Accepted Manuscript

Title: Meta-analysis of perinatal factors associated with

epilepsy in tropical countries

Authors: Marc Harris Dassi Tchoupa Revegue, Benoit Marin,

Euloge Ibinga, Farid Boumediene, Pierre-Marie Preux,
Edgard Brice Ngoungou

PII: S0920-1211(18)30088-3
DOI: https://doi.org/10.1016/j.eplepsyres.2018.07.004
Reference: EPIRES 5986

To appear in: Epilepsy Research

Received date: 9-2-2018

Revised date: 27-6-2018
Accepted date: 14-7-2018

Please cite this article as: Dassi Tchoupa Revegue MH, Marin B, Ibinga
E, Boumediene F, Preux P-Marie, Ngoungou EB, Meta-analysis of perinatal
factors associated with epilepsy in tropical countries, Epilepsy Research (2018),
https://doi.org/10.1016/j.eplepsyres.2018.07.004

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 Meta-analysis of perinatal factors associated with epilepsy in tropical countries
Marc Harris DASSI TCHOUPA REVEGUEa *, Benoit MARINb, Euloge IBINGAc, Farid
BOUMEDIENEd, Pierre-Marie PREUXe, Edgard Brice NGOUNGOUf .

a.INSERM, University of Limoges, University Hospital Centre, UMR_S 1094, Tropical Neuroepidemiology,
Institute of Neuroepidemiology and Tropical Neurology, Limoges, France.
2 rue du Dr. Marcland - 87 025 Limoges Cedex. harrisdassi@gmail.com
University of Health Sciences, DEBIM, EA NEMIT, Faculty of Medicine, Libreville, Gabon.
BP: 4009 Libreville, Gabon.
Regional Hospital Centre George Rawiri of Lambarene (CHRGRL)

b. INSERM, University of Limoges, University Hospital Centre, UMR_S 1094, Tropical Neuroepidemiology,

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Institute of Neuroepidemiology and Tropical Neurology, Limoges, France.
2 rue du Dr. Marcland - 87 025 Limoges Cedex. benoit.marin@unilim.fr

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CHU, CEBIMER, Limoges, France.

c. INSERM, University of Limoges, University Hospital Centre, UMR_S 1094, Tropical Neuroepidemiology,

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Institute of Neuroepidemiology and Tropical Neurology, Limoges, France.
2 rue du Dr. Marcland - 87 025 Limoges Cedex. kmarail@yahoo.fr

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University of Health Sciences, DEBIM, EA NEMIT, Faculty of Medicine, Libreville, Gabon.
BP: 4009 Libreville, Gabon

d. INSERM, University of Limoges, University Hospital Centre, UMR_S 1094, Tropical Neuroepidemiology,

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Institute of Neuroepidemiology and Tropical Neurology, Limoges, France.
2 rue du Dr. Marcland - 87 025 Limoges Cedex. farid.boumediene@unilim.fr
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CHU, CEBIMER, Limoges, France.

e. INSERM, University of Limoges, University Hospital Centre, UMR_S 1094, Tropical Neuroepidemiology,
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Institute of Neuroepidemiology and Tropical Neurology, Limoges, France.
2 rue du Dr. Marcland - 87 025 Limoges Cedex. pierre-marie.preux@unilim.fr
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CHU, CEBIMER, Limoges, France.

f. INSERM, University of Limoges, University Hospital Centre, UMR_S 1094, Tropical Neuroepidemiology,
Institute of Neuroepidemiology and Tropical Neurology, Limoges, France.
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2 rue du Dr. Marcland - 87 025 Limoges Cedex. benoit.marin@unilim.fr

University of Health Sciences, DEBIM, EA NEMIT, Faculty of Medicine, Libreville, Gabon.
BP: 4009 Libreville, Gabon. ngoungou2001@yahoo.fr
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*Corresponding author:
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Address: UMR 1027 INSERM-Université Toulouse III, Hôpital Paule de Viguier, 330 avenue de
Grande-Bretagne TSA 70034; 31 059 Toulouse Cedex 9
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harrisdassi@gmail.com
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Highlights:
 Adverse perinatal events can disturb normal brain development during intra-uterine life,
at birth and during the first days of life.
 There is a limited number of studies assessing association between perinatal factors and
the occurrence of epilepsy in tropical countries.
  Home birth, complicated delivery, and premature birth are most studied and increase
the risk of epilepsy in tropical countries.

