Antenatal Screening For Haemoglobinopathies Research Articles

The design and post-implementation review of an algorithm for antenatal haemoglobinopathy screening

Background: Haemoglobinopathies are autosomal recessive disorders caused by quantitative (thalassaemia) or qualitative (variants) changes in alpha or beta-globin chains due to variants in HBA1, HBA2 and HBB. An effective carrier screening program requires identification of couples at risk of offspring affected by clinically severe disease.

Thalassaemia

Thalassaemias are among the most common genetic disorders worldwide; an estimated 1.5% of the global population carries a thalassaemia mutation. Originally associated with tropical and sub-tropical regions, migration has facilitated wider dispersal, concentrated in larger multi-ethnic conurbations. Thalassaemias are heterogeneous, ranging from asymptomatic to causing severe haemolytic anaemia with pan-corporal sequelae and complications. Carriers benefit from access to pre-conception and antenatal advice and screening. The National Health Service Antenatal Haemoglobinopathy Screening Programme has operated since 2001, but carrier diagnoses may still emerge incidentally. This article provides an overview of the genetics, presentation and management of thalassaemia.

Undiagnosed haemoglobinopathies among pregnant women attending antenatal care clinics in Pune, India.

Pregnant women with iron deficiency and those who are carriers of haemoglobinopathies present with anaemia of varying severity. There is no antenatal screening for haemoglobinopathies in India. The objective of this study was to determine the prevalence of undiagnosed haemoglobinopathy carriers in a random sample of pregnant women attending antenatal care clinics in Pune city, India. Biobanked DNA of 360 randomly selected pregnant women was genotyped for six common mutations and two common haemoglobin variants, HbS and HbE. Odds ratios (OR) with 95% confidence intervals were computed to determine association of carrier status with socio-demographic, haematological and clinical characteristics. The prevalence of undiagnosed haemoglobinopathy carriers was 6.3% (95% CI 4.2-9.4%) of which 3.3% (95% CI 1.9-5.7%) were beta thalassaemia carriers. There was an increased odds that beta thalassaemia carriers had moderate anaemia (OR 10.59, 95% CI 1.15-96.90). This study reveals the high prevalence of undiagnosed haemoglobinopathy carriers among pregnant women, indicating the need to immediately implement carrier screening and genetic counselling services across the country.

Antenatal haemoglobinopathy screening - Experiences of a large Australian Centre.

Antenatal screening is vital to identifying couples at risk of having children with a clinically significant haemoglobinopathy. In Australia, immigration is increasing carrier incidence. A retrospective analysis was performed of full blood count, high-performance liquid chromatography and haemoglobin electrophoresis of women and their partners who underwent antenatal haemoglobinopathy screening over three years at a major NSW laboratory. Genetic testing results were included where available. One thousand six hundred and twenty-eight women and 729 male partners were screened at a median gestation of 14 weeks. 8.2% of women had a clinically significant result, with a median 16-day interval to partner testing. In 35% of couples screened simultaneously, the partner did not require testing. Genetic confirmatory testing was performed in 65% of high risk couples. There was a significant delay to antenatal haemoglobinopathy screening for mothers, limiting time for genetic diagnosis, prenatal diagnosis and management of affected pregnancies. Screening should be performed earlier. Simultaneous couple testing is not cost-effective.

Adherence to a selective antenatal haemoglobinopathy screening policy within a tertiary level obstetric unit in Australia.

