0.0,
2.6)
0.7 (0.0,
4.0)
4.3 (1.6,
9.4)
UNCLASSIFIED
Palestine East Jerusalem and Southern
West Bank
Dudin A [124] 1986–1993 54.9
[a]
(46.1,
63.7)
a
Non-NTDs such as syndromes, chromosomal abnormalities, and spina bifida occulta were not included in our calculations
b
May include non-NTDs, but could not stratify in our calculation
c
Referred cases were not included in our calculation
d
Individual NTDs do not sum to total NTDs (e.g., only isolated NTD counts were provided, but prevalence includes multiple NTDs)
e
Spina bifida cases included encephalocele
f
Recalculated NTD prevalence was inconsistent with the original authors’published rate
g
Regions may be impacted by Chernobyl disaster
N/A = Not applicable
*If prevalence cell is blank, data were either not reported, not stratified by specific type of NTD, or unclear
¥
Sum of all NTDs reported, which includes spina bifida and/or anencephaly and encephalocele, depending on what NTDs the authors of the original study assessed
doi:10.1371/journal.pone.0151586.t001
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 13 / 31

Furthermore, we observed that among studies that reported stratified data for all three types
of NTDs, on average, spina bifida attributed the highest percentage to total NTD prevalence,
followed by anencephaly and then encephalocele (Fig 3). When stratified by country income
level, we noticed a general decrease in the median prevalence for each specific type of NTD
from the lower-middle to high income countries (Fig 4). NTD prevalence estimates by WHO
region are as follows:
Fig 2. Neural Tube Defects Prevalence and Confidence Intervals by World Bank Income
Classifications (Log Scale)[18].
doi:10.1371/journal.pone.0151586.g002
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 14 / 31

Fig 3. Percent of all Neural Tube Defects (NTDs) Attributable to Each Condition for Studies that
Reported all Three Types of NTDs: Anencephaly, Spina Bifida, and Encephalocele. Bars Indicate the
Median Percent for Each Condition.
doi:10.1371/journal.pone.0151586.g003
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
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African Region: Data from eight of 47 WHO member countries, represented by 11 studies,
met our inclusion criteria (Fig 5). The lowest reported NTD prevalence for the region was
reported in Nigeria (5.2 per 10,000 births) [24] and the highest was reported in Algeria (75.4
per 10,000 births) [19]. The median NTD prevalence was 11.7 per 10,000 births. Data from this
region were primarily gathered from hospital-based retrospective case reviews.
Eastern Mediterranean Region: Published data were available for 12 of the 21 countries in
the region and were represented by 31 studies (Fig 6). This region exhibited variability in
reported NTD prevalence as well, with estimates as low as 2.1 per 10,000 births in the United
Arab Emirates [60] and as high as 124.1 per 10,000 births in Swat, Pakistan [48]. This region
had the highest median prevalence (21.9 per 10,000 births). Elevated NTD prevalence estimates
were consistently observed in Pakistan. All five studies in Pakistan reported estimates between
38.6 and 124.1 per 10,000 births [48–52].
European Region: We identified a total of 60 different studies/reports spanning a total of 26
countries of the 53 countries in the region (Fig 7). Ninety-five percent of NTD data from
Europe came from regional or national registries/surveillance systems. The reported NTD
prevalence estimates in this region were relatively less variable than other regions (range: 1.3–
35.9 per 10,000 births) [61,70]. The median for the European region was 9.0 per 10,000 births.
Americas Region: Data from 21 studies/reports representing 15 of the 35 countries were
available (Fig 8). This region had the least variability in reported NTD prevalence estimates.
Fig 4. Prevalence per 10,000 Births for Specific Types of Neural Tube Defects by World Bank Income
Classifications [18]. Bars Indicate the Median Prevalence for Each Condition.
doi:10.1371/journal.pone.0151586.g004
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 16 / 31

