Demographic modelling of haemoglobinopathies incidence in Germany: A call for targeted public health policy responses

Demographic modelling of haemoglobinopathies incidence in Germany: A call for targeted public health policy responses | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Demographic modelling of haemoglobinopathies incidence in Germany: A call for targeted public health policy responses Dani Hakimeh, Juan Lázaro Navarro, Derya Balci-Hakimeh, Michael Abou-Dakn, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7935231/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract In recent years, Germany has become one of the most popular destinations for international migrants and refugees, mostly from countries with a high prevalence of haemoglobinopathies. The concurrent lack of awareness among healthcare professionals, of systematic data, and of targeted screening carry the risk of disparities in patient care. In this context, a change in public health policy is urgently needed. In this article, we argue for a tailored prenatal screening algorithm supported by an analysis of open-source data showing a significant increase in pregnancies at risk of carrying a haemoglobinopathy. We also advocate for multifaceted interventions including the expansion of counselling services, healthcare professional education, community engagement and dedicated research funding to establish a robust framework for the management of haemoglobinopathies in Germany. Health sciences/Health care/Public health/Epidemiology Health sciences/Diseases/Haematological diseases/Anaemia Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Haemoglobinopathies, mainly represented by sickle cell disease (SCD) and thalassaemia syndromes, are among the most prevalent monogenic diseases worldwide, belonging to the global health challenges of the 21st century. 1 As migration increases, high-income countries with low carrier frequencies, such as in Central and Northern Europe, still face difficulties in providing adequate care for affected individuals. This results from a lack of awareness, systematic data, and evidence-based management. 2 These challenges lead to disparities and potential malpractice in patient care with serious consequences, inappropriate for developed healthcare systems. 3 Germany is among some of the highest densely populated countries in Europe. 4 Over the recent decades, it has become the second most popular destination for international migrants and one of the top five host countries for refugees. 5 According to available estimates, a relatively low proportion of the German population (0.36% to 0.48%) carry a haemoglobinopathy gene, which is most commonly identified in non-indigenous communities. 6 , 7 Due to the recent abrupt increase in immigration between 2014 and 2016, mostly from countries with high carrier frequencies for haemoglobinopathies, we expect the number of carriers in the current German population to be increasing. 8 This demographic shift indicates an emerging risk of mutation transmission to next generations in the German population, influenced by additional factors including consanguinity, endogamy and fertility rates. 9 This underscores the necessity for evaluating the imperative, feasibility, and timing of haemoglobinopathy carriage screening and the expansion of specialized counselling services within the German healthcare framework. Germany’s introduction of a newborn screening programme for SCD in 2021 marked a pivotal stride in secondary prevention. In the first year, 137 out of 732,791 newborns (1:5349) were diagnosed with SCD, making it one of the most common diagnoses in the German newborn screening programme. 10 However, with developing migration, the evolution of carrier frequencies cannot be predicted. This is burdened by two main factors: a lack of awareness among healthcare professionals and a lack of routine screening for heterozygosity. 6 This absence, coupled with the clinical diversity of haemoglobinopathies, lead to an odyssey of incorrect and delayed diagnoses. 11 Screening for heterozygosity has proven its effectiveness in the management of haemoglobinopathies in many European (including the UK, Denmark, France, the Netherlands, Greece, and Italy) and non-European countries. 2 , 12 , 13 Adopting a similar strategy to address low awareness in Germany seems appropriate given its vastly diverse population and developed healthcare infrastructure. Available estimates indicate that 0.54% of pregnant women in Germany are carriers of at least one haemoglobin disorder. 7 Despite this, existing German maternity guidelines fall short of established recommendations for antenatal screening, which typically involves at least a full blood count. 