Haemoglobinopathies represent the most common single gene disorder worldwide; however, significant centre to centre variations in antenatal screening practices exist. To assess performance of a selective antenatal haemoglobinopathy screening policy within a presumed low-prevalence Australian population. Primary outcome was the failure to screen rate for women with at least one identifiable risk factor. Secondary outcomes included outcomes of maternal screening and rates, gestations and outcomes of paternal, prenatal and neonatal testing. A two-year retrospective cohort study identifying all women attending for public antenatal care with at least one identifiable risk factor for haemoglobinopathy. At least one risk factor for haemoglobinopathy was identified in 8.8% of the entire pregnant cohort; however, the failure to screen rate was high at 83.7% overall. Screening was significantly more likely to be undertaken in multiparous women, those with multiple risk factors and women originating from the Middle East. Twenty percent of screened women returned an abnormal result; however, this led to paternal haemoglobinopathy screening in only 66.6%. Where completed, the addition of partner screening reclassified offspring to low-risk status in 85.7% of cases. This study demonstrates an 83.7% screen failure rate within a selective screening model raising concerns regarding the clinical utility and health equity of this approach. This major drawback of selective screening suggests that institution of a universal antenatal screening system for haemoglobinopathies, even in anticipated low-prevalence areas, will improve detection rates and ensure families receive appropriate and timely counselling.

Cohort profile: targeted antenatal screening for haemoglobinopathies in Basel

PurposeThe pregnancy cohort was established to examine the prevalence and variety of haemoglobinopathies in a high-risk group of pregnant women.ParticipantsThe pregnancy cohort is located in the Department of Obstetrics and...

Antenatal screening for haemoglobinopathies: current status, barriers and ethics.

Sickle cell disease (SCD) and thalassaemia are genetic disorders that are caused by errors in the genes for haemoglobin and are some of the most common significant genetic disorders in the world, resulting in significant morbidity and mortality. Great disparities exist in the outcome of these conditions between resource- rich and resource-poor nations. Antenatal screening for these disorders aims to provide couples with information about their reproductive risk and enable them to make informed reproductive choices; ultimately reducing the likelihood of children being born with these conditions. This review provides an overview of the current status of antenatal, pre-marital and population screening of SCD and thalassaemia in countries with both high-and low prevalence of these conditions, methods of screening in use, and discusses some of the pitfalls, ethical issues and controversies surrounding antenatal screening. It also discusses outcomes of some screening programmes and recognises the need for the establishment of antenatal screening in areas where their prevalence is highest; namely sub-Saharan Africa and India.

Antenatal Screening for Haemoglobinopathies by Using High Performance Liquid Chromatography

Antenatal Screening for Haemoglobinopathies by Using High Performance Liquid Chromatography

380. Adherence to a selective antenatal haemoglobinopathy screening policy within a tertiary level obstetric unit in Australia

There is no national Australian antenatal haemoglobinopathy screening policy and a previous Australian study of antenatal haemoglobin electrophoresis requests highlighted poor patient selection. Whilst benefits of screening have been well demonstrated, adherence to selective screening protocols in low prevalence populations has not been well described. This study aims to assess adherence to an established selective antenatal screening policy within a low prevalence Australian population. This single-centre retrospective cohort study identifies all women attending for routine public antenatal care with estimated due date between 1st January 2014 and 31st December 2016 who meet criteria for selective screening on the basis of established guidelines. The primary outcome was the proportion of eligible women who were appropriately screened. Secondary outcomes included rates of partner testing and rates of specialist referral where fetal risk was identified. A total of 11,709 births were recorded during the study period. Eligibility for screening was identified on the basis of ethnicity in 1076 (9.1%), abnormal red cell indices in 427 (3.6%) and known personal or family history in 77 (0.6%). 158 (10%) had haemoglobin electrophoresis results documented during the antenatal course with 64 (4%) initiated by obstetric staff during the index pregnancy at a median gestation of 22 weeks. Partner testing was documented in 140 (88.6%) of “at risk” pregnancies and of these, appropriate specialist referral was indicated in 28 (20%) but occurred in only 17. This is the first Australian study to describe the rate of pregnancies meeting established criteria for selective screening in a low prevalence population. This data demonstrates poor identification of “at risk” patients leading to limitation of informed choice for affected families. The demonstration of poor adherence within the clinical setting supports arguments for universal screening which becomes increasingly cost effective as the selective screen failure rate rises.

