Modelled epidemiological data for selected congenital disorders in South Africa.

Congenital disorders (CD) remain an unprioritized health care issue in South Africa with national surveillance underreporting by > 95%. This lack of empiric data contributes to an underestimation of the CD disease burden, resulting in a lack of services for those affected. Modelling offers estimated figures for policymakers to plan services until surveillance is improved. This study applied the Modell Global Database (MGDb) method to quantify the South African CD disease burden in 2012. The MGDb combines birth prevalence data from well-established registries with local demographic data to generate national baseline estimates (birth prevalence and outcomes) for specific early-onset, endogenous CDs. The MGBd was adapted with local South African demographic data to generate baseline (no care) and current care national and provincial estimates for a sub-set of early-onset endogenous CDs. Access to care/impact of interventions was quantified using the infant mortality rate as proxy. With available care in 2012, baseline birth prevalence (27.56 per 1000 live births, n = 32,190) decreased by 7% with 2130 less affected births, with 5400 (17%) less under-5 CD-related deaths and 3530 (11%) more survivors at 5 years, including 4720 (15%) effectively cured and 1190 (4%) less living with disability. Results indicate a higher proportion of CD-affected births than currently indicated by national surveillance. By offering evidence-based estimates, the MGDb may be considered a tool for policymakers until accurate empiric data becomes available. Further work is needed on key CD groups and costing of specific interventions.

The Prevention of Thalassemia Revisited: A Historical and Ethical Perspective by the Thalassemia International Federation.

Hemoglobinopathies are the most common monogenic disorders in humans; among them, thalassemia constitutes a serious medical and public health problem in high prevalence regions, in a geographical zone ranging from the Mediterranean Basin to China. In addition, migrations over the years have introduced thalassemia to many parts of the world. Although disease-specific programs are in place and accessible to most patients in prosperous countries, this is not the case in developing economies, where more than 75.0% of the patient population is born and lives; this concerns both prevention and treatment programs. In view of the significant improvements in public health and healthcare systems over the past few years, the Thalassemia International Federation has revisited the thalassemia prevention programs, initiatives and policies in some of its member countries, discussing their effectiveness and whether any changes in policy or public attitudes to thalassemia prevention have occurred through the recent years.

Historical overview of development in methods to estimate burden of disease due to congenital disorders.

Congenital disorders (often also called birth defects) are an important cause of mortality and disability. They encompass a wide range of disorders with differing severity that can affect any aspect of structure or function. Understanding their epidemiology is important in developing appropriate services both for their prevention and treatment. The need for epidemiological data on congenital disorders has been recognised for many decades. Here, we provide a historical overview of work that has led to the development of the Modell Global Database of Congenital Disorders (MGDb)-a tool that can be used to generate evidence-based country, regional and global estimates of the birth prevalence and outcomes of congenital disorders.

Estimating the birth prevalence and pregnancy outcomes of congenital malformations worldwide.

Congenital anomaly registries have two main surveillance aims: firstly to define baseline epidemiology of important congenital anomalies to facilitate programme, policy and resource planning, and secondly to identify clusters of cases and any other epidemiological changes that could give early warning of environmental or infectious hazards. However, setting up a sustainable registry and surveillance system is resource-intensive requiring national infrastructure for recording all cases and diagnostic facilities to identify those malformations that that are not externally visible. Consequently, not all countries have yet established robust surveillance systems. For these countries, methods are needed to generate estimates of prevalence of these disorders which can act as a starting point for assessing disease burden and service implications. Here, we describe how registry data from high-income settings can be used for generating reference rates that can be used as provisional estimates for countries with little or no observational data on non-syndromic congenital malformations.

Rare single gene disorders: estimating baseline prevalence and outcomes worldwide.

As child mortality rates overall are decreasing, non-communicable conditions, such as genetic disorders, constitute an increasing proportion of child mortality, morbidity and disability. To date, policy and public health programmes have focused on common genetic disorders. Rare single gene disorders are an important source of morbidity and premature mortality for affected families. When considered collectively, they account for an important public health burden, which is frequently under-recognised. To document the collective frequency and health burden of rare single gene disorders, it is necessary to aggregate them into large manageable groupings and take account of their family implications, effective interventions and service needs. Here, we present an approach to estimate the burden of these conditions up to 5 years of age in settings without empirical data. This approaches uses population-level demographic data, combined with assumptions based on empirical data from settings with data available, to provide population-level estimates which programmes and policy-makers when planning services can use.

