A review of key terminology and definitions used for birth defects globally.

Birth defects, also known as congenital disorders, are a significant health issue impacting at least five million births annually worldwide. For policymakers to mount a relevant healthcare response to care for those affected, the burden of disease of these conditions must be quantified. Estimates of the contribution of birth defects to under-5 child mortality and morbidity are generated by several groups globally. These estimates often differ, causing confusion for policymakers. While some differences may be attributed to the data sources and methods used, much is due to a lack of clarity in the terminology used for the group of disorders classed as "congenital". This study aimed to gain insight into the diversity of terms and definitions for birth defects, including those used routinely by relevant international/national organisations and in the peer-reviewed literature. This two-part study included (1) scoping review of peer-reviewed literature to identify terms and definitions in use for birth defects and (2) review of key websites and grey literature to identify terms and definitions used. The results of this study indicate a wide variety of terms being used, often interchangeably and undefined, in peer-reviewed publications, on institutional websites and related literature. This suggests a lack of clarity related to terminology and sets the scene for further discussion, recommending that the community of practice working on birth defects comes to a consensus on standard terminology and definitions for global uptake and implementation. Such standardisation will facilitate a common understanding of the burden of these disorders globally, regionally and within countries so that action can be taken to support affected children and their families.

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.

Addressing key issues in the consanguinity-related risk of autosomal recessive disorders in consanguineous communities: lessons from a qualitative study of British Pakistanis.

Currently, there is no consensus regarding services required to help families with consanguineous marriages manage their increased genetic reproductive risk. Genetic services for communities with a preference for consanguineous marriage in the UK remain patchy, often poor. Receiving two disparate explanations of the cause of recessive disorders (cousin marriage and recessive inheritance) leads to confusion among families. Further, the realisation that couples in non-consanguineous relationships have affected children leads to mistrust of professional advice. British Pakistani families at-risk for recessive disorders lack an understanding of recessive disorders and their inheritance. Such an understanding is empowering and can be shared within the extended family to enable informed choice. In a three-site qualitative study of British Pakistanis, we explored family and health professional perspectives on recessively inherited conditions. Our findings suggest, firstly, that family networks hold strong potential for cascading genetic information, making the adoption of a family-centred approach an efficient strategy for this community. However, this is dependent on provision of high-quality and timely information from health care providers. Secondly, families' experience was of ill-coordinated and time-starved services, with few having access to specialist provision from Regional Genetics Services; these perspectives were consistent with health professionals' views of services. Thirdly, we confirm previous findings that genetic information is difficult to communicate and comprehend, further complicated by the need to communicate the relationship between cousin marriage and recessive disorders. A communication tool we developed and piloted is described and offered as a useful resource for communicating complex genetic information.

A Toolkit to assess health needs for congenital disorders in low- and middle-income countries: an instrument for public health action.

BACKGROUND: In 2010 the World Health Assembly called for action to improve the care and prevention of congenital disorders, noting that technical guidance would be required for this task, especially in low- and middle-income countries. Responding to this call, we have developed a freely available web-accessible Toolkit for assessing health needs for congenital disorders. METHODS: Materials for the Toolkit website (http://toolkit.phgfoundation.org) were prepared by an iterative process of writing, discussion and modification by the project team, with advice from external experts. A customized database was developed using epidemiological, demographic, socio-economic and health-services data from a range of validated sources. Document-processing and data integration software combines data from the database with a template to generate topic- and country-specific Calculator documents for quantitative analysis. RESULTS: The Toolkit guides users through selection of topics (including both clinical conditions and relevant health services), assembly and evaluation of qualitative and quantitative information, assessment of the potential effects of selected interventions, and planning and prioritization of actions to reduce the risk or prevalence of congenital disorders. CONCLUSIONS: The Toolkit enables users without epidemiological or public health expertise to undertake health needs assessment as a prerequisite for strategic planning in relation to congenital disorders in their country or region.

Examining the family-centred approach to genetic testing and counselling among UK Pakistanis: a community perspective.