ABSTRACT
Most people with epilepsy live in tropical countries. Perinatal factors seem to play a significant

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role in the occurrence of epilepsy. Available data provide different and sometimes contradictory

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conclusions on the role and the burden of these factors. The aim of our study was to evaluate
the effect of these perinatal factors on the development of epilepsy in tropical countries. The

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main databases were screened, regardless the language, for all eligible studies published up to

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March 2017. Exposures were perinatal factors whilst the disease was epilepsy. After selection
and data extraction, we calculated a pooled measure of association for each perinatal factor

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using fixed or random-effect models. We tested the heterogeneity and the publication bias. The
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degree of significance was 5%. We screened 22,581 articles and identified 13 studies. Among
the perinatal factors studied, home birth (OR 1.36, 95%CI: 1.21-1.54), complicated delivery
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(OR 2.10, 95%CI: 1.05-4.20) and premature birth (OR 2.80, 95%CI: 2.07-3.78) were associated
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with the occurrence of epilepsy. The attributable risk of premature birth and home birth was
estimated to be responsible for 17% and 20% of the cases of epilepsy, respectively, in tropical
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countries. Despite the limited number of studies identified, we demonstrated that some perinatal
factors are risk factors for epilepsy in tropical countries. The three most studied risk factors are
modifiable. Therefore, prevention strategies should target them. Further studies are essential to
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improve the understanding of the burden of these factors in the development of epilepsy.
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Keywords: epilepsy, perinatal factors, meta-analysis, tropics, tropical countries

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1.INTRODUCTION
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Epilepsy is a chronic ubiquitous neurological disease that affects almost 70 million people
worldwide (Ngugi et al., 2010). The prevalence is higher in developing countries than in
developed countries (Ba-Diop et al., 2014; Ngoungou et al., 2006; Preux and Druet-Cabanac,
2005). In Sub-Saharan Africa, the global prevalence of epilepsy is 9.39/1,000 inhabitants, and
the median is 14.2/1,000 inhabitants (Ba-Diop et al., 2014). In Latin America, the median
prevalence of epilepsy is 15.8/1,000 inhabitants (Bruno et al., 2013). In contrast, in Europe and
North America, epilepsy prevalence remains generally below 8/1,000 inhabitants (Forsgren et
al., 2005; Theodore et al., 2006).

The aetiological factors of epilepsy are numerous and vary according to age (Bhalla et al.,
2011). Among them, perinatal factors, that disturb normal brain development during intra-
uterine life, at birth and during the first days of life, might play a significant role in the
occurrence of this disorder (Kuate et al., 2014). Several studies suggested that perinatal factors

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such as maternal pre-eclampsia, eclampsia, maternal infections during pregnancy, neonatal

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seizures, asphyxia neonatorum, low birth weight, neonatal hypoglycaemia, low Apgar score at
birth, prematurity or post-term pregnancy are associated with a high incidence of epilepsy (Fong

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and Harvey, 2014; Jackson et al., 2014; Kuate et al., 2014; Lamblin and d’Allest, 2001; Ngugi

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et al., 2013; Senanayake and Román, 1993).

However, the proportion of these perinatal factors of epilepsy vary a lot in the literature. And,

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associations between these factors and the occurrence of epilepsy seem contradictory, from a
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study to another (Thomas, 2004). In developing countries, perinatal and obstetric events might
be significant risk factors for epilepsy. Perinatal causes play a major role in the tropics since
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many deliveries occur at home, without qualified assistance, or occur in poor-equipped
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facilities. Furthermore, maternal health status during pregnancy such as mother nutritional
status might also be involved (Farnarier and Gueye, 1998; Ngoungou et al., 2006; Preux and
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Druet-Cabanac, 2005; Prevett, 2013; Yemadje et al., 2011).

The aim of our meta-analysis was to evaluate the association between perinatal factors and the
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development of epilepsy in tropical countries. The evaluation of perinatal events, involved in

the onset of epilepsy, could improve knowledge of the analytical epidemiology of epilepsy. Our
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findings would support health policy makers while designing preventive strategies against this
disorder. Since many of these factors could be prevented (Islam and Yoshida, 2009) with better
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antenatal cares.
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2. METHODS

We complied with the PRISMA statement (Moher et al., 2009) to report this study.