12 , 14 – 16 Antenatal screening programmes facilitate informed decision-making and counselling for couples at risk, as well as specialized care for identified mothers with high-risk pregnancies, including those with SCD. In this perspective, we present and discuss key findings of our analysis, assessing the need for a customised pre- and antenatal screening algorithms for expecting mothers in Germany. Methods In the absence of data on pregnant nationalities in Germany we estimated the prevalence of pregnancies at risk of carrying a haemoglobinopathy using open access sources, including the German Federal Statistical Office database (GENESIS), Modell's haemoglobinopathologist's Almanac, and the World Bank database (Fig. 1 ). Assuming a low carrier frequency in the German population, we estimated the carriage risk only for non-German resident women to assess their contribution to the proportion of pregnancies at risk of carrying a haemoglobinopathy. Since only limited information on the nationality of a pregnant woman is recorded during perinatal care in Germany (European nationalities are documented, otherwise only the continent-of-origin), it was not possible to analyse birth data directly by mother's country-of-origin. We therefore calculated the probability of pregnancy among different nationalities living in Germany using publicly available statistical data on the number of live births and the number of resident women of childbearing age by country-of-origin from the GENESIS database of the German Federal Statistical Office. Childbearing age was defined as between 15 and 50 years of age. The data were extracted by federal state and per year for the period 2010–2024. (supplementary material: data sources) As the number of live births per woman, also known as total fertility rate (TFR), can vary widely between countries-of-origin, it was necessary to include it when estimating the risk of an inherited condition with high geographical variation in carrier frequency, such as haemoglobinopathies. Here we used the TFRs published by the World Bank for the year 2023 as a reference for all countries-of-origin included in our analysis (supplementary material: data sources). Existing data on Turkish migrants in Germany describe many factors that influence immigrants' fertility behaviour after arrival including length of stay in the country, age, and marital status at the time of migration. 17 – 19 To reflect the uncertainty in our estimate, we assessed the effect of the TFR on the number of pregnancy in non-German women in two ways: First, we used a simple ratio between the share of births from non-German mothers and the share of non-German women of childbearing age. This approach assumes a homogeneous fertility behaviour among all non-German nationalities. As this assumption is unrealistic, we adjusted the results by using a country-specific fertility rate weighting in the second approach. Here we added a multiplier calculated by dividing the TFR of a country by the median of all TFRs reported for all countries-of-origin of all foreign women living in Germany (supplementary material: applied equations). This approach is expected to reflect the heterogeneity of fertility behaviour between nationalities more accurately, as we assume that women from countries with higher TFRs are likely to have a higher number of children and vice versa. For carrier frequencies of haemoglobinopathies, we used the published estimates by Modell and Darlison as a reference (supplementary material: data sources). We included data on carrier frequencies among pregnancies by country-of-origin for two categories: all variants and only significant haemoglobin variants, where the coexistence of α- and β-globin variants is allowed. Significant haemoglobin variants represent genetic changes that can cause severe clinical phenotypes in homozygosity and compound heterozygosity, which include haemoglobin S, -C, -E, -D, β-thalassaemia, and α 0 -thalassaemia. No measures of uncertainty were available for any of the datasets used. By combining the carrier frequencies with the two approaches described above for the probability of pregnancy in non-German women of childbearing age, we estimated the number of those at risk for carrying a haemoglobinopathy. We stratified the results by including or excluding the country-specific fertility rate weighting (results in figures are indicated as “(cw)”: country-weighted fertility rate) for both abovementioned categories. Figure 1 illustrates data collection and processing. Results Our analysis revealed a significant increase in the share of births by non-German mothers along with a substantial increase in the proportion of non-German women of childbearing age. On average, mothers lacking German heritage had about 32% more children than German nationals during the period analysed (supplementary table S1 ). These averages varied considerably between German federal states, highlighting the different fertility patterns within the non-German population (supplementary tables S2-17). Our analysis indicates an increased proportion of pregnancies at risk of carrying a haemoglobinopathy in all federal states up to over 500%. The dominant increase was between 2014 and 2016, coinciding with the large influx of refugees into Germany mainly from Middle Eastern, Central Asian, and African countries (Figs. 2 – 3 , supplementary tables S2-17). 20 To highlight the clinical relevance, we stratified our results into carriers of significant and any haemoglobin variants and used different fertility rate weighting approaches to demonstrate the local evolution of significant haemoglobin variant carriers (supplementary material: applied equations). Bremen, Hamburg, Berlin, and Hesse had the highest estimated proportions in 2024, whereas federal states in East Germany: Saxony, Saxony-Anhalt, Brandenburg, and Thuringia, experienced the strongest increase in the estimated proportions of pregnancies at risk of carrying a haemoglobinopathy between 2010 and 2024 (Figs. 3 – 4 , supplementary tables S18-20). In conclusion, our analysis indicates a strong development to the proportion of mothers at risk for carrying a haemoglobinopathy in the current population of Germany, with a high degree of regional heterogeneity across all German federal states. Discussion According to the micro-census in 2024, 30.4% (= 25,164,000) of the population living in Germany were individuals with a migration background. 