WHO advice suggests a family-centred approach for managing the elevated risk of recessively inherited disorders in consanguineous communities, whilst emerging policy recommends community engagement as an integral component of genetic service development. This paper explores the feasibility of the family-centred approach in the UK Pakistani origin community. The study took place within a context of debate in the media, professional and lay circles about cousin marriage causing disability in children. Using qualitative methods, a total of six single-sex focus group discussions (n = 50) were conducted in three UK cities with a high settlement of people of Pakistani origin. Tape-recorded transcripts were analysed using framework analysis. Kinship networks within Pakistani origin communities are being sustained and marriage between close blood relatives continues to take place alongside other marriage options. Study participants were critical of what was perceived as a prevalent notion that cousin marriage causes disability in children. They were willing to discuss cousin marriage and disability, share genetic information and engage with genetic issues. A desire for accurate information and a public informed about genetic issues was articulated whilst ineffective communication of genetic risk information undermined professionals in their support role. This study suggests a community that is embracing change, one in which kinship networks are still active and genetic information exchange is taking place. At the community level, these are conditions supportive of the family-centred approach to genetic testing and counselling.

Epidemiology of oral clefts 2012: an international perspective.

Classical descriptive epidemiology in the field of cleft lip and palate aims to quantify the problem, and in the higher income countries it is possible to do this with varying degrees of accuracy. This is not however possible in every country in the world, and epidemiology should seek to identify these data gaps with a view to improvement in the situation. Epidemiology must also be investigative and look for trends, associations and inter-population differences, with the aim of supporting aetiological research and advancing the translational agenda. This chapter is set out in three parts and seeks to address all three of the above areas. Birth defects in general and orofacial clefting in particular remain a relatively common and significant problem for not only the individual patients born with these defects in terms of death or disability, but also for their families and for society in general in terms of burden of care and health inequality. In high-income countries, despite very significant advances in treatment, problems in access to care and evidence base for cleft care still exist whereas in the developing world the consequences are lack of access to care and lack of infrastructure to help with quantification of the problem and consequently the ability to address it. The major questions in contemporary cleft lip and palate research surround ways of improving the evidence base for the treatment interventions used to optimise quality of care, and the ultimate scientific and humanitarian objective is primary prevention of those diseases and disorders that are preventable. Descriptive epidemiology underpins research enquiry in both of these major areas.

Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfusional haemosiderosis) in patients suffering with chronic anaemia: a systematic review and economic evaluation.

OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of deferasirox for the treatment of iron overload associated with regular blood transfusions in patients with chronic anaemia such as beta-thalassaemia major (beta-TM) and sickle cell disease (SCD). DATA SOURCES: Electronic databases were searched up to March 2007. REVIEW METHODS: Methods followed accepted procedures for conducting and reporting systematic reviews and economic evaluations. RESULTS: A total of 14 randomised controlled trials (RCTs) involving a study population of 1480 (ranging from 13 to 586) met the inclusion criteria. There was a high degree of heterogeneity between trials in terms of trial design and outcome reporting. As such it was only possible to meta-analyse serum ferritin data from six trials making comparisons between deferiprone and DFO and combination therapy and DFO. Only one of the results was statistically significant, favouring combination therapy over DFO alone for serum ferritin at 12 months. How this translates into iron loading in organs such as the heart is unclear, nor was it possible to determine the long-term benefits of chelation therapy. Eight full economic evaluations (one full paper; seven abstracts) were included in the review. The results were generally consistent and appear to demonstrate the cost-effectiveness of deferasirox compared with DFO for the treatment of iron overload in a number of different patient populations and study locations. However, a number of assumptions and, in the case of the long-term studies, extrapolation from short-term RCT data were required, which render the results highly speculative at best. Because of the paucity of long-term data we developed a simple, short-term (1 year) model to assess the costs and benefits of deferasirox, deferiprone and DFO in patients with beta-TM and SCD from an NHS perspective. A number of assumptions were required to generate results and, as such, they should be interpreted as indicative rather than factual. Our model suggests that deferasirox may be a cost-effective strategy compared with DFO, at a cost per quality-adjusted life-year (QALY) below 30,000 pounds per year, for patients with beta-TM and SCD. However, this is highly dependent upon the age of the patient and the use and benefits of balloon infusers to administer DFO. Deferasirox compared with deferiprone is likely to be cost-effective only for young children. Furthermore, if deferiprone is proven to offer the same health benefits as deferasirox, the latter will not be cost-effective for any patient compared with deferiprone. CONCLUSIONS: In the short term there is little clinical difference between any of the three chelators in terms of removing iron from the blood and liver. Deferasirox may be cost-effective compared with DFO in patients with beta-TM and SCD, but it is unlikely to be cost-effective compared with deferiprone. Elucidating the long-term benefits of chelation therapy, including issues of adverse events and adherence, should be the primary focus for future research. Future work should aim for consistency and transparency in reporting study design and results to aid decision-making when making comparisons across trials.