Antenatal haemoglobinopathy screening: Patterns within a large obstetric service. Working towards a standard of care.

Antenatal screening can predict clinically significant haemoglobinopathies, however in Australia, practices are not standardised and are evolving as the population becomes more ethnically diverse. This study describes antenatal screening practices in a large Australian laboratory/antenatal service. Data were collected retrospectively on consecutive antenatal haemoglobin electrophoresis over 16 months and correlated with obstetric data, obtained from the local obstetric database. 462 patients were included, with an average gestation of 25.8 weeks. 'Pregnancy' was the most common stated indication, with absent indication/clinical information in 8%. Gestational age was documented in 54%. In 15%, no contact details of the referrer were documented and partner screening was traceable in only 25 cases (5.4%). In 82% of cases, no abnormalities were detected. Beta thalassemia trait was the most common positive result. Only 52% of patients had recent iron studies. The mean haemoglobin was 111.6 g/L and mean cell volume was 80.5 fl at the time of testing. Ethnicity was documented on the request form in 3%. After Australasia, the most common ethnicity of patients was South East Asia and the Middle East. Referral patterns in our health service are diverse and reflect our changing population and care practices. Detailed guidelines are required and we propose a comprehensive algorithm for general use where selective screening is practiced within an Australasian population or one with similar demographics.

Sickle cell disease and β‐thalassaemia major in pregnancy

Key content Pregnancy in women with sickle cell disease continues to show high rates of maternal and fetal mortality and morbidity. This applies to all forms of sickle cell disease. The place of blood transfusions in helping women with sickle cell disease in pregnancy continues to be controversial. Genetic counselling for women with haemoglobinopathies should be provided as part of the UK national Antenatal Haemoglobinopathy Screening Programme, which was introduced in 2001. There is an increased incidence of venous thromboembolism in individuals with sickle cell disease, transfusion‐dependent β‐thalassaemia and sickle cell trait. Individuals with β‐thalassaemia major who are able to survive childhood by virtue of the availability of regular and frequent blood transfusions frequently acquire the organ damage caused by haemosiderosis. Among the organs involved are the pituitary, the thyroid, the islet cells of the pancreas, the heart and the liver. The main concern for women with β‐thalassaemia major contemplating pregnancy is the possibility of cardiac dysfunction, resulting from myocardial haemosiderosis, causing both ventricular pump failure and arrythmias. Learning objectives To understand the key care requirements of women with sickle cell disease and β‐thalassaemia major, prior to pregnancy, during pregnancy and in the postnatal period. To appreciate the importance of knowledgeable care for this relatively uncommon group of patients, and to be able to work collaboratively with haematologists and others who have such experience and expertise. To understand the principles relevant to antenatal screening for haemoglobinopathies, and to be able to give appropriate advice to couples. Ethical issues Suboptimal care is sometimes given when patients are cared for in hospitals with little experience of the condition, and outcomes can be improved by arranging care in centres with specialist expertise. Should pregnancy be encouraged, and fertility treatment given for women with a reduced life expectancy? How should this be balanced with respect for patient autonomy?

Antenatal screening for haemoglobinopathies in primary care: a cohort study and cluster randomised trial to inform a simulation model. The Screening for Haemoglobinopathies in First Trimester (SHIFT) trial