Among studies that included spina bifida and at least one other NTD, the lowest prevalence
was 3.3 per 10,000 births [82,87]. A study from Brazil which only counted spina bifida
reported a prevalence of 1.4 per 10,000 births [75]. In this region, the highest prevalence was
reported in Guatemala (27.9 per 10,000 births) [83]. The median prevalence was 11.5 per
10,000 births.
South-East Asian Region: There were 14 studies representing four of the 11 countries in
South-East Asia (Fig 9). The lowest prevalence estimate for the region was 1.9 per 10,000 births
in Thailand [101] and the highest was 66.2 per 10,000 births in India [93]. Most of the data
for this region came from either Thailand or India; three and nine studies, respectively. The
median prevalence in this region was 15.8 per 10,000 births.
Fig 5. African Region Neural Tube Defects Prevalence Estimates (Location, Number of Hospitals). If
there were national data available for more than one NTD, the entire country was filled-in based on the
prevalence per 10,000 births. In instances where multiple prevalence estimates were availableat the national
level, the prevalence reported by the study/report with the least risk-of-bias was selected. Countries colored
in grey are not a part of the World Health Organization region. Shapefile reprinted from http://www.diva-gis.
org under a CC BY license, with permission from DIVA-GIS and Dr. Robert Hijmans.
doi:10.1371/journal.pone.0151586.g005
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 17 / 31

Western Pacific Region: Of the 27 countries, data were available for nine countries from 22
studies/reports (Fig 10). This region had the lowest median prevalence value (6.9 per 10,000
births). As stated previously, China exhibited the greatest variability in reported NTD preva-
lence estimates (range: 0.3–199.4 per 10,000 births) [113,112]. As seen in Li et al., NTD esti-
mates tend to be higher in northern China (18.7 per 10,000 births) than in the southern part of
the country (9.7 per 10,000 births) [108]. When excluding data from China, reported NTD
prevalence in this region ranged from as low as 1.2 per 10,000 births in Singapore [122]toas
high as 19.5 per 10,000 births in Australia [104].
Surveillance System/Registry Coverage
Fig 11 shows the types of NTD data collection worldwide, categorized as national surveillance
system/registry, regional surveillance system/registry, or other (i.e., no surveillance system/reg-
istry but has data collected using another methodology). The map illustrates that there are lim-
ited amounts of data derived from surveillance/registry programs in countries in the African
(1/8) and South-East Asian (2/4) regions. In contrast, the Americas (11/15) and European (26/
26) countries had higher utilization of surveillance/registries. Furthermore, the presence of a
NTD surveillance system/registry increased with country income status: low income (0%),
lower-middle (25%), upper-middle (70%), and high income (91%).
Fig 6. Eastern Mediterranean Region Neural Tube Defects Prevalence Estimates (Location, Number of Hospitals). If there were national data
available for more than one NTD, the entire country was filled-in based on the prevalence per 10,000 births. In instances where multiple prevalence estimates
were available at the national level, the prevalence reported by the study/report with the leastrisk-of-bias was selected. Countries colored in grey are not a
part of the World Health Organization region. Shapefile reprinted from http://www.diva-gis.org under a CC BY license, with permission from DIVA-GIS and Dr.
Robert Hijmans.
doi:10.1371/journal.pone.0151586.g006
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 18 / 31

Risk-of-Bias (RoB)
The RoB evaluation generated scores ranging from 0.0 to 14.0 (possible range 0.0 to 18.0), with
lower scores indicating lower RoB. When average RoB scores were classified by WHO region,
studies/reports from Europe had the lowest (5.0), while studies/reports from the Eastern Medi-
terranean (10.9), South-East Asian (11.3) and African (11.5) regions had the highest RoB
scores (Fig 12). In addition, we observed an inverse relationship between RoB score and coun-
try income level. As the income level of countries increased, their average RoB scores decreased
(Fig 13).
Discussion
Our review provides a comprehensive global assessment of NTD prevalence as observed from
75 countries at the national, regional, or local levels, which represents about 40% of the total
number of WHO member states (194) [125]. The African and South-East Asian regions have
minimal data available, demonstrating the need to establish surveillance and other mechanisms
that can provide countries with standardized data to better determine the burden of birth
defects in general, and NTDs in particular. More complete ascertainment of data will be useful
in determining country level needs for prevention of NTDs, monitoring trends through time,
helping to evaluate the impact of prevention efforts, and developing services for those affected.
Fig 7. European Region Neural Tube Defects Prevalence Estimates (Location, Number of Hospitals).
The majority of data from the European region was population based. All data based on hospital studies from
regions is indicated with the number of hospitals. If there were national or regional data available for more
than one NTD, the entire country or region was filled-in based on the prevalence per 10,000 births. In
instances where multiple prevalence estimates were available at the national level, the prevalence reported
by the study/report with the least risk-of-bias was selected. Countries colored in grey are not a partof the
World Health Organization region. A national study from Israel is not represented on this map since it only
provided prevalence by ethnicity. Shapefile reprinted from http://www.gadm.org under a CC BY license, with
permission from Global Administrative Areas and Dr. Robert Hijmans.
doi:10.1371/journal.pone.0151586.g007
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 19 / 31