Methods to estimate access to care and the effect of interventions on the outcomes of congenital disorders.

In the absence of intervention, early-onset congenital disorders lead to pregnancy loss, early death, or disability. Currently, lack of epidemiological data from many settings limits the understanding of the burden of these conditions, thus impeding health planning, policy-making, and commensurate resource allocation. The Modell Global Database of Congenital Disorders (MGDb) seeks to meet this need by combining general biological principles with observational and demographic data, to generate estimates of the burden of congenital disorders. A range of interventions along the life course can modify adverse outcomes associated with congenital disorders. Hence, access to and quality of services available for the prevention and care of congenital disorders affects both their birth prevalence and the outcomes for affected individuals. Information on this is therefore important to enable burden estimates for settings with limited observational data, but is lacking from many settings. This paper, the third in this special issue on methods used in the MGDb for estimating the global burden of congenital disorders, describes key interventions that impact on outcomes of congenital disorders and methods used to estimate their coverage where empirical data are not available.

Estimates of global and regional prevalence of neural tube defects for 2015: a systematic analysis.

Neural tube defects (NTDs) are associated with substantial mortality, morbidity, disability, and psychological and economic costs. Many are preventable with folic acid, and access to appropriate services for those affected can improve survival and quality of life. We used a compartmental model to estimate global and regional birth prevalence of NTDs (live births, stillbirths, and elective terminations of pregnancy) and subsequent under-5 mortality. Data were identified through web-based reviews of birth defect registry databases and systematic literature reviews. Meta-analyses were undertaken where appropriate. For 2015, our model estimated 260,100 (uncertainty interval (UI): 213,800-322,000) NTD-affected birth outcomes worldwide (prevalence 18.6 (15.3-23.0)/10,000 live births). Approximately 50% of cases were elective terminations of pregnancy for fetal anomalies (UI: 59,300 (47,900-74,500)) or stillbirths (57,800 (UI: 35,000-88,600)). Of NTD-affected live births, 117,900 (∼75%) (UI: 105,500-186,600) resulted in under-5 deaths. Our systematic review showed a paucity of high-quality data in the regions of the world with the highest burden. Despite knowledge about prevention, NTDs remain highly prevalent worldwide. Lack of surveillance and incomplete ascertainment of affected pregnancies make NTDs invisible to policy makers. Improved surveillance of all adverse outcomes is needed to improve the robustness of total NTD prevalence estimation, evaluate effectiveness of prevention through folic acid fortification, and improve outcomes through care and rehabilitation.

An overview of concepts and approaches used in estimating the burden of congenital disorders globally.

Congenital disorders are an important cause of pregnancy loss, premature death and life-long disability. A range of interventions can greatly reduce their burden, but the absence of local epidemiological data on their prevalence and the impact of interventions impede policy and service development in many countries. In an attempt to overcome these deficiencies, we have developed a tool-The Modell Global Database of Congenital Disorders (MGDb) that combines general biological principles and available observational data with demographic data, to generate estimates of the birth prevalence and effects of interventions on mortality and disability due to congenital disorders. MGDb aims to support policy development by generating country, regional and global epidemiological estimates. Here we provide an overview of the concepts and methodological approach used to develop MGDb.

Chromosomal disorders: estimating baseline birth prevalence and pregnancy outcomes worldwide.

Chromosomal disorders, of which Down syndrome is the most common, can cause multi-domain disability. In addition, compared to the general population, there is a higher frequency of death before the age of five. In many settings, large gaps in data availability have hampered policy-making, programme priorities and resource allocation for these important conditions. We have developed methods, which overcome this lack of data and allow estimation of the burden of affected pregnancies and their outcomes in different settings worldwide. For example, the methods include a simple equation relating the percentage of mothers 35 and over to Down syndrome birth prevalence. The results obtained provide a starting point for consideration of services that can be implemented for the care and prevention of these disorders.

Systematic Review and Meta-Analysis of the Birth Prevalence of Orofacial Clefts in Low- and Middle-Income Countries.

