Version Changes
Revised. Amendments from Version 2
In our Discussion, we have included fetal alcohol exposure as a risk factor that should be investigated because of its high burden in some low and middle income countries like South Africa.
Abstract
Background: Childhood mortality from infectious diseases has declined steadily in many low and middle-income (LAMIC) countries, with increased recognition of non-communicable diseases such as neurodevelopmental disorders (NDD). There is lack of data on the burden of NDD in LAMIC. Current global burden of these disorders are largely extrapolated from high-income countries. The main objective of the study was therefore to estimate the burden of NDD in LAMIC using meta-analytic techniques.
Methods: We systematically searched online databases including Medline/PubMed, PsychoInfo, and Embase for studies that reported prevalence or incidence of NDD. Pooled prevalence, heterogeneity and risk factors for prevalence were determined using meta-analytic techniques.
Results: We identified 4,802 records, but only 51 studies met the eligibility criteria. Most studies were from Asia-Pacific (52.2%) and most were on neurological disorders (63.1%). The median pooled prevalence per 1,000 for any NDD was 7.6 (95%CI 7.5-7.7), being 11.3 (11.7-12.0) for neurological disorders and 3.2 (95%CI 3.1-3.3) for mental conditions such as attention-deficit hyperactivity disorder (ADHD). The type of NDD was significantly associated with the greatest prevalence ratio in the multivariable model (PR=2.6(95%CI 0.6-11.6) (P>0.05). Incidence was only reported for epilepsy (mean of 447.7 (95%CI 415.3-481.9) per 100,000). Perinatal complications were the commonest risk factor for NDD.
Conclusion: The burden of NDD in LAMIC is considerable. Epidemiological surveys on NDD should screen all types of NDD to provide reliable estimates.
Keywords: neurodevelopment, low and middle-income countries
Introduction
Neurodevelopmental disorders (NDD) are a group of disorders that typically manifest early in development and are characterised by developmental deficits that produce impairments of personal, social, academic, or occupational functioning 1. They include autism spectrum disorders (ASD), attention-deficit hyperactivity disorder (ADHD), epilepsy, intellectual disability, hearing impairments, visual impairments and motor impairments including cerebral palsy, among others. Some disorders overlap, for example in children with epilepsy, ASD occurs in 22% 2, ADHD in 33% 2, and behavioural/emotional problems in 30–50% 3, 4. Although more than 80% of the world’s births occur in low and middle-income countries (LAMIC) 5, most of the epidemiology of NDD is based on data from developed countries 6– 8. The lack of precise epidemiological data on NDD in poorer countries affects planning of public health interventions.
In the past decade, infant mortality has declined in many LAMIC and preventing childhood morbidity is becoming a public health priority. However, there are few studies on the epidemiology of NDD in LAMIC, where the burden could be greatest because: (i) the incidence of risk factors for NDD such as perinatal complications 9, head injury, parasitic infections 10 and nutritional deficiencies are higher in LAMIC according to the global burden of disease study 11; (ii) following the successful control of infectious diseases, children with neurological disability are surviving 12.
So far, no precise estimate exists for NDD in LAMIC. Available studies focus mostly on a few conditions 13, are conducted in a small number of countries. In particular the Ten Questions Questionnaire (TQQ) has been used to determine the prevalence of neurological impairment and disability, but this screening tool is poor at detecting NDD such as ASD and ADHD. It is unclear if the variation in estimates is due to methodological differences or is dependent upon NDD type/condition, calling for the need to review the available studies to measure the causes of variation in estimates.
To fill the knowledge gap that exists regarding the epidemiology of NDD in LAMIC, we conducted a systematic review of studies reporting prevalence and incidence of NDD. We pooled the estimates for different types of NDD and determined the causes of heterogeneity. We also described the risk factors associated with NDD among the studies included in the burden estimates.
Methods
Search strategy
We searched all articles of population studies on prevalence or incidence of NDD in the electronic databases MEDLINE and EMBASE, African Index Medicus and CINHL databases. Our last search was conducted on 31/06/2017.
We included references from identified articles that met the inclusion criteria. The main search terms were (“neurodev*” and “prevalence”) or (“neurodev*” and “incidence”) with limits (humans, journal article) in MEDLINE and EMBASE ( Table 1). We used recommendations of National Health Service Centre for Reviews and Disseminations to develop a search strategy where the review question was broken down to search terms.
Table 1. Search terms.
((epidemiology) OR (prevalence) OR (incidence) OR (burden)) AND
((neurodevelopmental disorder*) OR (behav* problem*) OR (behav* disorder*) OR (cogniti* impairment*) OR (language difficult*) OR (learning disabilit*) OR (Hearing difficult*) OR (hearing impairment*) OR (visual impairment*) OR (psychotic disorder*) OR (hyperkinetic*) OR (psychiatric disorder*) OR (ataxia) OR (motor impairment*) OR (psychomotor disorder*) OR (attention deficit and hyperactivity disorder*) OR (autis*) OR (epilepsy) OR (cerebral palsy)) AND ((Children) OR (infant) OR (kids) OR (teen*) OR (adolescent*)) AND ((risk factor*) OR (factor*) OR (predisposing factor)) AND ((low income countr*) OR (low-income countr*) OR (middle income countr*) OR (middle-income countr*) OR (developing countr*) OR (developing nation*) OR (Africa) OR (south America) OR (asia) OR (resource poor countr*) OR (third world)) AND “humans”[MeSH Terms] AND (“0001/01/01”[PDAT] : “2017/06/31”[PDAT]) |
Two authors (MAB and SK) reviewed the titles and abstracts of articles obtained from online searches. We reviewed full texts of eligible articles from this initial evaluation stage. Reporting of findings followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines 14.