To assess the effectiveness, cost-effectiveness, acceptability and feasibility of offering universal antenatal sickle cell and thalassaemia (SCT) screening in primary care when pregnancy is first confirmed and to model the cost-effectiveness of early screening in primary care versus standard care. A population-based cohort study, cluster randomised trial and refinement of a published decision model. Twenty-five general practices from two UK primary care trusts (PCTs) in two inner city boroughs with a high proportion of residents from minority ethnic groups. Practices were considered eligible if they agreed to be randomised and they were able to provide anonymous data on all eligible pregnant women. Participants were at least 18 years old and consented to take part in the evaluation. Practices were allocated to intervention, using minimisation and stratifying for PCT and number of partners at the practice, as follows: screening in primary care with parallel father testing (test offered to mother and father simultaneously; n = 8 clusters, 1010 participants); screening in primary care with sequential father testing (test offered to father only if mother identified as carrier; n = 9 clusters, 792 participants); and screening in secondary care with sequential father testing (standard care; n = 8 clusters, 619 participants). Data on gestational age at pregnancy confirmation and screening date were collected from trial practices for 6 months before randomisation in the cohort phase. The primary outcome measure was timing of SCT screening, measured as the proportion of women screened before 70 days' (10 weeks') gestation. Other outcomes included: offer of screening, rates of informed choice and proportion of women who knew the carrier status of their baby's father by 77 days (11 weeks). For 1441 eligible women in the cohort phase, the median [interquartile range (IQR)] gestational age at pregnancy confirmation was 7.6 weeks (6.0 to 10.7 weeks) and 74% presented in primary care before 10 weeks. The median gestational age at screening was 15.3 weeks (IQR 12.6 to 18.0 weeks). Only 4.4% were screened before 10 weeks. The median delay between pregnancy confirmation and screening was 6.9 weeks (4.7 to 9.3 weeks). In the intervention phase, 1708 pregnancies from 25 practices were assessed for the primary outcome measure. Completed questionnaires were obtained from 464 women who met eligibility criteria for the main analysis. The proportion of women screened by 10 weeks (70 days) was 9/441 (2%) in standard care, compared with 161/677 (24%) in primary care with parallel testing, and 167/590 (28%) in primary care with sequential testing. The proportion of women offered screening by 10 weeks (70 days) was 3/90 (3%) in standard care (note offer of test ascertained for questionnaire respondents only), compared with 321/677 (47%) in primary care with parallel testing, and 281/590 (48%) in primary care with sequential testing. The proportion of women screened by 26 weeks (182 days) was similar across the three groups: 324/441 (73%) in standard care, 571/677 (84%, 0.09) in primary care with parallel testing, and 481/590 (82%, 0.148) in primary care with sequential testing. The screening uptake of fathers was 51/677 (8%) in primary care with parallel testing, and 16/590 (3%) in primary care with sequential testing, and 13/441 (3%) in standard care. The predicted average total cost per pregnancy of offering antenatal SCT screening was estimated to be 13 pounds in standard care, 18.50 pounds in primary care with parallel testing, and 16.40 pounds in primary care with sequential testing. The incremental cost-effectiveness ratio (ICER) was 23 pounds in primary care with parallel testing and 12 pounds in primary care with sequential testing when compared with standard care. Women offered testing in primary care were as likely to make an informed choice as those offered screening by midwives later in pregnancy, but less than one-third of women overall made an informed choice about screening. Offering antenatal SCT screening as part of pregnancy-confirmation consultations significantly increased the proportion of women screened before 10 weeks (70 days), from 2% in standard care to between 16% and 27% in primary care, but additional resources may be required to implement this. There was no evidence to support offering fathers screening at the same time as women. Current Controlled Trials ISRCTN00677850.

Significant haemoglobinopathies: guidelines for screening and diagnosis

Antenatal screening/testing of pregnant women should be carried out according to the guidelines of the NHS Sickle Cell and Thalassaemia Screening programme. Newborn screening and, when necessary, follow up testing and referral, should be carried out according to the guidelines of the NHS Sickle Cell and Thalassaemia Screening programme. All babies under 1 year of age arriving in the UK should be offered screening for sickle cell disease. Preoperative screening for sickle cell disease should be carried out in patients from ethnic groups in which there is a significant prevalence of the condition. Emergency screening with sickle solubility tests must always be followed by definitive analysis. Laboratories performing antenatal screening should utilize methods capable of detecting significant variants and be capable of quantitating haemoglobins A 2 and F at the cut-off points required by the national antenatal screening programme. The laboratory must ensure a provisional report is available within three working days from sample receipt.