21 More than half of these individuals (51.7%) were German nationals, with or without migration experience. Among the main countries-of-origin, of all individuals with a migration background, were Turkey (12%), Syria (4,9%), Romania (4,4%) and Italy (3,4%; supplementary table S21). Given the significantly higher carrier rates for haemoglobinopathies in pregnancies reported in these countries (2.1%, 6.0%, 1.0%, and 3.5% for significant variants respectively; supplementary tables S1-17) compared to Germany (0.54%), our results likely underestimate the proportion of pregnancies at risk, particularly by excluding German women with a migration background defined as natives in available statistical data. Despite this, we expect a 104% increase in the proportion of pregnancies at risk of carrying haemoglobinopathy with significant variants at national level between 2010 and 2024. An estimated annual increase of 0.04% arose, mainly due to mutations affecting the beta-globin chain (supplementary table S22). Comparing our results with data from regional pilot studies of the universal newborn screening for SCD in Germany from 2011 to 2019, we observed similar results (supplementary table S23). In these studies, approximately one child in 250 (0.4%) was found to have a sickle cell trait, which suggests an average probability of haemoglobin S carriage of 0.2% for pregnant women in Germany. Our estimates closely align with these findings, showing an average haemoglobin S carrier frequency of 0.23% for the same period (Fig. 2 ). Furthermore, our current findings are consistent with a previous study in which we examined thalassaemia carriage probability in blood count data from 35,717 randomly selected pregnant women in Berlin between 2014 and 2020 (dissertation data Hakimeh). 22 Higher carrier rates calculated from blood count data underscore the relevance of carrier risk among German nationals, who were not included in our present analysis. Due to the elevated flow of migration to Germany, haemoglobin disorders are on the steady rise. Our findings highlight the need for targeted interventions to address the increasing carrier risk of haemoglobinopathies. As the estimated proportion of pregnancies at risk of carrying significant variants was at 1% or more in six federal states (Fig. 5 , supplementary table S24), a non-targeted prenatal screening including a blood smear and a haemoglobin analysis at least on regional level seems to be appropriate. These additional screenings would ensure comprehensive testing, reliable counselling, informed decision-making, and specialized care for pregnant women at risk in Germany. While regional and national policies are largely lacking, we see a high need for prospective studies to confirm our findings and to extend the current German maternity guidelines regarding the implementation of a screening algorithm for haemoglobin disorders in antenatal care in accordance with the World Health Organization’s prevention recommendations. 23 Since comparable carrier rates in other European countries with developed health care systems, such as the UK, Denmark, France and the Netherlands have prompted the establishment of national screening programmes, we see an urgent need for expansion of counselling services including multilingual and culturally competent education programmes, community involvement to support patient empowerment, healthcare professional education, and thematic research funding along with the expansion of testing offer and specialized care facilities. 7,12,13 Declarations Authors’ contributions: DH: designed the methodology, analysed and interpreted the data and principally wrote the manuscript; JLN: contributed to the development of the manuscript; DBH, MAD, LH, ASS, NN: discussed the results and contributed to manuscript finalisation; UG: performed regression analysis and discussed the methodology; CE and LO: discussed the methodology and results and contributed to the development of the manuscript. 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Title: “Personen mit Migrationshintergrund (i.w.S.) aus Hauptwohnsitzhaushalten: Deutschland, Jahre, Geschlecht, Geburtsland bzw. Geburtsland der Eltern”. Access date: 11.09.2025 Hakimeh D. Der Einfluss von Migration auf die Prävalenz der Thalassämie in einer Kohorte von Schwangeren in Berlin. Refubium: Charité - Universitätsmedizin Berlin; 2023. EXECUTIVE BOARD 118th Session (EB118/5), World Health Organization. Thalassaemia and other haemoglobinopathies. WHO 2006. Additional Declarations There is no duality of interest Supplementary Files Supplementarymaterial.docx Supplementary material Supplementarytables.xlsx Supplementary tables Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7935231","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":573184323,"identity":"607e9ad4-21e2-4245-ba6d-4e1867f2b82c","order_by":0,"name":"Dani 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07:56:21","extension":"html","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":63986,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7935231/v1/bb51b017f837c3d8eb5d4cb9.html"},{"id":100367671,"identity":"14f3edca-d449-4108-89fb-a7182d48ddff","added_by":"auto","created_at":"2026-01-16 