Inclusion and exclusion criteria
All population-based studies measuring the prevalence or incidence of any of the NDD listed were included. A population denominator was an inclusion criterion for research database studies. We only considered studies with a sample population of <19 years or if results were stratified by age, and a population denominator for sample <19 years was provided. We excluded studies that were not conducted in a LAMIC as defined by the current World Bank Classification of Economies 15. We also excluded reviews, editorials, letters, commentaries, case series and case reports, abstracts without full texts and special-group studies, e.g., prevalence of cerebral palsy in children with a history of birth trauma, or duplicate populations. In addition, we report the findings from studies that used the TQQ, since this is the longest established screening tool and most widely reported.
Procedures
We collected all the relevant study level information required for analysis using a data extraction template designed and piloted a priori by the authors. MAB and SK extracted data independently. We resolved disagreements by consensus. For included studies, we recorded information on the NDD under investigation, author, year of publication, country, study design, study population, data collection and ascertainment method (medical records or questionnaires [with physical examination] in population-based studies), age, number of cases, and the prevalence/incidence estimate. The quality of all the studies that met the inclusion criteria was investigated using the Joanna Briggs Institute Prevalence Critical Appraisal Tool 16.
Statistical analysis
We tabulated crude prevalence estimates expressed per 1,000 persons and the incidence expressed per 100,000 persons per year in summary tables along with their 95% confidence intervals (95%CI), stratified according to the region where the study was conducted. Where an eligible study did not report the prevalence of NDD, we derived the prevalence through dividing the total cases reported by the total sample studied, and then expressed per 1,000 population. We obtained a range using the 5th and 95th percentiles as m ± 1.96τ, where τ is the standard deviation. The computed prevalence was then utilised in the meta-analysis approach described below. We collected data on incidence as reported in a study. To estimate pooled prevalence estimates and assess for heterogeneity, we log-transformed observed prevalence and fitted random effects models to these estimates using the “metan” command in STATA v 13.1 (StataCorp., TX). The random effects model approach is robust where there is significant heterogeneity across study estimates. It uses information on prevalence and study size. It assumes that the outcomes being estimated in the different studies are not identical, but follow a lognormal distribution, allowing for among-study variation 17. We then back-transformed the log estimates to the original scale to obtain prevalence estimates the confidence intervals around the estimates.
We used forest plots 18 to visualize heterogeneity among studies. Using the Cochran chi-square (χ2) test, we examined the null hypothesis that the observed heterogeneity was due to sampling error. We anticipated heterogeneity because of methodological differences so we quantified the degree of heterogeneity across studies using the statistic I 2, from the random effect meta-analysis model. I 2 describes the percentage of the variability in estimates that is due to true differences in prevalence rather than sampling error 19, 20. A value >50% is considered as substantial heterogeneity.
We investigated six study level covariates for their association with prevalence estimates: the quality score of the study, continent of the study, the year, the domain studied, the method of case identification (clinical diagnosis or screening only) and the study setting (rural/urban). We examined the influence of these variables on study prevalence using both univariate and multivariable random effects meta-regression models fitted using the “metareg” command in STATA. This approach assumes two additive components of variance, one representing the variance between studies and the other the variance within studies (i.e., error variance). The proportion of heterogeneity explained by each of the covariates was estimated by comparing the between-studies component of variance in the null model (τ 0 2) with the estimate of τ 2 for the model including covariates ((τ 0 2– τ 2)/τ 0 2).
Results
Details of eligible studies
Electronic database search yielded 4,802 articles of which 51 studies on a total population sample size of 2,925,139 included in the meta-analysis ( Figure 1). Majority of the studies were from Asia-Pacific region (n=27 (52.9%)) and Africa (n=16 (31.4%)), with six (11.8%) from Latin America and two (3.9%) from two or more continents. Table 2 summarized the study characteristics of included studies.
Table 2. Summary of study characteristics for studies included in the meta-analysis.