A review and critique of modelling in prioritising and designing screening programmes

To undertake a structured review and critical appraisal of methods for the model-based cost-utility analysis of screening programmes. Also to develop guidelines and an assessment checklist of good practice in the development of screening models. Major electronic databases of healthcare and operational research literatures were searched up to June 2003. Searches of the literature were undertaken to identify applied and methodological studies of economic evaluations of healthcare screening programmes. All applied screening models were also reviewed in three broad disease areas (cancer, cardiovascular disease and diabetes), as well as antenatal screening. A second-level review focused on particular aspects of the modelling process through case study assessments of screening models for three specific disease areas (colorectal cancer, abdominal aortic aneurysms and antenatal screening for haemoglobinopathies). A separate literature review of studies reporting the utility effects of screening was also undertaken. Guidelines and an assessment checklist for good practice for screening modelling were developed. Few relevant methodological studies were identified, and no studies reporting direct empirical comparisons of alternative methodologies were retrieved. From the review of disease-based screening models, it was apparent that many alternative modelling methods had been applied, including some relatively new approaches that had not been widely disseminated. Natural history modelling is the preferred approach. Alternative modelling approaches were generally only used to extrapolate the observed effects of screening and were unsuitable for evaluating unobserved screening options. More complex model structures may incorporate important additional aspects of the disease natural history, although any benefits should outweigh the consequences of additional unobservable input parameters and increased complexity in implementing the model. No direct comparisons of more detailed and less detailed screening model structures informed areas in which more realistic representations of the disease process may be most beneficial, so only general aspects of good practice could be defined. Two structural aspects that were not well handled by existing screening models included post-diagnosis disease progression and screening uptake. Most models described the former using historical mortality rates, rather than treatment models that are representative of current treatment patterns for different stages of the disease. Constant screening uptake rates were applied to all screening programmes and attendance was not linked to disease incidence or progression. Evidence exists to inform a more detailed representation of screening uptake. The most commonly applied modelling techniques were cohort Markov models and individual sampling simulation models. Individual sampling simulation models may provide more flexibility in their representation of a screening decision problem, but any benefits should outweigh the consequences of the need to assess both variability and uncertainty. Complex mathematical models describing input parameters as continuous variables have analysed the cost-effectiveness of screening; these require further development to estimate the cost-utility of screening directly, or to inform a more detailed representation of the preclinical section of a natural history model (with a traditional state-based model describing pathways' post-clinical presentation). Calibration is a common aspect of screening models, whereby models are fitted to observed data describing outputs of the model in order to populate unobserved input parameters. The review concluded that the estimation of a reference case input parameter set is not recommended. The review of methods for the model-based cost-utility analysis of screening programmes identified the natural history modelling approach as the preferred general method of evaluation for screening programmes. State transition models have generally been used to represent disease natural histories, with individual sampling models more prevalent than in treatment intervention evaluations. No comparative methodological studies were identified, so no empirical data were available to inform the relative merits of alternative methodologies. The defined guidelines and assessment checklist are informed, therefore, by theoretical interpretations of the impact of alternative approaches to different components of the modelling process when applied to the cost-utility analysis of screening programmes. Further research is needed into methods with the potential to improve the accuracy of screening models, and to respond to the needs of model users.

A pilot study of 'fast track' antenatal screening for haemoglobinopathies.

The NHS Plan launched in 2000 advocated a linked antenatal and neonatal screening programme for haemoglobinopathies. Currently screening practices vary widely across the UK and patient sampling is generally performed in a hospital setting. The process is flawed and frequently fails to provide accurate and timely information. In this study we demonstrate that organisational changes can improve the efficiency and quality of screening. The primary care screening process described here has increased partner testing rates and allowed early identification of at risk couples.

What are Pakistani women's experiences of antenatal carrier screening for beta-thalassaemia in the UK? Why it is difficult to answer this question?