07:57:13","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":730968,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart of data sources and processing\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7935231/v1/49e918d9a4a6df4bb5e993dd.png"},{"id":100366486,"identity":"d974c5df-6ed8-4d8a-88ac-99bac69ef1de","added_by":"auto","created_at":"2026-01-16 07:56:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1031653,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEstimated proportion of pregnancies at risk of carrying a haemoglobinopathy in Germany (2010-2024), considering only non-German women\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) Pregnancies at risk stratified for carriage of significant or any haemoglobin variants, with or without country-specific fertility rate weighting. \u003cem\u003eAll Var.\u003c/em\u003e: any haemoglobin variant; (\u003cem\u003ecw)\u003c/em\u003e: with country-specific fertility rate weighting; \u003cem\u003eSign. Var.\u003c/em\u003e: only significant haemoglobin variants.\u003c/p\u003e\n\u003cp\u003e(b) Estimated carriage risk of only significant haemoglobin variants with country-specific fertility rate weighting, stratified by most common significant haemoglobin trait variants (HbS-, β-thalassemia-, HbC- and HbE-trait).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7935231/v1/251a4e5bd8ac3002022ebe5f.png"},{"id":100134242,"identity":"5e960d35-624b-4d9d-a2bc-03eb7afbf5a9","added_by":"auto","created_at":"2026-01-13 10:32:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1189465,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEstimated proportion of pregnancies at risk of carrying a haemoglobinopathy in each state German (2010-2024), considering only non-German women\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePregnancies at risk stratified for carriage of significant or any haemoglobin variants, with or without country-specific fertility rate weighting. \u003cem\u003eAll Var.\u003c/em\u003e: any haemoglobin variant; (\u003cem\u003ecw)\u003c/em\u003e: with country-specific fertility rate weighting; \u003cem\u003eSign. Var.\u003c/em\u003e: only significant haemoglobin variants.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7935231/v1/5812cc7f260781a2fbbc0170.png"},{"id":100134233,"identity":"d95e4ec8-2229-4c92-a66e-c2c6798f73bf","added_by":"auto","created_at":"2026-01-13 10:32:34","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1054055,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChange in the estimated proportion of pregnancies at risk for carrying a haemoglobinopathy in each German state between 2010 and 2024, considering only non-German women:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA bar chart and a heat map show the increase in pregnancies at risk stratified for significant and any haemoglobin variants, with or without country-specific fertility rate weighting, ploted in barchart and a heat map. \u003cem\u003eAll Var.\u003c/em\u003e: any haemoglobin variant; (\u003cem\u003ecw)\u003c/em\u003e: with country-specific fertility rate weighting; \u003cem\u003eSign. Var.\u003c/em\u003e: only significant haemoglobin variants.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7935231/v1/e1f4530736d73648558fc953.png"},{"id":100134234,"identity":"e07c5a0c-1964-40d7-9404-e0025fc1a328","added_by":"auto","created_at":"2026-01-13 10:32:34","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":612538,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEstimated proportion of pregnancies at risk for carrying a haemoglobinopathy in each German state in 2024, considering only non-German women:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA bar chart and a heat map show the proportion of pregnancies at risk stratified for significant and any haemoglobin variants.\u003cem\u003e All Var.\u003c/em\u003e: any haemoglobin variant; (\u003cem\u003ecw)\u003c/em\u003e: with country-specific fertility rate weighting; \u003cem\u003eSign. Var.\u003c/em\u003e: only significant haemoglobin variants.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7935231/v1/3fdf5f31e19b834f51502af9.png"},{"id":100382464,"identity":"95722f42-1da2-489b-afdd-8585a9cbfb20","added_by":"auto","created_at":"2026-01-16 10:42:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5249937,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7935231/v1/7c484fda-1ca5-4511-bf0d-125e18be927d.pdf"},{"id":100134227,"identity":"6b24d2b8-8bb6-4f16-bc93-725538af0274","added_by":"auto","created_at":"2026-01-13 10:32:34","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":29646,"visible":true,"origin":"","legend":"Supplementary material","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-7935231/v1/01ee7a60b621301a61d14a65.docx"},{"id":100367896,"identity":"5529834a-937c-4331-b736-2400a76a2a6a","added_by":"auto","created_at":"2026-01-16 07:57:25","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":4772128,"visible":true,"origin":"","legend":"Supplementary tables","description":"","filename":"Supplementarytables.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7935231/v1/bb313726c5d975989fadec29.xlsx"}],"financialInterests":"There is no duality of interest","formattedTitle":"Demographic modelling of haemoglobinopathies incidence in Germany: A call for targeted public health policy responses","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHaemoglobinopathies, mainly represented by sickle cell disease (SCD) and thalassaemia syndromes, are among the most prevalent monogenic diseases worldwide, belonging to the global health challenges of the 21st century.