2.1.Research strategy
The search was performed without language or date restriction in PubMed, ScienceDirect,
Google Scholar, Lilacs, African Journal of Neurological Sciences, Sudoc. We searched in
addition, in the database of the French Institute of Neurological Epidemiology and Tropical
Neurology (http://www-ient.unilim.fr/), the virtual library of African neurology (BVNA). The
BVNA contains articles published in African medical journals that are not indexed in Public
databases. The search was conducted up until March 2017.

The "Medical Subject Heading" (MeSH) terms identified beforehand were combined as

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follows: "Epilepsy" AND "perinatal care" OR "prenatal injuries" OR "pregnancy" OR

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"newborn" OR "infant" OR "child" OR "risk factor" OR "aetiology" OR "epidemiologic
factors" OR "perinatal factor" AND "country". The list of tropical countries was established

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according to the geographic organisation of the world regions by the united nations (UN)

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(“United Nations Statistics Division | Indicateurs du Millénaire,” n.d.).

At first, studies were selected according to their title by MHDTR, who checked whether the

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articles covered risk factors of epilepsy and then read their abstracts and full texts subsequently.
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In addition, we searched for studies, in the reference lists of available reviews. We also
consulted the references of the articles selected. Duplicated articles were only counted once.
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When additional data were required, we contacted the authors to request them.
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2.2.Selecting the studies

Analytical studies (case-control and exposed unexposed), cohort studies with the following
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characteristics were selected: (1) the presence of control group; (2) the method and criteria for
recruitment of participants (case, controls, exposed subjects, unexposed subjects) were
explained and adapted; (3) the diagnosis method of epilepsy was specified and compliant with
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the ILAE definition: The occurrence of at least two seizures, at an interval of 24 hours, without
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any event directly causing these seizures (Fisher et al., 2014); (4) the diagnosis of the different
perinatal factors was adapted (exposure during the perinatal period in the mother as well as the
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fetus or baby diagnosed by a validated questionnaire or medical records) according to the World
Health Organization, the perinatal period being the period between the 22nd week of gestation
and the 8th day following birth, from a health and fetal or newborn survival standpoint (Europe,
2000); (5) the number of subjects included in different groups of the sample monitored was
available. These criteria were validated by MHDTR and his two supervisors BM and EBN
(Professors of Public Health). MHDTR selected the studies and the selection was validated by
BM.
Literature review, abstracts, case studies, editorials and letters to the editor were excluded. As
well, studies that only concerned symptomatic epileptic attacks, specific epileptic attacks or
epileptic syndromes were excluded.

2.3.Data extraction

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For each article, we recorded the title, the main author, the country, the environment (rural or
urban), the year of publication, the objectives, the type of study, the duration of monitoring, the

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recruitment method, the diagnosis method of epilepsy, the characteristics of the population

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(size, gender and age group), the perinatal factors studied as well as their definitions and
diagnosis, the relative risks (RR) or the estimated odds ratios (OR), the number of exposed and
unexposed subjects among the cases and controls, the number of events and non-events among
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the exposed and unexposed subjects and the adjustment variables. Perinatal factors were first
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transcribed into text. They were compiled together when they reflected the exact same thing.
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2.4.Evaluation of the quality of studies
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The quality of studies was evaluated using the Newcastle Ottawa Scale (NOS) for observational
studies (Wells et al., n.d.). This scale has eight items divided into three parts: (1) the selection;
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(2) the comparability and according to the type of study; (3) the event (cohort studies) or
exposure (case-control study). A rating was done with several stars for each item, with a
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maximum total of nine stars. Studies with a score of at least seven stars were of very good
quality and below seven stars as poorer quality.
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2.5.Statistical analysis

We used STATA® software (Version 12) and its packages metan, metafunnel and metabiais for
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statistical analysis. First, we double checked for measures of association (OR and RR) provided
in each study. The 95% Confidence Interval of these OR and RR were also calculated for each
perinatal factor, in the different studies included.