Overall, reported prevalence estimates varied greatly between, and also, within countries
ranging from 0.3 to 199.4 NTDs per 10,000 births. Through the RoB assessment, we discovered
this may be in part due to variation in data collection methodology among individual studies.
For example, both studies from post-fortification Brazil had a 10-fold difference in spina bifida
prevalence estimates: 1.4 per 10,000 live births (95% CI: 1.2, 1.5) in the Orioli et al. study [76]
and 14.2 per 10,000 births (95% CI: 11.8, 16.6) in the Lopez-Camelo et al. study [75]. Orioli
Fig 8. American Region Neural Tube Defects Prevalence Estimates (Location, Number of Hospitals). If
there were national data available for more than one NTD, the entire country was filled-in based on the
prevalence per 10,000 births. In instances where multiple prevalence estimates were availableat the national
level, the prevalence reported by the study/report with the least risk-of-bias was selected. Shapefile reprinted
from http://www.diva-gis.org under a CC BY license, with permission from DIVA-GIS and Dr. Robert Hijmans.
doi:10.1371/journal.pone.0151586.g008
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 20 / 31

et al. assessed spina bifida prevalence in 2006 in a population-based cross-sectional study that
included millions of live births from the Live Births Information System. The system used to
estimate NTDs in the Orioli et al. paper had some limitations with case ascertainment, case def-
inition, and lack of standardized diagnoses that may impact the validity and reliability of the
estimates [76,126]. The Lopez-Camelo et al. study used data from the Latin American Collabo-
rative Study of Congenital Anomalies (ECLAMC) which is a hospital-based, voluntary birth
defects surveillance network that includes 19 hospitals throughout Brazil. It is important to
note that the NTD prevalence variability we found in our review could also be true differences,
resulting from other factors including nutritional factors, genetics, routine folic acid supple-
mentation, and the presence of folic acid fortification programs [127–129].
By conducting our RoB assessment, we found that case ascertainment methods and data
quality varied greatly among studies. Therefore, the prevalence estimates from different studies
are not directly comparable nor can they be used to calculate a combined estimate [130]. For
example, the scope of studies varied from single-hospital studies done over the span of one
year to studies using established nationally representative surveillance systems. In addition,
many studies did not clearly define NTDs or provide inclusion criteria (e.g., gestational age and
birth outcome). While we attempted to re-calculate reported prevalence to match our defini-
tion (e.g., removing chromosomal NTDs and spina bifida occulta), many times this was not
possible because data were not stratified by type of NTD. Standardized protocols (i.e., case defi-
nitions, inclusion criteria, variables collected, reporting) for birth defects surveillance would
Fig 9. South-East Asian Region Neural Tube Defects Prevalence Estimates (Location, Number of
Hospitals). If there were national data available for more than one NTD, the entire country was filled-in based
on the prevalence per 10,000 births. In instances where multiple prevalence estimates were availableat the
national level, the prevalence reported by the study/report with the least risk-of-bias was selected. North
Korea had no reported data and was not shown in map due to scaling considerations. Shapefile reprinted
from http://www.diva-gis.org under a CC BY license, with permission from DIVA-GIS and Dr. Robert Hijmans.
doi:10.1371/journal.pone.0151586.g009
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 21 / 31

allow better comparison among studies. In addition, improved methodology can make preva-
lence estimates more accurate. For example, including cases among pregnancies terminated for
fetal anomalies, especially in countries where this is legal, usually leads to higher and more
accurate prevalence estimates due to better case ascertainment. Recently, standardized tools for
birth defects surveillance have been developed through a collaborative effort of health organi-
zations including WHO, CDC, and ICBDSR. The Birth Defects Surveillance Manual and Atlas
of Selected Congenital Anomalies are available in three languages (English, Spanish, and
French) and have been developed specifically for low and middle income countries [131,132].
Fig 10. Western Pacific Region Neural Tube Defects Prevalence Estimates (Location, Number of
Hospitals). If there were national data available for more than one NTD, the entire country was filled-in based
on the prevalence per 10,000 births. In instances where multiple prevalence estimates were availableat the
national level, the prevalence reported by the study/report with the least risk-of-bias was selected. Countries
colored in grey are not a part of the World Health Organization region. Shapefile reprinted from http://www.
diva-gis.org under a CC BY license, with permission from DIVA-GIS and Dr. Robert Hijmans.
doi:10.1371/journal.pone.0151586.g010
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 22 / 31