Epidemiology of haemoglobin disorders in Europe: an overview.

OBJECTIVE: As a result of global population movements, haemoglobin disorders (thalassaemias and sickle cell disorders) are increasingly common in the formerly non-indigenous countries of Northern and Western Europe and in the indigenous countries of Southern Europe. This article presents an overview of the changing picture and a method for assessing service needs. METHOD: Data on country of birth or ethnic origin of residents are adjusted to obtain the estimated proportions of residents and births in non-indigenous groups at risk for haemoglobin disorders in European countries. The results are combined with prevalence data in each country of origin to obtain country prevalence estimates. Service indicators (annual tests or other interventions required to ensure equitable delivery of treatment and prevention) are then derived by country. RESULTS: Haemoglobin disorders now occur at comparable frequency throughout Northern, Western and Southern Europe. Annually, there are more affected conceptions in Northern and Western than in Southern Europe, and sickle cell disorders are more common than thalassaemias. There is growing need for health policy-makers to support motivated professionals working to develop optimal patient care, carrier diagnosis, genetic counselling and access to prenatal diagnosis throughout the Region. CONCLUSION: There is a strong case for pan-European collaboration on haemoglobin disorders to share policies, standards and the instruments required to support them. These include methods for needs assessment, service standards, education and information strategies and materials, and methods for evaluating service delivery.

Microcytosis, iron deficiency and thalassaemia in a multi-ethnic community: a pilot study.

The high prevalence of microcytosis (defined here as mean cell haemoglobin<27 pg) with no other abnormality is a principal cause of confusion in screening for haemoglobin disorders. Here we report the results of a small pilot study aiming to resolve this confusion by routinely proceeding to plasma ferritin and HPLC assay, using the original sequestrene blood sample, when microcytosis is detected. Participants comprised a random sample of 1,302 people referred for a full blood count by their General Practitioner (GP) to the laboratory of a North London district general hospital serving a multi-ethnic inner-city population. Ethnicity was established by questionnaire. In North Europeans, microcytosis was present in 3% of males (half were iron-deficient) and 11% of females (most were iron-deficient). Among ethnic minorities, microcytosis was present in 35% of males (one tenth were iron-deficient), and 45% of females (less than half were iron-deficient): an exclusion diagnosis of "probable alpha thalassaemia" could be made in the remainder. We conclude that when microcytosis is present, routine further analysis of the original sequestrene sample by plasma ferritin assay and haemoglobinopathy screening could lead to a more efficient and cost-effective laboratory service for primary care and maternity services.

Quality of life in thalassemia.

Morbidity and mortality related to thalassemia have been reduced significantly with modern medical treatment, and quality of life (QOL) should now be considered an important index of effective health care. An assessment of QOL differs from other forms of medical assessment in that it focuses on the individuals' own views of their well-being and assesses other aspects of life, giving a more holistic view of well-being. There is very little published work on evaluation of QOL in thalassemia. A suitable tool should be reproducible, sensitive to the major features of the condition that affect patients' lives, and applicable in the range of different cultural, age, and social settings. Such an instrument would be valuable in evaluating new forms of treatment and in comparing health outcomes between different clinics. Two instruments have been assessed, one derived from the WHOQOL-100 questionnaire, and one designed specifically for thalassemia, which assesses psychosocial and clinical burden, as they affect adult patients, parents, and children. Further studies are required to develop and assess such tools for use in thalassemia. Another approach is to seek patients' own views of their routine treatment and the extent to which medical treatment affects QOL. Results from patient questionnaires in the United Kingdom and Cyprus are consistent in finding problems with organization of transfusions, insufficient options with chelation therapy, and poor communication. Practical measures could be taken to address these issues.