Through the methods described to carry out the meta-analysis (Palmer and Sterne, 2016), for
each perinatal factor identified in at least two studies, we carried out a pooled analysis with
calculation of an odds ratio. The 95% Confidence Interval and the result of the analysis were
presented on a forest plot. We first carried out the analysis using fixed effects model. We tested
the heterogeneity of studies with Cochran's Q test (a value of p <0.05 was statistically
significant) and the I2 index (values of 25%, 50% and 75% representing respectively low,
moderate and high levels of heterogeneity). We used random-effects model if heterogeneity
was statistically significant. We illustrated publication bias on a funnel plot, and we used Egger
test to detect this publication bias (significance at p <0.05).

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When the estimated global effect was significant, we calculated the attributable risk fraction of

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this factor in the general population. We chose the proportion of the population exposed to each
perinatal factor according to the data available in the literature concerning this factor.

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3. RESULTS

3.1. Research and characteristics of the studies

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Initially, 22,581 articles were retrieved from databases. Through a selection process using titles,
we selected 167 publications. Out of these 167 articles, 132 did not assess/report perinatal
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factors. We retained 35 articles for a full assessment. After application of both inclusion and
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exclusion criteria, 15 studies were identified. Then we excluded two studies (Ae-Ngibise et al.,
2015; Wagner et al., 2014) in which data were included in a larger multi-centered study (Ngugi
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et al., 2013). Finally 13 studies were kept for the meta-analysis (Attumalil et al., 2011; Bhalla
et al., 2012; Burton et al., 2012; Edwards et al., 2008; Hackett et al., 1997; Kannoth et al., 2009;
Kuate et al., 2014; Lekoubou et al., 2012; Matuja et al., 2001; Mung’ala-Odera et al., 2008;
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Ngugi et al., 2013; Nunes and Geib, 2011; Ogunrin et al., 2014) (Fig 1).
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One study was conducted in Latin America (Nunes and Geib, 2011), four studies in South-East
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Asia (Attumalil et al., 2011; Bhalla et al., 2012; Hackett et al., 1997; Kannoth et al., 2009) and
eight studies in Sub-Saharan Africa (Burton et al., 2012; Edwards et al., 2008; Kuate et al.,
2014; Lekoubou et al., 2012; Matuja et al., 2001; Mung’ala-Odera et al., 2008; Ngugi et al.,
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2013; Ogunrin et al., 2014). Detailed characteristics of studies included in this meta-analysis
are given in Table 1.

3.2.Evaluation of the quality of studies

The 13 studies selected were evaluated using the NOS (Table 2). Out of the 13 studies, four
(30.8%) studies - two conducted in India, one in Cameroon, and one in Nigeria respectively -
were of very poor quality (Attumalil et al., 2011; Hackett et al., 1997; Kuate et al., 2014;
Ogunrin et al., 2014). Indeed, the first Indian study (Attumalil et al., 2011) had problems of
comparability between the cases and the controls, there was no matching and the non-response
rate was imprecise. The other Indian study (Hackett et al., 1997) had problems of
representativeness of cases, the non-response rate was imprecise and problems of
comparability. Regarding the Cameroonian study (Kuate et al., 2014) it had problems of

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representativeness of cases, the non-response rate was imprecise and it had comparability issues

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as well. Lastly, the Nigeria study in (Ogunrin et al., 2014) had problems of representativeness

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of cases, inconsistent definition of controls, and the non-response rate was imprecise.

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3.3.Perinatal factors identified

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The number and type of perinatal risk factors in each study were variable (Table 3). Some
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perinatal risk factors could not be pooled for analysis, given that their association with epilepsy
were studied and reported only in a single study (Table 4).
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3.4.Meta-analysis
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A total of 11 perinatal factors were analysed (Fig. 2). When studies of poor quality were
excluded, there was no modification in the direction of the association between the perinatal
factors examined and epilepsy. However, the weight of the association was slightly modified
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(Online resource 1). The perinatal factors with a statistically significant association with
epilepsy were: Home birth (OR 1.36, 95%CI: 1.21-1.54), complicated delivery (OR 2.10,
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95%CI: 1.05-4.20), premature birth (OR 2.80, 95%CI: 2.07-3.78), neonatal complications (OR
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7.15, 95%CI: 2.10-24.38,), abnormal maternal antenatal period (OR 2.42, 95%CI: 1.81-3.23),
and medicines intake during pregnancy (OR 4.12, 95%CI: 1.94-8.73).
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Heterogeneity tests were significant for complicated delivery (Q test: p=0.016 and I2 test=67%),
neonatal complications (Q test: p=0.001 and I2 test =86%), neonatal resuscitation (Q test:
p=0.001 and I2 test=90%), late crying at birth (Q test: p=0.002 and I2 test=89%). In these cases,
the estimations were based on random-effects models.
The publication bias (Online resource 2) was significant for premature birth (Egger's test:
p<0.001).