BACKGROUND: In the last comprehensive review of the literature published in 2002, little information on the prevalence of orofacial clefts was available from low- and middle-income countries (LMICs). OBJECTIVE: To analyze published data on the birth prevalence of cleft lip and/or palate (CL/P) from LMIC. DESIGN: Systematic review of the literature and meta-analysis of data from original papers on the birth prevalence of cleft lip and/or cleft palate (CL/P) in LMICs between 1990 and 2014. Secondary inclusion criteria were developed to analyze lower-quality studies from countries with scarce data. MAIN OUTCOME MEASURE: Birth prevalence of undifferentiated CL/P (with or without associated syndrome or other anomaly). RESULTS: Twenty-eight studies met strict inclusion criteria. Among 31,475,278 total births, the pooled birth prevalence of undifferentiated CL/P was 1.38 per 1000 births (95% confidence interval [CI]: 1.20 to 1.56). Four studies met criteria for secondary analysis, providing data on 75,627 births, with a pooled prevalence of 0.75 CL/P cases per 1000 births (95% CI: 0.56 to 0.95). Comparison of studies was limited by variable definitions of cases and of the reference population and by inconsistent reporting of outcomes. There is significant heterogeneity in the findings. CONCLUSIONS: In LMICs, approximately 1 in every 730 children is born with CL/P. To optimize comparability across settings, future research should use a standard classification system and standard criteria for data collection and presentation. As clefting is associated with deprivation, understanding the true scale, risks, and preventive measures for orofacial clefts in LMIC is a matter of both scientific and humanitarian importance.

The changing epidemiology of ß-thalassemia in the Greek-Cypriot population.

The first epidemiological study for thalassemia in Cyprus was performed by Fawdry in 1946. The study determined that the frequency of ß-thalassemia (ß-thal) carriers was around 18.0% and that of α(0)-thal carriers (individuals with both cis α-globin genes inactive) at around 2.0%. In 1998, another study concluded that Cyprus had one of the highest frequencies of ß-thal carriers worldwide (17.2%). Based on Haldane's hypothesis that malaria might be the selective agent responsible for the maintenance of high levels of thalassemia and sickle cell disease in many populations around the world, it is expected that following the eradication of the disease in Cyprus in 1948, the carriers of ß-thal should decline with each generation. In order to determine whether this has been the case, we compiled frequency data for ß-thal carriers from three separate surveys performed as part of the Cyprus National Thalassaemia Screening Programme (NTSP). The surveys were carried out in 1986, 2003 and 2010 involving 9622, 6711 and 5228 subjects, respectively. The expected drop in the prevalence of ß-thal carriers for each successive generation following the eradication of malaria, i.e., in the absence of selection pressure, was calculated using the Hardy-Weinberg equation and the mathematical model of Hartl and Clark. The surveys provide supporting evidence for the decrease of the frequency of the ß-thal carriers in the Greek Cypriot population, with a drop of 1.89% in 24 years.

Falling prevalence of beta-thalassaemia and eradication of malaria in the Maldives.

Carriers of haemoglobin disorders have protection against falciparum malaria. Therefore, where this is common, carrier prevalence rises until this selective advantage is offset by deaths of affected children. Theory predicts a corresponding fall in carrier frequency following malaria eradication, but this has not been reported in practice. In the Maldives, malaria eradication (in 1972-1975) unmasked highly prevalent beta-thalassaemia and led to services for patient care and outreach carrier screening. Analysis of 68,986 laboratory screening records for subjects born between 1960 and 1990 showed carrier prevalences ranging from 10.1% to 28.2% by atoll (related to the prevalence of falciparum malaria before eradication) and a steady fall in average carrier prevalence from 21.3% among those born in 1970 to 16% in those born in 1989. Data for individuals born before 1970 suggest that earlier, when malaria was uncontrolled, carrier prevalence was 23-25%. The observed fall in carrier prevalence was broadly consistent with a model based on genetic theory, allowing for the heterogeneous distribution of carrier prevalence and the potential contribution of consanguineous marriage. The possible effects of population mixing and reproductive compensation were calculated, and any contribution to falling carrier prevalence was excluded. It is concluded that the observed fall in thalassaemia carrier prevalence in the Maldives is consistent with the predicted effect of malaria eradication and supportive of the population genetic theory. The observed fall in average carrier prevalence corresponds to a fall in minimum affected birth prevalence from approximately 12/1,000 in 1970 to approximately 6.9/1,000 in 2007. Allowing for this effect, the National Thalassaemia Register has documented a more than 60% fall in affected birth prevalence since outreach population screening was established in 1997. The main contributing factors are considered to be limitation of final family size by informed at-risk couples and utilisation of prenatal diagnosis.

Primary care morbidity in Eastern Cape Province.