In the UK antenatal screening of Pakastani women for thalassaemia carrier status is commonplace. This paper describes our attempts to investigate women’s experiences of such screening and the reasons why this proved difficult to do. These included a pregnancy per year and communications failure between different health professionals involved in antenatal haemoglobinopathy screening. These issues have implications for the way in which such screening is conducted and these are discussed.

Antenatal haemoglobinopathy screening cost effective

Antenatal haemoglobinopathy screening cost effective

Organisation and cost-effectiveness of antenatal haemoglobinopathy screening and follow up in a community-based programme.

To consider the organisation cost and effectiveness, of universal, community-based antenatal screening for the haemoglobinopathies, and to estimate the cost-effectiveness of programmes at different levels of prevalence and mix of haemoglobinopathy traits. Retrospective review of laboratory and Sickle Cell and Thalassaemia Centre worksheets with costing of capital equipment, consumables, salaries and overheads, and estimation of costs in a range of circumstances. A haematology department, including a Sickle Cell and Thalassaemia Centre, providing antenatal and neonatal screening programmes in Inner London. Two thousand one hundred and one women booking at the antenatal clinic whose samples were referred for screening during 1994. In addition to assessing the cost-effectiveness of antenatal haemoglobinopathy screening in a number of settings, the following specific financial information was assembled for the service in Brent: 1. cost of identifying abnormal haemoglobin in mother (ł209); 2. cost of identifying at-risk fetus before confirmation by prenatal diagnosis (ł2,455); 3. cost of providing genetic information and counselling to mother with abnormal haemoglobin (ł109); 4. programme savings from cases averted (ł61,000). Conclusions Antenatal screening with follow up counselling can be self-financing at most prevalences of haemoglobinopathy traits, with greater savings where a high proportion of the traits are beta thalassaemia. There is a net financial cost (ł1,350) only at prevalences below 2.5% of traits if these are mainly for sickle cell disease. Since there are other benefits is it likely that antenatal screening will be considered cost-effective even at quite low levels of trait prevalence.

An analysis of relative costs and potential benefits of different policies for antenatal screening for beta thalassaemia trait and variant haemoglobins.

AIMS: To investigate the costs and potential benefits of different policies for antenatal screening for haemoglobinopathies in two multiethnic London communities. METHODS: 1000 consecutive antenatal patient samples referred to each...

Outcomes of universal antenatal screening for haemoglobinopathies.

To evaluate universal antenatal screening for haemoglobinopathies. District general hospital serving a London borough with 45% ethnic minorities. Retrospective cohort study of 1444 women referred in 1688 pregnancies and 95 tertiary referrals during 101 pregnancies. Unselected women at risk for sickle cell disease booked 2.7 weeks (95% confidence interval (CI) 0.14 to 5.1) later in gestation than those at risk for beta thalassaemia were less likely to attend counselling (83% v 93%, relative risk (RR) 0.89; 95% CI 0.85 to 0.94), their partners were less likely to be tested (77% v 95%, RR 0.81; 0.77 to 0.83), and they were less likely to accept prenatal diagnosis (22% v 90%, RR 0.37; 0.24 to 0.57). Over 99% of tertiary referrals attended counselling and had their partners tested. There were no significant differences in acceptance of prenatal diagnosis between those at risk of sickle cell disease and beta thalassaemia (55% v 67%). Unselected women at risk of sickle cell disease were significantly less likely to have their partner tested or to accept prenatal diagnosis than tertiary referrals, but not those at risk of beta thalassaemia. 80% of beta thalassaemia and 16% of SS births were prevented. Uptake of prenatal diagnosis among unselected women at risk of beta thalassaemia is similar to that reported by tertiary centres. It is considerably lower for sickle cell disease but could increase considerably if screening occurred earlier in gestation. Acceptance of counselling is universally high, suggesting that informed choices are made, and indicating a need to measure these outcomes for cost effectiveness studies.