3.5.Attributable risk

In developing countries, it is estimated that 70% of the subjects are prone to give birth at home
(Montagu et al., 2011). The risk attributable to this factor based on a measure of association of
OR 1.36, 95%CI: 1.21-1.54 is estimated at 20.1%. In addition, based on a proportion of subjects
exposed to premature delivery in tropical environments of 11.8% (Blencowe et al., 2012) and

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on a measure of association of OR 2.80, 95%CI: 2.07-3.78, the attributable risk fraction is

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estimated at 17.5%.

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4. DISCUSSION

We identified perinatal factors associated with epilepsy in tropical countries examined through

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13 studies. Home birth, complicated delivery, and premature birth are the most reported risk
factors.
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To the best of our knowledge, this meta-analysis is the first work, on this topic, that has been
conducted in the tropics. It provided comprehensive and quantitative information concerning
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the burden of perinatal factors. Our methodology enabled us to be exhaustive in the search for
studies and to ensure the reproducibility of the study. Our study highlighted the need for
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conducting other studies on these perinatal risk factors using valid methodologies. The
heterogeneity identified in this research might be explained by the difference of definitions and
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measurements of these factors among studies, differences in age between the studied
populations, and the difference of questionnaires used to evaluate the perinatal factors (Pal,
1999; Preux, 2000).
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There were very few studies included in the meta-analyses. Access to unpublished data in
tropical countries remains difficult and university thesis catalogs often inaccessible. This may
contribute to publication biases. We were, therefore, unable to carry out analyses in sub-groups
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or analyses by tropical region. Such analyses would have been of great interest, given that one
study suggested that the distribution of perinatal factors is one of the key factors responsible
for differences seen in the prevalence of epilepsy between regions (Yemadje et al., 2011).

The relationship between many perinatal factors and epilepsy was not published in tropical
countries. One Canadian study showed an association between neonatal infections and epilepsy
with a relative risk of 1.6 (95%CI: 1.3-2.0) (Whitehead et al., 2006). In developing countries,
neonatal infections reported figures of 0.8 to 6.1 per 1,000 live births in Africa and Asia (Thaver
and Zaidi, 2009). In addition, in Cameroon, 50% of late neonatal infections were meningitis
infections (Kemeze et al., 2016). These data justify documenting this association.

Sun and colleagues (2011) demonstrated the protective effect of breastfeeding on epilepsy.
This protection was even more significant with a longer period of breastfeeding (Sun et al.,
2011). Mother antibodies transferred to the child during breastfeeding, and their protection

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against infections might explain this protective effect against epilepsy.

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Home birth presents a risk in developing countries due to septic conditions. In Timor-Leste,
South-East Asia, 74% of the women give birth at home (Khanal et al., 2014). In Ethiopia, almost

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90% of births take place at home (Joseph et al., 2016). Among the reasons for these deliveries

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at home: the low level of alphabetisation, the lack of pregnancy-related social support, a low
household income, and the fact of living in rural areas (Devasenapathy et al., 2014; Joseph et