BACKGROUND: Primary health care in rural South Africa is predominantly provided by remote clinics and health centres. In 1994, health centres were upgraded and new health centres developed to serve as a health care filter between community clinics and district hospitals. AIM: To describe the spectrum of clinical problems encountered at a new health centre in an area of high economic deprivation and compare this with an adjacent community clinic and district hospital. DESIGN: Cross-sectional survey. SETTING: A rural clinic, health centre and district hospital in Eastern Cape Province, South Africa. METHODS: The International Classification of Primary Care-2 (ICPC-2) was used to code data collected over a 13-week period from patients presenting at a community clinic, health centre and district hospital. RESULTS: Altogether, 4 383 patient encounters were recorded across all three sites in 2001. Most contacts at the clinic (97%) and the health centre (80%) were with a nurse. Females over 15 years of age comprised over half of all contacts at health facilities (53%). The most common diagnosis category was respiratory (23%). Cough was the most common symptom. Thirty per cent of children up to 5 years of age were seen for immunisations. Most childhood immunisations (79%) were carried out at the health centre. CONCLUSION: Of all the health care facilities surveyed, the health centre had the highest throughput of patients, indicating that the health centre is an efficient filter between the community and hospital. The ICPC-2 can be successfully used to monitor encounters at similar African health care facilities.

Folic acid to reduce neonatal mortality from neural tube disorders.

BACKGROUND: Neural tube defects (NTDs) remain an important, preventable cause of mortality and morbidity. High-income countries have reported large reductions in NTDs associated with folic acid supplementation or fortification. The burden of NTDs in low-income countries and the effectiveness of folic acid fortification/supplementation are unclear. OBJECTIVE: To review the evidence for, and estimate the effect of, folic acid fortification/supplementation on neonatal mortality due to NTDs, especially in low-income countries. METHODS: We conducted systematic reviews, abstracted data meeting inclusion criteria and evaluated evidence quality using adapted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Where appropriate, meta-analyses were performed. RESULTS: Meta-analysis of three randomized controlled trials (RCTs) of folic acid supplementation for women with a previous pregnancy with NTD indicates a 70% [95% confidence interval (CI): 35-86] reduction in recurrence (secondary prevention). For NTD primary prevention through folic acid supplementation, combining one RCT with three cohort studies which adjusted for confounding, suggested a reduction of 62% (95% CI: 49-71). A meta-analysis of eight population-based observational studies examining folic acid food fortification gave an estimated reduction in NTD incidence of 46% (95% CI: 37-54). In low-income countries an estimated 29% of neonatal deaths related to visible congenital abnormalities are attributed to NTD. Assuming that fortification reduces the incidence of NTDs, but does not alter severity or case-fatality rates, we estimate that folic acid fortification could prevent 13% of neonatal deaths currently attributed to congenital abnormalities in low-income countries. DISCUSSION: Scale-up of periconceptional supplementation programmes is challenging. Our final effect estimate was therefore based on folic acid fortification data. If folic acid food fortification achieved 100% population coverage the number of NTDs in low-income countries could be approximately halved. CONCLUSION: The evidence supports both folic acid supplementation and fortification as effective in reducing neonatal mortality from NTDs.

Improved survival of thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance.

BACKGROUND: The UK Thalassaemia Register records births, deaths and selected clinical data of patients with thalassaemia who are resident in the UK. A study of survival and causes of death was undertaken which aimed to include the possible impact of T2* cardiovascular magnetic resonance (CMR). METHODS: The Register was updated to the end of 2003, copies of death certificates were obtained, and causes of death in beta thalassaemia major were extracted. In addition, patients who had T2* CMR assessment of cardiac iron load and/or received the oral iron chelator deferiprone were identified from clinical records. RESULTS: The main causes of death were anaemia (before 1980), infections, complications of bone marrow transplantation and cardiac disease due to iron overload. From 1980 to 1999 there were 12.7 deaths from all causes per 1,000 patient years. Forty per cent of patients born before 1980 had T2* cardiovascular magnetic resonance between 2000 and 2003, and 36% of these patients were prescribed deferiprone before end of 2003. In 2000-2003, the death rate from all causes fell significantly to 4.3 per 1,000 patient years (-62%, p < 0.05). This was mainly driven by the reduction in the rate of deaths from iron overload which fell from 7.9 to 2.3 deaths per 1,000 patient years (-71%, p < 0.05). CONCLUSION: Since 1999, there has been a marked improvement in survival in thalassaemia major in the UK, which has been mainly driven by a reduction in deaths due to cardiac iron overload. The most likely causes for this include the introduction of T2* CMR to identify myocardial siderosis and appropriate intensification of iron chelation treatment, alongside other improvements in clinical care.