Author | Year of
publication |
Country | Study
setting |
Domain studied | Total
sample |
Overall
prevalence |
---|---|---|---|---|---|---|
Wagner RG 21 | 2014 | South Africa | Epilepsy | 36816 | 2 | |
Bevilacqua MC 22 | 2013 | Brazil | Urban | Hearing impairment | 218 | 1.4 |
Ngugi AK | 2013 | Kenya | Rural | Epilepsy | 129069 | 3 |
Ngugi AK | 2013 | Multisite | Mixed | Epilepsy | 308028 | 9.4 |
Ebrahimi H 23 | 2012 | Iran | Urban | Epilepsy | 568 | 15.8 |
Caca I 24 | 2013 | Turkey | Visual impairment | 21062 | 493.4 | |
Arruda MA 25 | 2015 | Brazil | Attention deficit hyperactivity disorder,
emotional and behavioural problems |
1830 | 51 | |
Burton KJ 26 | 2012 | Tanzania | Epilepsy | 38523 | 2.9 | |
Basu M 27 | 2011 | India | Urban | Visual impairment | 3002 | 152.2 |
Prasad R | 2011 | Brazil | Attention deficit hyperactivity disorder | 4423 | 199 | |
Raina SK 28 | 2011 | India | Cerebral palsy | 3966 | 2.27 | |
Czechowicz JA 29 | 2010 | Peru | Urban | Hearing impairment | 355 | 64.8 |
Tasci Y 30 | 2010 | Turkey | Hearing impairment | 16975 | 2.2 | |
Winkler AS 31 | 2009 | Tanzania | Rural | Epilepsy | 7399 | 11.2 |
Saldir M 32 | 2010 | Turkey | Urban | Mild neurological dysfunction,
cerebral palsy |
169 | 165.7 |
Perera H 33 | 2009 | Sri Lanka | Autism | 374 | 10.7 | |
Khan NZ 34 | 2009 | Bangladesh | Rural | Behaviour problems | 499 | 146 |
Mung'ala-odera V 35 | 2008 | Kenya | Rural | Epilepsy | 10218 | 10.7 |
Wong VC 36 | 2008 | China | Urban | Autism spectrum disorder | 1174322 | 1.6 |
Velez van
meerbeke A 37 |
2007 | Colombia | Urban | Neurodevelopmental delay disorders | 2043 | 30.8 |
Zeidan Z 38 | 2007 | Sudan | Urban | Blindness | 29048 | 1.4 |
Del brutto OH 39 | 2005 | Ecuador | Rural | Epilepsy | 1083 | 5.5 |
Ersan EE 40 | 2004 | Turkey | Attention deficit hyperactivity disorder,
oppositional defiant disorder |
1425 | 81 | |
Serdaroglu IU 41 A | 2004 | Turkey | Epilepsy | 46813 | 8 | |
Wong V 36 | 2004 | China | Epilepsy | 1103 | 4.5 | |
Mousa Thabet AA 42 | 2001 | Gaza | Behavioural/emotional problems | 959 | 481.8 | |
Couper J 43 | 2002 | South Africa | Rural | Learning disability, cerebral palsy,
perceptual disability, seizure disorder |
2036 | 17 |
Bulgan T 44 | 2002 | Mongolia | Visual impairment | 416 | .2 | |
Zainal M 45 | 2002 | Malaysia | Visual impairment | 8504 | 10.3 | |
Onal AE 46 | 2002 | Turkey | Epilepsy | 903 | 8.9 | |
Rao RS 47 | 2002 | India | Rural | Hearing impairment | 855 | 119 |
Liu XZ 48 | 2001 | China | Hearing impairment | 34157 | 6.6 | |
Olusanya BO 49 | 2000 | Nigeria | Urban | Hearing loss | 359 | 139 |
Liu J 50 | 2000 | China | Cerebral palsy | 385185 | 1.5 | |
Liu JM | 1999 | China | Urban | Cerebral palsy | 388192 | 1.6 |
Brito GN 51 | 1999 | Brazil | Urban | Attention deficit hyperactivity disorder | 402 | 32 |
Hackett RJ 52 | 1997 | India | Urban | Epilepsy | 1172 | 22.2 |
Morioka I 53 | 1996 | China | Rural | Hearing impairment | 282 | 198.6 |
Okan N 54 | 1995 | Turkey | Neurological disorders | 5002 | 66 | |
Mulatu MS 55 | 1995 | Ethiopia | Urban | Psychopathology | 611 | 270 |
Rwiza HT 56 | 1992 | Tanzania | Epilepsy | 11023 | 6.6 | |
Koul R 57 | 1988 | India | Epilepsy | 26419 | 3.2 | |
Osuntokun
BO 58 |
1987 | Nigeria | Urban | Epilepsy | 10978 | 6 |
Bash KW | 1987 | South Africa | Rural | Motor impairment | 1022 | 14.7 |
Taha AA 59 | 2015 | Egypt | Both | Hearing loss | 555 | 20.9 |
Wamithi S 60 | 2015 | Kenya | Urban | Attention deficit hyperactivity disorder | 240 | 6.3 |
Durkin MS 61 | 1992 | Multiple | Rural | Epilepsy | 22125 | |
Yoshito Kawakatsu 62 | 2012 | Kenya | Rural | Neurological impairments * | 6362 | 29 |
Shahnaz HI 63 | 2012 | Pakistan | Rural | Neurological impairments | 176364 | 5.5 |
Biritwum RB | 2001 | Ghana | Rural | Neurological impairments | 2550 | 6.7 |
Singhi P 64 | 2007 | India | Rural | Neurological impairments | 1763 | 4.3 |
Ilyas Mirza 65 | 2008 | Pakistan | Rural | Neurological impairments | 1789 | 248 |
* These included epilepsy, cognition, hearing, motor and visual impairments.
Critical appraisal of study quality
The median quality score for all the 51 eligible studies was 80% (IQR 66.7-90.0) as summarized in Table 3. Of the 51 studies, 9 (20%) fulfilled all the criteria for high quality in observational studies, with the remainder being of acceptable quality. Of these 9 studies, 6 had all the 10 criteria presents while for 3 studies, the last criteria (“Were subpopulations identified using objective criteria”) was not applicable. The range of the median age (where available) was 0.7–19.0 years. The median percentage female participants in the study was 48.5% (IQR 47.8-50.1) and they were not under-represented, compared to males (p=0.903).