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al., 2016; Khanal et al., 2014). Several studies showed that premature birth is a risk factor for
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epilepsy in Denmark (RR 5.41, 95%CI: 4.44-6.59) (Sun et al., 2008), in Sweden (OR 1.98,
95%CI: 1.26-3.13) (Crump et al., 2011) and in Scotland (OR 1.95, 95%CI: 1.19-3.19) (Murphy
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et al., 2004). We were unable to measure the weight of association according to the degree of
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prematurity. Prematurity might be a major factor of epilepsy in tropical countries, due to the
low availability of neonatal intensive care units. Neonatal infections, which were not studied,
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are leading causes of preterm birth in tropical countries (Steer Philip, 2005). They should
account for the role of preterm birth on the onset of epilepsy.
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Two studies did not find any association between delivery complications and epilepsy
(Greenwood et al., 1998; Whitehead et al., 2006). The comparison of our results with these
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studies would not be appropriate because in the studies included in our meta-analysis precisions
on the types of complications were lacking. Also, for the association with drugs intake during
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pregnancy, there is no detail on the type, the dosage, the regimen, and the duration of the
medicines. Danish children whose mothers had taken antidepressants during pregnancy had
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27% more risk of epilepsy than those who were not exposed (Mao et al., 2016). Although our
results did not mention any association between cesarean section, pregnancy-induced high
blood pressure, neonatal resuscitation, and epilepsy, we cannot formally conclude that it is
absent. Neonatal resuscitation is indicated in neonatal infectious, metabolic disorders or
traumatic stress. In the context of tropical countries, further studies on the question are needed.
To prevent epilepsy in tropical countries, it is urgent to implement or improve public healthcare
and especially community policies that can ensure that each pregnant woman, in the tropics,
gives birth under the assistance of qualified personnel. In a broader framework, this is part of
the third sustainable development goal (“Sustainable development goals - United Nations,”
n.d.).

5.CONCLUSION

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This work provided us with knowledge on the perinatal factors associated with epilepsy in

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tropical countries. We identified six perinatal risk factors associated with epilepsy which are:

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home birth, complicated delivery, premature birth, medicines intake during pregnancy,

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abnormal antenatal period, and neonatal complications.

There is a need to conduct more studies to evaluate the effects of perinatal factors on the

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development of epilepsy, especially neonatal infections, pregnancy-induced high blood
pressure, caesarian delivery, asphyxia neonatorum, and breastfeeding. For this purpose, the
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methodology of the studies, terminologies, definitions, and concepts of perinatal factors should
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be standardised. In addition to the strategies that are currently established, it would be important
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to strengthen preventive measures for epilepsy in tropical countries by acting against both
premature birth and home births without qualified assistance.
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Disclosure of conflicts of interest

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Declarations of interest: none

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Formatting of funding sources

This research did not receive any specific grant from funding agencies in the public, private,
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nor non-governmental organizations.

Ethical publication statement

We confirm that we have read the Journal’s position on ethical issues and that our work fulfils
those guidelines.
Acknowledgments

We thank the researchers contacted for the additional data and for their pertinent articles, Prof.
Francesco PISANI, Prof. Johannes HEBEBRAND, Dr. Alain LEKOUBOU and Dr. Aline
MUHIGWA for their contribution.

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Figure legends

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Fig. 1 Flow chart of the literature search strategy for studies evaluating the association between
perinatal factors and epilepsy in tropical countries

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Fig. 2 Meta-analysis of studies evaluating the association (odds ratio) between perinatal factors

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and epilepsy in tropical countries .
*Weight are from random effects analysis

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Online resource 1 Meta-analysis considering only studies of very good quality evaluating the
association (odds ratio) between perinatal factors and epilepsy in tropical countries
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*Weight are from random effects analysis
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Online resource 2 Funnel plot of studies evaluating the association (odds ratio) between
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perinatal factors and epilepsy in tropical countries. a: Home birth. b: Complicated delivery. c:
Insufficient prenatal care. d: Caesarian section. e: Prematurity. f: Neonatal complication. g:
High blood pressure. h: Maternal abnormal antenatal period. i: Medicines intake during
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pregnancy. j: Neonatal resuscitation. k: Delayed cry at birth.

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Table legend

Table 1 Description of the methodological characteristics of the studies evaluating the

association between perinatal factors and epilepsy in tropical countries
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Table 2 Quality assessment of studies evaluating the association between perinatal factors
and epilepsy in tropical countries

Table 3 List of perinatal factors identified in each study included

Table 4 Perinatal factors identified by only one study evaluating the association between
perinatal factors and epilepsy in tropical countries
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Table 1 Description of the methodological characteristics of studies evaluating the association between perinatal factors and epilepsy in tropical

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countries

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Reference Countries Type of study Site Age N Cases Controls

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Kannoth et al. 2009 (Kannoth et al., 2009) India Case-control Rural and urban 6-85 years 724 362 362
Attumalil et al. 2011 (Attumalil et al., 2011) India Case-control Hospital 1-12 years 242 82 160