A national register for surveillance of inherited disorders: beta thalassaemia in the United Kingdom.

OBJECTIVE: To demonstrate the value of a national register for surveillance of services for an inherited disorder. METHODS: Data from the United Kingdom Thalassaemia Register and the United Kingdom Register of Prenatal Diagnosis for Haemoglobin Disorders were combined in a database; these registers include all fetuses known to have been diagnosed with beta thalassaemia major, beta thalassaemia intermedia, or haemoglobin E/beta thalassaemia in the United Kingdom. Data were extracted to show outcomes (selective abortion or live birth) of all fetuses and the status of those born with a disorder (alive, dead, successful bone marrow transplant, or lost to follow-up) by parents' region of residence and ethnicity. FINDINGS: At the end of 1999 the register included 1074 patients, 807 of whom were alive and residing in the United Kingdom. A successful bone marrow transplant has been performed for 117 out of 581 (20%) patients born since 1975. Residents of Pakistani origin are now the main group at risk in the United Kingdom, replacing residents of Cypriot origin. This has led to a marked shift in the need for services from the south-east of England to the Midlands and the north of England. Despite the acceptability of prenatal diagnosis, the proportion of affected births remains 50% higher than would be expected, reflecting a widespread failure to deliver timely screening and counselling to carriers. Even though effective treatment is available the annual number of deaths is rising, indicating that better tolerated treatments are needed. CONCLUSION: A national diagnosis register is a powerful instrument for monitoring the treatment and prevention of inherited disorders and for highlighting correctable shortcomings. In view of the increasing possibilities for genetic screening there is a strong case for central funding for such databases within modern health services.

Accuracy of prenatal diagnosis for haemoglobin disorders in the UK: 25 years' experience.

We have reviewed the accuracy of prenatal diagnosis for the thalassaemias and sickle cell disorders performed for UK residents since the service began in 1974. Prenatal diagnosis has been performed in 3254 pregnancies: 517 by fetal blood analysis, 681 by Southern blotting and 2056 by polymerase chain reaction (PCR) methods, the majority using the amplification refractory mutation system (ARMS). The number of homozygotes diagnosed was 808 (24.8%). Twenty-five diagnostic errors have been recorded, ten arising from non-laboratory errors (0.31%) and 15 due to technical problems associated with the diagnostic techniques. The latter group consisted of eight misdiagnoses by globin chain synthesis (1.55%), five by Southern blot analysis (0.73%) and two by PCR methods (0. 10%). The data show that the accuracy of prenatal diagnosis has improved with each development of diagnostic technique, and confirms that prenatal diagnosis of beta-thalassaemia and sickle cell disorders by ARMS-PCR is very accurate and reliable. The overall error rate for prenatal diagnosis by PCR methods in the UK is now 0. 41%.

Survival in beta-thalassaemia major in the UK: data from the UK Thalassaemia Register.

About 50% of UK patients with beta-thalassaemia major die before the age of 35 years, mainly because conventional iron-chelation therapy is too burdensome for full adherence. Patients require an individually-tailored treatment plan incorporating new, more tolerable approaches.

Long-term effect of prospective detection of high genetic risk on couples' reproductive life: data for thalassaemia.

Prospective risk detection with availability of prenatal diagnosis is the best service currently available for couples at high genetic risk Here we describe the long term effect of this service on the reproductive life of 102 couples at risk of thalassaemia, whose risk was detected prospectively by carrier screening, who made use of prenatal diagnosis, and where the woman is now over 40. Overall outcome for couples is described in terms of number of favourable versus unfavourable pregnancy outcomes. (A favourable pregnancy outcome = unaffected livebirth, or affected livebirth resulting from informed parental choice.) The 102 couples had a total of 356 pregnancies, including 302 viable pregnancies, and 88% achieved a family unburdened by thalassaemia. 68% of viable pregnancies had a favourable outcome, but only 43% of couples had only favourable outcomes, and 26% lost two or more viable wanted pregnancies. When early losses are included 58% of pregnancies had a favourable outcome, but only 30% of couples had only favourable outcomes, and 41% lost two or more pregnancies. Even with the best available service, at risk couples remain victims of chance, and a significant minority experience great difficulty in obtaining even one healthy child. Research is needed on approaches that may allow couples better control of reproductive outcomes.