Table 3. Critical appraisal of study articles using the Joanna Briggs Critical Appraisal Tool for Observational Studies.
Author | Year | Was the
sample representative of the target population? |
Were study
participants recruited in an appropriate way? |
Was the
sample size adequate? |
Were the
study subjects and setting described in detail? |
Is the data
analysis conducted with sufficient coverage of the identified sample? |
Were objective,
standard criteria used for measurement of the condition? |
Was the
condition measured reliably? |
Was there
appropriate statistical analysis? |
Are all
important confounding factors/ subgroups/ differences identified and accounted for? |
Were
subpopulations identified using objective criteria? |
Quality |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Wagner RG | 2014 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Not applicable | 100 |
Bevilacqua
MC |
2013 | Yes | Yes | Yes | Yes | Unclear | Yes | Yes | Unclear | Unclear | Yes | 70 |
Ngugi AK | 2013 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | 100 |
Ngugi AK | 2013 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | 100 |
Ebrahimi H | 2012 | Yes | Yes | Unclear | No | Unclear | Yes | Yes | Unclear | Unclear | Yes | 50 |
Caca I | 2013 | Yes | Yes | Yes | No | Yes | Yes | Yes | Yes | Unclear | Yes | 80 |
Arruda MA | 2015 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | 100 |
Burton KJ | 2012 | Yes | Yes | Yes | No | Yes | Yes | Yes | Yes | Yes | Not applicable | 88.9 |
Basu M | 2011 | Yes | Yes | Yes | No | Yes | Yes | Yes | Unclear | Unclear | Yes | 70 |
Raina SK | 2011 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | 100 |
Czechowicz
JA |
2010 | Yes | Yes | Unclear | Yes | Unclear | Yes | Yes | Yes | Yes | Yes | 80 |
Tasci Y | 2010 | Yes | Yes | Yes | No | Unclear | Yes | Yes | Unclear | Yes | Not applicable | 66.7 |
Winkler AS | 2009 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Unclear | Not applicable | 88.9 |
Saldir M | 2010 | Yes | Yes | Unclear | No | Yes | Yes | Yes | Yes | Yes | Not applicable | 77.8 |
Perera H | 2009 | Yes | Yes | Yes | No | Yes | Yes | Yes | Unclear | Unclear | Not applicable | 66.7 |
Khan NZ | 2009 | Yes | Yes | Yes | No | Yes | Yes | Yes | Yes | Unclear | Yes | 88.9 |
Mung'ala-
Odera V |
2008 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | 100 |
Wong VC | 2008 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Unclear | Yes | 90 |
Velez van
Meerbeke A |
2007 | No | No | Unclear | No | Unclear | Yes | Yes | Yes | Unclear | Yes | 40 |
Zeidan Z | 2007 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Unclear | Unclear | Yes | 80 |
Del Brutto
OH |
2005 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Not applicable | 100 |
Ersan EE | 2004 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No | Unclear | Yes | 90 |
Serdaro?Lu
A |
2004 | Yes | Yes | Yes | No | Yes | Yes | Yes | Yes | Unclear | Yes | 80 |
Wong V | 2004 | Yes | Yes | Yes | Yes | Unclear | Yes | Yes | Unclear | Yes | Yes | 80 |
Mousa
Thabet AA |
2001 | Unclear | Yes | Unclear | No | Yes | Yes | Yes | Yes | Unclear | Yes | 60 |
Couper J | 2002 | Yes | Yes | Yes | Yes | Unclear | Yes | Yes | Unclear | Yes | Yes | 80 |
Bulgan T | 2002 | No | No | Unclear | No | Unclear | Yes | Yes | Unclear | Unclear | Yes | 30 |
Zainal M | 2002 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Unclear | Yes | 90 |
Onal AE | 2002 | Yes | Yes | Yes | No | Yes | Yes | Yes | Yes | No | Yes | 80 |
Rao RS | 2002 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Unclear | Unclear | Not applicable | 77.8 |
Liu XZ | 2001 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Unclear | Not applicable | 88.9 |
Olusanya
BO |
2000 | Yes | Yes | Yes | No | Yes | Yes | Yes | Yes | Unclear | Not applicable | 77.8 |
Liu J | 2000 | Unclear | Unclear | Unclear | No | Yes | Unclear | Unclear | Yes | Unclear | Not applicable | 22.2 |
Liu JM | 1999 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Not applicable | 100 |
Brito GN | 1999 | Unclear | Yes | Unclear | No | Yes | Yes | Yes | Yes | Unclear | Yes | 60 |
Hackett RJ | 1997 | Unclear | Yes | Unclear | No | Unclear | Yes | No | Unclear | No | Not applicable | 22.2 |
Morioka I | 1996 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | 100 |
Okan N | 1995 | Yes | Yes | Yes | Yes | Unclear | Yes | Yes | Unclear | Unclear | Not applicable | 66.7 |
Mulatu MS | 1995 | Yes | Yes | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | 90 |
Rwiza HT | 1992 | Yes | Yes | Yes | Yes | Unclear | Yes | Yes | Unclear | No | Yes | 70 |
Koul R | 1988 | Yes | Yes | Yes | Yes | Unclear | Yes | Yes | Unclear | No | Yes | 70 |
Osuntokun BO | 1987 | Yes | Yes | Yes | Yes | Unclear | Yes | Yes | Unclear | Unclear | Yes | 70 |
Bash KW | 1987 | yes | yes | yes | yes | unclear | yes | yes | yes | yes | Not applicable | 88.9 |
Taha AA | 2010 | No | Yes | No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | 80 |
Wamithi S | 2015 | No | Yes | Unclear | Yes | Unclear | Yes | Yes | Yes | Unclear | Yes | 60 |
Durkin MS | 1992 | Yes | Yes | Yes | Yes | Unclear | Yes | Yes | Unclear | Unclear | Not applicable | 60 |
Each domain was marked using either “Yes”, “No”, “Unclear” or“ Not/Applicable”.