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Mung’ala-Odera et al. 2007 (Mung’ala- Kenya Case-control Rural ≥ 06 years 926 110 816
Odera et al., 2008)
Kuate-Tegueu et al. 2014 (Kuate et al., 2014)
ED Cameroon Case-control Rural 6-70 years 140 70 70
Lekoubou et al. 2012 (Lekoubou et al., 2012) Cameroon Case-control Rural 15-74 years 170 85 85
Matuja et al. 2001 (Matuja et al., 2001) Tanzania Case-control Rural 1-62 years 358 174 174
Burton et al. 2012 (Burton et al., 2012) Tanzania Transversal and case-control Rural 6-14 years 225 112 113
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Ogunrin et al. 2014 (Ogunrin et al., 2014) Nigeria Transversal and case-control Urban ≥ 10 years 488 244 244
Bhalla et al. 2012 (Bhalla et al., 2012) Cambodia Transversal and case-control Rural 3-70 years 284 96 192
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Edwards et al. 2008 (Edwards et al., 2008) Kenya Transversal and case-control Rural 6-18 years 517 314 203
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Hackett et al. 1997 (Hackett et al., 1997) India Transversal and case-control Rural and urban 08-12 years 301 26 275
Ngugi et al. 2013 (Ngugi et al., 2013) Multi-centred* Transversal and case-control Rural and urban < 18 years 1,801§ 797 1,004
All 3,499§ 1,651 1,848
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All 5,359§ 2,451 2,908

All 3,572§ 1,668 1,904
Nunes et al. 2011 (Nunes and Geib, 2011) Brazil Cohort Urban ≤ 04 years 542 11 531
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*: Kenya, South Africa, Uganda, Tanzania, Ghana : The population size varies according to the factor analysed
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Table 2 Quality assessment of studies evaluating the association between perinatal factors and epilepsy in tropical countries

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Reference Selection Comparability Exposure/Event Total

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Kannoth et al. 2009 (Kannoth et al., 2009) *** ** ** 07

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Attumalil et al. 2011 (Attumalil et al., 2011) ** ** 04

Ngugi et al. 2013 (Ngugi et al., 2013)

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Lekoubou et al. 2012 (Lekoubou et al., 2012) **** ** ** 08

Nunes et al. 2011 (Nunes and Geib, 2011) **** * ** 07

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Mung’ala-Odera et al. 2007 (Mung’ala-Odera et al., 2008) **** ** ** 08

Kuate-Tegueu et al. 2014 (Kuate et al., 2014) ** * ** 05

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Ogunrin et al. 2014 (Ogunrin et al., 2014) ** ** ** 06

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Matuja et al. 2001 (Matuja et al., 2001) **** ** ** 08

Burton et al. 2012 (Burton et al., 2012) **** ** ** 08

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Edwards et al. 2008 (Edwards et al., 2008) **** ** ** 08