Prenatal diagnosis of beta-thalassaemia in Pakistan: experience in a Muslim country.

A service for prenatal diagnosis of beta-thalassaemia was introduced in Pakistan in May 1994. Two renowned Islamic scholars, consulted before the service was introduced, ruled that a pregnancy can be terminated if the fetus is affected by a serious genetic disorder, and if termination is before 120 days (17 weeks) of gestation. During the first 3(1/2) years of the service 300 couples requested the test. Almost all the couples had been informed by their treating doctors. Most diagnoses were made between 10 and 16 weeks of gestation, and only 15 (5%) were reached after the 16th week. DNA analysis was by the amplification refractory mutation system (ARMS). A multiplex ARMS was developed in which three primer combinations identified the mutations in 91.5% of the couples. In 13 couples (4. 3%) linkage analysis was required for the fetal diagnosis. In 47/53 (88.7%) women carrying an affected fetus the pregnancy was terminated. In six cases it was declined principally on religious grounds. Postnatal confirmation of the prenatal diagnosis was possible in 117 unaffected children. One year after the start of the service, interviews with 141 couples with an affected child showed that 72% knew of the availability of prenatal diagnosis. Thirty-two of the informed couples had had a pregnancy, but only 18 (56%) used prenatal diagnosis. The main reasons for non-utilization of prenatal diagnosis were the cost of the test and fear of undergoing the test, though some gave no clear explanation. This study demonstrates that prenatal diagnosis is feasible and acceptable in a Muslim country such as Pakistan.

Informed choice in genetic screening for thalassaemia during pregnancy: audit from a national confidential inquiry.

OBJECTIVE: National audit of informed choice in antenatal screening for thalassaemia. DESIGN: Audit from the UK Confidential Enquiry into Counselling for Genetic Disorders. SETTING: Thalassaemia module of the UK Confidential Enquiry into Counselling for Genetic Disorders. SUBJECTS: 138 of 156 couples who had had a pregnancy affected by a major beta thalassaemia from 1990 to 1994. MAIN OUTCOME MEASURES: How and when genetic risk was identified for each couple, and whether and when prenatal diagnosis was offered. RESULTS: Risk was detected by screening before or during the first pregnancy in 49% (68/138) of couples and by diagnosis of an affected child in 28% (38/138) of couples. Prenatal diagnosis was offered in 69% (274/400) of pregnancies, ranging from 94% (122/130) for British Cypriots to 54% (80/149) for British Pakistanis and from 90% in the south east of England to 39% in the West Midlands. Uptake of prenatal diagnosis was 80% (216/274), ranging from 98% (117/120) among British Cypriots in either the first or second trimester to 73% (35/48) among British Pakistanis in the first trimester and 39% (11/28) in the second trimester. A demonstrable service failure occurred in 28% (110/400) of pregnancies, including 110 of 126 where prenatal diagnosis was not offered and 48 of 93 that ended with an affected liveborn infant. CONCLUSION: Although antenatal screening and counselling for haemoglobin disorders are standard practices in the United Kingdom, they are delivered inadequately and inequitably. An explicit national policy is needed, aiming to make prenatal diagnosis in the first trimester available to all couples and including ongoing national audit.

Study of hemoglobinopathies in Oman through a national register.

OBJECTIVES: A national register of symptomatic hemoglobinopathies has been developed in Oman to facilitate the development of the National Program for the control of genetic blood disorders. METHODS: The information was initially collected retrospectively through hospital records and was refined prospectively with data collected through a survey of pediatricians. The percentages of heterozygotes in different population groups and geographical locations, birth prevalence, age distribution of cases and factors determining frequencies of Hemoglobinopathies in different regions of the country were studied from the register. RESULTS: The register has identified 1757 cases of homozygous Sickle Cell Anemia and 243 cases of beta-thalassemia major in a population of 1.5 million in 1995. Register based national figures of heterozygote carriers approximate 10% for Sickle Cell Anemia and 4% for beta-thalassemia major. CONCLUSION: Defining regional and tribal variations can assist efficient targeting of health resources. This approach provides a simple model for other countries or regions to follow providing there is a health care system that facilitates registration.