Estimates of overall prevalence and heterogeneity
The pooled prevalence is reported for all the 51 studies. The pooled prevalence per 1,000 from the random effects model for any NDD was 7.5 (95% CI=7.4–7.6) ( Figure 2), 3.2 (95%CI 3.1-3.3) for mental disorders and 11.3 (95% CI 11.2-11.5) for neurological disorders. We repeated the pooled prevalence for high quality studies (quality score >80) and found a prevalence of 7.6 (95%CI 7.5-7.6) per 1,000 and for studies where cases were clinically confirmed vs those where only screening tools were used to identify cases and the prevalence among clinically confirmed cases was 14.8 (95% CI=14.6-15.0) vs 4.0 (95% CI=3.9-4.1 for those which used screening tools only. We calculated the pooled prevalence of studies that used the same screening tools. Only the TQQ had a sufficient number of studies to calculate the pooled prevalence which was 11.9 per 1000 population (95% CI=10.7-13.0).
The random effect model for all studies was associated with a very high between-study heterogeneity (p = 0.000, I 2=99.9%). Some studies plotted outside the funnel outline in the meta-funnel analysis ( Figure 3) suggesting publication, reporting and selection bias.
Factors explaining variation in documented overall prevalence
We assessed several factors in the univariable and multivariable models and six appeared to explain the highest variation in the documented median prevalence in terms of prevalence ratios. The type of NDD (whether a mental disorder or neurological disorder) was significantly associated with the greatest prevalence ratios in the multivariate analysis, (PR=2.6 (0.6-11.6, p<0.05). Table 4 summarizes these findings.
Table 4. Heterogeneity and factors contributing to heterogeneity.
Factor | Univariable analysis | Multivariable analysis | ||||
---|---|---|---|---|---|---|
Prevalence ratio
(95%CI) |
P value | Heterogeneity (%) | Prevalence ratio
(95%CI) |
P value | Heterogeneity (%) | |
Region (as defined by the
United Nations regional groups) |
1.2 (0.6-2.3) | 0.4 | 0.3 | 0.9 (0.5-1.9) | 0.9 | 1.6 |
Condition (mental or
neurological) |
2.9 (0.7-12.3) | 0.1 | 4.7 | 2.6 (0.6-11.6) | 0.0 | 1.6 |
Setting (rural, urban or mixed) | 0.8 (0.4-1.4) | 0.5 | 2.8 | 0.6 (0.3-1.1) | 0.2 | 1.6 |
Year | 1.2 (0.7-2.3) | 0.8 | 2.2 | 1.1(0.5-2.3) | 0.9 | 1.6 |
Quality score (%) | 1.0 (0.9-1.0) | 0.1 | 3.2 | 1.0 (0.9-1.0) | 0.3 | 1.6 |
Case identification method
(clinically confirmed vs screening tool only) |
1.6 (0.5-4.8) | 0.4 | 0.2 | 2.0 (0.6-7.4) | 0.4 | 1.6 |
Prevalence per 1000 of individual domains of neurodevelopmental disorders
Most studies were on epilepsy, n=16 (35%), followed by hearing impairment, n=8 (17%), visual impairment, n=5 (11%) and ADHD, n=5 (11%). Behavioural/emotional problems had the highest prevalence of 362 per 1,000 (95% CI=337.0-387.0) (based on 2 studies), while one study on mental disorders reported a prevalence of 232 (95% CI=199.0-268.0) per 1,000. ADHD had a prevalence of 61 (95% CI=54-69), epilepsy 8 (95% CI=7.8-8.2) and ASD 0.6 (95% CI=0.5-0.6) per 1000 ( Table 5).
Table 5. Mean Prevalence/incidence of individual neurodevelopmental disorders.