Hackett et al. 1997 (Hackett et al., 1997) *** ** 05

Bhalla et al. 2012 (Bhalla et al., 2012) **** ** *** 09


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Reference
Kannoth et al. 2009 (Kannoth et al., 2009)
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Attumalil et al. 2011 (Attumalil et al., 2011)
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Hackett et al. 1997 (Hackett et al., 1997)
Edwards et al. 2008 (Edwards et al., 2008)
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Ogunrin et al. 2014 (Ogunrin et al., 2014)
Matuja et al. 2001 (Matuja et al., 2001)
Burton et al. 2012 (Burton et al., 2012)
Mung’ala-Odera et al. 2007 (Mung’ala-Odera et al., 2008)
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Kuate-Tegueu et al. 2014 (Kuate et al., 2014)
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Lekoubou et al. 2012 (Lekoubou et al., 2012)
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Ngugi et al. 2013 (Ngugi et al., 2013)
Nunes et al. 2011 (Nunes and Geib, 2011)
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Bhalla et al. 2012 (Bhalla et al., 2012)
Table 3 List of perinatal factors identified in each study included.
Table 4 Perinatal factors identified by only one study evaluating the association between perinatal factors and epilepsy in tropical countries
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Perinatal factor studied
Birth in an apparent state of death, Home birth, Complicated delivery, Pre-eclampsia/Eclampsia,
Prematurity, Perinatal complication, Neonatal seizure, Caesarian delivery
Antenatal maternal infection, Maternal hypertension, Gestational diabetes, Antenatal use of medicines,
Pre/post term pregnancy, Extended delivery, Caesarian delivery, Meconium-stained amniotic fluid,
Late crying, Abnormal presentation, Cyanotic at birth, Incessant crying during the first week of life,
Admission to neonatal intensive care, Neonatal distress, Maternal addiction
Assisted delivery, prematurity, Low birth weight, Perinatal complications
History of perinatal events
Asphyxia neonatorum
Intrapartum neonatal complications
Abnormal perinatal event
Insufficient prenatal care, Home birth, Difficult delivery, Neonatal complications
Unqualified assistance with delivery
Home birth, Prematurity, Caesarian delivery, Abnormal pregnancy, Dystoical delivery, Resuscitation at
birth
Poor obstetric history, Use of forceps, Crying at birth, Prematurity, Difficult or extended delivery,
Place of birth
Abnormal delivery, Other postnatal problems, Postnatal complications, Difficulty feeding, breathing or
crying, Home birth, Abnormal antenatal period
Drinking alcohol during pregnancy, Smoking during pregnancy, Taking medicines during pregnancy,
Number of prenatal check-ups
Pregnancy without incident for the mother, Prematurity, Long and difficult pregnancy, Crying after
birth, Taking medicines during pregnancy
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Perinatal factors N E+ E- E+ and F+ E- and F+ OR (95%CI) p value
Birth in an apparent state of death (Kannoth et al., 2009) 724 362 362 44 22 2.14 (1.25-3.65) 0.006

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Neonatal seizure (Kannoth et al., 2009) 724 362 362 38 2 21.18 (5.07-88.47) <0.001

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Antenatal maternal infection (Attumalil et al., 2011) 242 82 160 6 7 1.73 (0.56-5.31) 0.25
Gestational diabetes (Attumalil et al., 2011) 242 82 160 5 4 2.53 (0.66-9.7) 0.14

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Extended labour (Attumalil et al., 2011) 242 82 160 27 10 7.5 (3.4-16.52) <0.001

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Meconium-stained amniotic fluid (Attumalil et al., 2011) 242 82 160 3 4 1.5 (0.33-6.87) 0.436
Abnormal presentation (Attumalil et al., 2011) 242 82 160 1 7 0.23 (0.04-2.50) 0.564
Cyanotic at birth (Attumalil et al., 2011)
ED 242 82 160 8 4 4.24 (1.25-14.65) 0.017
Maternal addiction (Attumalil et al., 2011) 242 82 160 0 1 0.99 (0.98-1.0) 0.66
Assisted delivery (Hackett et al., 1997) 301 26 275 4 17 2.67 (0.89-7.98) 0.06
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Low birth weight (Hackett et al., 1997) 301 26 275 8 55 1.82 (0.78-4.25) 0.2
History of perinatal events (Edwards et al., 2008) 517 314 203 32 11 5.15 (2.4-11.6) <0.001
Asphyxia neonatorum (Ogunrin et al., 2014) 488 244 244 64 12 6.87 (3.60-13.12) <0.001
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Abnormal perinatal event (Burton et al., 2012) 225 112 113 16 0 18.9 (2.4-146.5) 0.005
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Unqualified assistance with delivery (Mung’ala-Odera et al., 2008) 926 110 816 77 572 3.33 (2.15-5.24) <0.001
Forceps delivery (Lekoubou et al., 2012) 170 85 85 2 1 2.02 (0.1-120.8) 0.560
Alcohol use during pregnancy (Nunes and Geib, 2011) 542 11 531 10 445 1.93 (0.27-84.82) 0.53
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Smoking during pregnancy (Nunes and Geib, 2011) 542 11 531 10 417 2.73 (0.381-119.65) 0.320
Difficulties feeding, breathing or crying (Ngugi et al., 2013) 1,797 816 1,014 96 16 10.23 (5.87-17.88) < 0.0001
Postnatal complications (Ngugi et al., 2013) 5,359 2,451 2,908 224 64 4.98 (3.74-6.70) <0.001
E+: Subjects living with epilepsy; E-: Subjects without epilepsy;
E+ and F+: Subjects living with epilepsy and exposed to perinatal factors E- and F+: Subjects without epilepsy and exposed to perinatal factors
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