In our review, although some data were available from low and middle income countries,
most of the data were not derived from surveillance systems or registries. Often data from
these countries were collected in limited geographic areas (single hospital studies), were not
population-based, and lacked well defined procedures for collecting birth defects data. NTD
prevalence data from surveillance systems and registries, such as EUROCAT, that used stan-
dardized and more comprehensive case ascertainment protocols (e.g., reporting cases from ter-
mination of pregnancy where it is legal) and had greater geographic and population coverage
are more likely to estimate the true burden of NTDs in those regions more accurately.
This review advances the state of knowledge in three ways: first, this is the most current sys-
tematic review on global NTD prevalence; second, this review was able to identify large gaps in
data collection and highlight international differences; and third, through the RoB assessment
this study was able to document the wide variation in the quality and methodology of current
reports. Our review supports the findings of previously published literature and demonstrates
there is a high burden of NTDs globally. However, our review purposefully does not model
data to non-reporting regions in an effort to highlight the lack of data globally. Moreover, it
expands the scope of previously published systematic reviews that only included studies/
reports from countries in one region or select income levels.
Limitations
Beyond issues related to the abstracted data and study-specific methodologic issues, our review
is also limited by factors related to our search criteria. Since this review only searched English
and Spanish literature and excluded studies with small study populations, it may not have
incorporated all relevant NTD prevalence information. In select studies, our review was unable
Fig 11. Data Source: Surveillance/Registry Coverage by Geographic Level. Shapefile reprinted from
http://www.diva-gis.org under a CC BY license, with permission from DIVA-GIS and Dr. Robert Hijmans.
doi:10.1371/journal.pone.0151586.g011
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 23 / 31

to report prevalence estimates for each specific type of NTD since individual values were not
always stratified. Lastly, presence of birth outcome data (i.e., live birth, stillbirth, and termina-
tion of pregnancy) was only used for the RoB analysis. Ideally, prevalence data should be strati-
fied by birth outcome, however, many studies did not describe the birth outcome in sufficient
detail (i.e., whether it was in the numerator, denominator, or both) or at all.
Conclusions
This review describes the available data on the current burden of NTDs throughout the world.
Despite methodological variations and coverage gaps in data collection, high NTD prevalence
estimates throughout the literature indicate that NTDs remain an important preventable public
health problem. This review provides a snapshot of areas in need of greater coverage and qual-
ity of NTD monitoring and surveillance and identifies opportunities for development such as
standard reporting of birth defects as recommended by the World Health Assembly resolution.
More importantly, regions that include large portions of the global population (e.g., South-East
Asia) are lacking surveillance/registry data and case ascertainment methods that include all
birth outcomes which provide the most reliable and valid estimates. In response to this need,
Fig 12. Average Study Risk-of-Bias by World Health Organization Region.
doi:10.1371/journal.pone.0151586.g012
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 24 / 31

CDC’s Birth Defects COUNT global initiative is working with partners in South-East Asia,
East and Central Africa, and Latin America to implement and improve surveillance of NTDs
as well as other birth defects [133].
Supporting Information
S1 Document. PRISMA Checklist.
(DOC)
S2 Document. Permission to publish map shapefiles.
(DOCX)
Acknowledgments
We would like to thank Barbara Landreth, CDC librarian, for her assistance with the literature
search. We would also like to thank Csaba Siffel, Cho-Hee Schrader, and Chelsey Brack for
their assistance in abstract review. Finally, we would like to thank Diana Valencia for her assis-
tance in abstracting data recorded in Spanish.
Disclaimer: The findings and conclusions in this report are those of the authors and do not
necessarily represent the official position of the Centers for Disease Control and Prevention.
Fig 13. Average Study Risk-of-Bias by World Bank Income Classification [18].
doi:10.1371/journal.pone.0151586.g013
Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review
PLOS ONE | DOI:10.1371/journal.pone.0151586 April 11, 2016 25 / 31

Author Contributions
Conceived and designed the experiments: IZ AS BLT JW HR JM JES MJC JR. Performed the
experiments: IZ AS BLT JW HR JM JES MJC JR. Analyzed the data: IZ AS MJC JR. Wrote the
paper: IZ AS BLT JW HR JM JES MJC JR.
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