Condition | Number of studies reporting
the condition (N=46) |
Total sample size
N=2740728 |
Mean prevalence
per 1000 (95% CI) |
Mean Incidence per
100000 (95% CI) |
---|---|---|---|---|
ADHD | 5 (10.9%) | 3897 (0.1%) | 60.8 (53.5-68.8) | - |
Behavior problems | 2 (4.3%) | 1458 (0.1%) | 362.1 (337.4-387.4) | - |
Cerebral palsy | 3 (6.6%) | 777343 (28.4%) | 1.6 (1.4-1.6) | - |
Epilepsy | 16 (34.8%) | 652240 (23.8%) | 8.0 (7.8-8.2) | 447.7 (415.3-481.9) |
Hearing impairment | 8 (17.4%) | 53756 (2.0%) | 11.4 (10.5-12.4) | - |
Motor impairments | 1 (2.2%) | 1022 (0.0%) | 14.6 (8.2-24.1) | - |
Neurological dysfunction | 2 (4.3%) | 5171 (0.2%) | 75.2 (68.2-82.8) | - |
Visual impairment | 5 (10.9%) | 62032 (2.3%) | 177.8 (174.8-180.8) | - |
Learning disabilities | 1 (2.2%) | 2036 (0.1%) | 80.0 (68.6-92.7) | - |
Neurodevelopmental delay | 1 (2.2%) | 2043 (0.1%) | 32.8 (25.5-41.5) | - |
Other mental disorders* | 1 (2.2%) | 611 (0.0%) | 232.4 (199.5-268.0) | - |
Incidence of neurodevelopmental disorders
Three studies reported the incidence of epilepsy with a mean annual incidence of 447.7 (95% CI 415.3-481.9) per 100,000 31, 35, 56. The study characteristics of all studies included in the meta-analysis are reported on Table 2.
Regional distribution of neurodevelopmental disorders
The studies were distributed as follows: Africa n=16 (31.4%) (77.6%), Asia-Pacific n=19 (37.3%), Western-European n=7 (13.7%), Latin-America n=7 (13.7%), Multisite n=2 (3.9%).
Asia-Pacific had the highest number of domains studied (N=8, 73%) followed by Africa (N=6, 55%) then Latin America (N=3, 27%). Latin America had the highest pooled overall prevalence per 1,000 for all NDD of 33.4 (95% CI=28.9-38.0), whereas Africa had the least 4.4 (95% CI=4.2-4.6). Epilepsy was the most reported condition in Asia and Africa. ADHD and hearing impairments most reported in South America.
Analysis of the settings of the studies (rural or urban), findings were available for 27 (57.4%) studies of which 15 (56%) were conducted in an urban setting, 10 (37%) in rural and 2 (6%) in both settings. The overall pooled prevalence in rural areas was 6.1 (95%CI 5.7-6.4) and was 2.1 (95%CI 2.1-2.2) per 1,000 in urban areas. We provide a summary of regional findings of the prevalence of individual domains of neurodevelopmental disorders in Table 6.
Table 6. Regional summary of spectrum of neurodevelopmental disorders.
NDD | Asia-Pacific (N=2122324) | Africa (N=277897) | Latin America
(N=10354) |
Mixed
(N=330153) |
---|---|---|---|---|
Pooled overall prevalence of all NDD (per
1000) and their corresponding 95% CI |
7.5 (7.4-7.6) | 4.4 (4.2-4.6) | 33.4 (28.9-38.0) | 9.4 (9.0-9.7) |
Mean prevalence per 1000 for individual neurodevelopmental disorders and their corresponding 95% CI | ||||
Autism spectrum disorders | 0.6 (0.5-0.6) | - | - | - |
ADHD | 80.7 (67.1-96.1) | 62.5 (35.4-101.0) | 47.9 (39.4-57.6) | |
Epilepsy | 6.7 (6.1-7.3) | 3.9 (3.7-4.2) | 5.5(2.0-12.0) | 9.4 (9.0-9.7) |
Behavioural/emotional problems | 362.1 (337.4-387.4) | - | - | - |
Cerebral palsy | 1.6 (1.5-1.6) | - | - | - |
Learning disability | - | 80 (68.6-92.7) | - | |
Hearing impairments | 8.1 (7.3-8.9) | 125.8 (105.0-149.1) | 45.4 (29.9-65.8) | - |
Visual impairments | 333.6 (328.5-338.7) | - | - | - |
Motor impairments | - | 14.7 (8.2-24.1) | - | |
Other mild neurological impairments | 75.2 (68.2-82.8) | - | 32.8 (25.5-41.5) | - |
Other psychopathologies | - | 232.4 (199.4-268.0) | - |
These results do not include studies from Turkey which is the only country in the Western European category because the studies were too few to provide a pooled estimate.
Risk factors for neurodevelopmental disorders
Risk factors were reported in 13/51 (28%) studies included. Perinatal complications were the most prevalent risk factors across the NDDs. They were as significant in four out of the five (80%) conditions for which risk factor data was available. The highest median odds ratio (OR=9.4 (IQR 4.9-13.8) for perinatal complications was on participants with hearing impairments. History of febrile seizures was significantly associated with epilepsy OR=2 (95%CI 1.7-10.8), hearing impairments OR=5.6 (95%CI 4.7-9.0) and mild neurological dysfunction OR=6.7 (95%CI 2.1-25.5). Environmental factors such as parental smoking and a history of febrile illness were also prevalent risk factors. Table 7 summarizes other risk factors data available from eligible studies.
Table 7. Risk factors for neurodevelopmental disorders and the corresponding median odds ratios with interquartile ranges.
No. of studies
(total =13 studies) |
Epilepsy | Hearing
impairment |
Mild
neurological dysfunction |
Cerebral
palsy |
Psychopathology | |
---|---|---|---|---|---|---|
Congenital malformations and
injuries of the head |
3 | 2.0 * | 9.4 (4.9-13.8) | - | - | - |
Family history | 6 | 2.8 (1.7-4.0) | 5.1 (2.9-7.3) | - | - | - |
Environmental factors such as
parental smoking and families with substantial psychosocial stress |
4 | 5.5 (1.8-8.6) | 0.3 (0.2-5.1) | - | - | 1.7
* (95% CI
2.76-7.52) |
Seropositivity to cysticercosis | 1 | 4.2
* (95% CI
1.6-11.2) |
- | - | - | - |
Sex male | 2 | 1.9 (1.5-2.3) | - | - | - | - |
Perinatal complications | 8 | 2.8 (2.2-10.2) | - | 1.1
* (95% CI
1.1-1.2) |
6.5
*(95% CI
4.4-9.3) |
- |
History of a febrile illness | 5 | 2.0 (1.7-10.8) | 5.6 (4.7-9.0) | 6.7
* (95% CI
2.1-25.5) |
- | - |
History of snoring | 1 | 6.5
* (95%CI
4.5–9.5) |
- | - | - | |
Non febrile illnesses such as
jaundice |
2 | - | 5.6 (0.2-15.8) | - | - | - |
Maternal complications | 1 | - | 0.2 (0.1-0.2) | - | - | 4.6
* (95% CI
2.76-7.52) |
*Only one study reported this finding hence we provided the confidence interval from this study
The overall median prevalence per 1000 for neurological impairments was 13.0 (IQR= 6.1-45.0) and the mean was 47.5 (95% CI=6.5-101.6). The pooled median prevalence estimate for neurological impairments is 11.1(95% CI=10.7-11.5)
**Snoring when caused by upper highway obstructing may be associated with poor oxygen perfusion in the brain. Subsequent brain damage may lower seizure threshold eventually leading to epilepsy.
Discussion
This review provides an estimate of the burden of NDD and associated risk factors in LAMIC. Only 51 eligible studies reported the epidemiology of NDD, with a wide range of prevalence or incidence estimates for each condition. This indicates that in many LAMIC, there is a paucity of data on even the most basic epidemiology of NDD, particularly of mental health disorders. The wide range of prevalence estimates even within the same regions is comparable to that found in a review by Durkin 61. It may be due to methodological differences 66 perhaps because of the difficulties involved in diagnosing most NDD particularly mental disorders for which there were fewer studies. The age of the child can complicate detection of NDDs since some disorders only manifest later in life, and the tools for detecting other disorders are relatively insensitive during early life. Furthermore, since there is considerable co-morbidity between these conditions complicating the estimates of the burden. Few studies reported risk factors for NDD with perinatal complications being the commonest risk factor for all NDD and febrile seizures for neurological disorders such as epilepsy.
Most studies were from Asia-Pacific; Africa and Latin America were under-represented. Although this may have affected the overall prevalence estimate, Polanczyk et al. in their review on ADHD demonstrated that geographical locations do not greatly influence prevalence outcomes 66. While the pooled estimates were comparable between Asia, Africa and Latin America, there were very few studies from the latter two continents. The minimum-pooled prevalence for all NDD was 7.5 per 1000, being higher for neurological disorders (11.3/1000) than for mental disorder studies (3.2/1000). This may be because of overrepresentation of studies on epilepsy, which is more widely studied in LAMIC. The estimates for mental disorders observed in this review are unexpectedly low, perhaps because detection of mental disorders such as ADHD and ASD is poor in LAMIC due to lack of tools and expertise for Measuring neurodevelopment in low-resource settings 67 and also because of some children dying early before diagnosis 68. In addition, surveys conducted in very young children may not detect ADHD. Prevalence of NDD is higher in rural areas compared to urban areas; which is consistent with previous studies of epilepsy 69 suggesting that risk factors might be more common in the rural areas. There was substantial differences between studies heterogeneity in the pooled estimates. The prevalence showed substantial variation between individual NDDs, being highest for visual impairment and lowest for ASD. The high heterogeneity observed for visual impairment may be related to the variability from the number of eligible studies included compared to ASD, but also to lack of standardised assessment. Only three studies documented incidence estimates and we could therefore not pool the findings.
This review shows that the burden of NDD is not precise and is probably greater than we have estimated. For instance, a robust study from rural Kenya utilising a demographic surveillance system on neurological impairments and disability had a much higher estimate (67/1000) than the one presented in this review 13. The low estimates from the review demonstrate that studies of individual conditions may not provide the true burden of NDD. A comprehensive study design approach to studying all NDD is important since these conditions overlap, and may be reliably screened together with a group of questions collated in one tool 70. The comprehensive screening approach would have important public health implication since many NDD overlap and the associated sequelae may be addressed by similar interventions.
The study showed disproportionately many studies of neurological impairments which may have skewed the overall pooled estimates. While some neurological impairments overlap with NDD 71– 73 a substantial proportion of common NDDs such as ADHD and emotional problems present without neurological comorbidities. The multivariate meta-regression analysis showed that neurological studies might have influenced the estimates, compared to mental disorder studies. Visual impairments, which are easier to detect, were the commonest NDD, perhaps also contributing to the high prevalence of neurological impairments 74. The paucity of mental disorder studies in these poor regions of the world may be related to the challenges in identifying these conditions such as lack of child and adolescent psychiatrists 75, 76. In ADHD for instance, studies relied on reports from teachers and parents to make diagnosis 51. It is difficult to translate these reports into valid and reliable case definitions because of the varying definitions of “normal behaviour” in different societies. However with the current success in local adaptation of tools for assessing behavioural 77 and developmental disorders 78 quality studies on mental disorder conditions such as ADHD and ASD should be possible in poor regions of the world.
The low prevalence of mental disorders is likely contributed by ASD. The prevalence of ASD is much lower than the burden documented in literature, suggesting possible under recognition of ASD in LAMIC particularly Africa. A recent review of ASD in sub-Saharan Africa found only one study on the prevalence of ASD 79. On the contrary, other mental disorders may be easily recognised and assessed, for example, behavioural/emotional problems were reported in 36%, ADHD in 6% and other mental disorders in 23%, albeit all were based on less than five studies. It is likely that there are sporadic low-quality studies in LAMIC that are not published or are placed in unindexed journals, based on the evidence of publication bias from the funnel plots. More robust studies on mental disorders in children are needed in LAMIC. The identification of NDD in poor regions is becoming easier following the advent of cheap and easy assessment approaches including the mental health gap action program intervention guide 80. Tools such as WHO’s Ten Questions Screen can be used to screen those to be prioritised for diagnosis of NDD 35, 81, 82.
Few studies reported several risk factors ( Table 4). Perinatal complications 21 and family history of febrile seizures 26, 35, 46, 83 were common across a different number of NDD, particularly epilepsy. The role of perinatal complications in the risk of neurological conditions is recognised in previous studies 83 and improvement in obstetric services may be helpful. Family history of seizures was associated with neurological disorders in rural Kenya 13. Family history of seizures may represent genetic susceptibility or shared environmental factors for NDD, the later is supported by the high incidence of febrile infections in these regions. While environmental factors such as parental smoking are important in in mental health problems in children, few NDD studies from LAMIC investigated this factor. Gene-environment interactions should be explored as the risk for NDD in these poor regions of the world. Some of the risk factors mentioned have a higher incidence in LAMIC than in high-income countries, and could have an additive interaction effect with each other 84– 86 which probably explains the higher burden of NDD in the former parts of the world. Other risk factors such as fetal alcohol exposure which has been shown to have a high burden in some LAMIC 87, 88 and which result in neurodevelopmental impairments such as intellectual disability were not explored in the included studies and should be examined in future studies.
Limitations
There were methodological differences and lack of use of standardized measures to assess NDD in most studies. To mitigate the effect of methodological differences on the prevalence estimates, we conducted a sub-analysis of prevalence estimates for studies that used the same methods of case ascertainment. Additionally, the pathophysiology of individual NDD varies widely and this limits the generalizability of intervention strategies. For example, whereas biomedical interventions such as medications and surgery may be more helpful in neurological impairments, alternative interventions such as behavioural therapy may be more helpful for mental health disorders. Subjective methods such as reports from teachers and parents were used to assess for the presence of impairments. This limits the reliability of the estimates provided in this study. The effect of sex on NDD could not be explored since prevalence results were not aggregated based on sex, despite evidence of male/female propensity in some NDDs such as ASD. We did not separate crude from adjusted estimates therefore the estimates we have provided may still be under estimates. Currently, there is no standard validated tool for assessing quality of evidence presented in observational studies hence, although we appraised the studies included in our meta-analysis, there may still be methodological limitations. Studies on neurological impairments such as epilepsy, which have lower prevalence than other mental disorders in other parts of the world, were overrepresented in the sample and that influenced the overall prevalence estimate. The estimates of ASD were lower than reports from high-income countries, which may have lowered the overall estimates of NDD. Lack of data on the severity of the NDDs limits the clinical implications of this study. Although NDD manifests early in development, delayed diagnosis in many LMIC may have delayed detection of these disorders at the time of the study. Some countries may have transitioned to high-income countries based on the World Bank classification of Economies and this may change the estimates provided in this study. For the studies where prevalence was not reported, we calculated it as a proportion cases over the total study sample. This method may have resulted in underestimation of the prevalence since there was no background information to adjust calculated prevalence for attrition and sensitivities of screening tools.
Conclusions
This review indicates that the burden of NDD in LAMIC is considerable, but there is lack of reliable epidemiological data on some NDD such as ASD which may underestimate the true burden of NDD in LAMIC. Screening for all NDD in epidemiological surveys is recommended to provide reliable estimates for planning purposes e.g. to inform resource allocation towards the rehabilitation of affected children. Mental disorders such as ADHD and ASD were rarely reported, and more studies particularly in Africa and Latin America are required to provide reliable estimates since neurological conditions such as epilepsy usually have conserved estimates compared to mental disorders. The risk factors investigated were few with the role of perinatal complications and history of febrile seizures being consistent with previous studies. Studies considering all potential risk factors are required to inform preventive interventions aimed at mitigating the risk factors for neurodevelopmental disorders.
Data availability
Final dataset for the systematic review is available on OSF: http://doi.org/10.17605/OSF.IO/9E2WY 89
Data are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).
Acknowledgements
We would like to acknowledge Fred Ibinda, who was involved in the initial stages of this study, but subsequently died.
Funding Statement
SK and CRJCN are supported by the Wellcome Trust [099782] and [083744], respectively.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
[version 3; referees: 2 approved, 2 approved with reservations]
Supplementary material
Supplementary File 1: PRISMA checklist.
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