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e As migration increases, high-income countries with low carrier frequencies, such as in Central and Northern Europe, still face difficulties in providing adequate care for affected individuals. This results from a lack of awareness, systematic data, and evidence-based management.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e These challenges lead to disparities and potential malpractice in patient care with serious consequences, inappropriate for developed healthcare systems.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eGermany is among some of the highest densely populated countries in Europe.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Over the recent decades, it has become the second most popular destination for international migrants and one of the top five host countries for refugees.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e According to available estimates, a relatively low proportion of the German population (0.36% to 0.48%) carry a haemoglobinopathy gene, which is most commonly identified in non-indigenous communities.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Due to the recent abrupt increase in immigration between 2014 and 2016, mostly from countries with high carrier frequencies for haemoglobinopathies, we expect the number of carriers in the current German population to be increasing.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e This demographic shift indicates an emerging risk of mutation transmission to next generations in the German population, influenced by additional factors including consanguinity, endogamy and fertility rates.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e This underscores the necessity for evaluating the imperative, feasibility, and timing of haemoglobinopathy carriage screening and the expansion of specialized counselling services within the German healthcare framework.\u003c/p\u003e \u003cp\u003eGermany\u0026rsquo;s introduction of a newborn screening programme for SCD in 2021 marked a pivotal stride in secondary prevention. In the first year, 137 out of 732,791 newborns (1:5349) were diagnosed with SCD, making it one of the most common diagnoses in the German newborn screening programme.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e However, with developing migration, the evolution of carrier frequencies cannot be predicted. This is burdened by two main factors: a lack of awareness among healthcare professionals and a lack of routine screening for heterozygosity.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e This absence, coupled with the clinical diversity of haemoglobinopathies, lead to an odyssey of incorrect and delayed diagnoses.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Screening for heterozygosity has proven its effectiveness in the management of haemoglobinopathies in many European (including the UK, Denmark, France, the Netherlands, Greece, and Italy) and non-European countries.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Adopting a similar strategy to address low awareness in Germany seems appropriate given its vastly diverse population and developed healthcare infrastructure. Available estimates indicate that 0.54% of pregnant women in Germany are carriers of at least one haemoglobin disorder.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Despite this, existing German maternity guidelines fall short of established recommendations for antenatal screening, which typically involves at least a full blood count.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Antenatal screening programmes facilitate informed decision-making and counselling for couples at risk, as well as specialized care for identified mothers with high-risk pregnancies, including those with SCD. In this perspective, we present and discuss key findings of our analysis, assessing the need for a customised pre- and antenatal screening algorithms for expecting mothers in Germany.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eIn the absence of data on pregnant nationalities in Germany we estimated the prevalence of pregnancies at risk of carrying a haemoglobinopathy using open access sources, including the German Federal Statistical Office database (GENESIS), Modell's haemoglobinopathologist's Almanac, and the World Bank database (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Assuming a low carrier frequency in the German population, we estimated the carriage risk only for non-German resident women to assess their contribution to the proportion of pregnancies at risk of carrying a haemoglobinopathy.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSince only limited information on the nationality of a pregnant woman is recorded during perinatal care in Germany (European nationalities are documented, otherwise only the continent-of-origin), it was not possible to analyse birth data directly by mother's country-of-origin. We therefore calculated the probability of pregnancy among different nationalities living in Germany using publicly available statistical data on the number of live births and the number of resident women of childbearing age by country-of-origin from the GENESIS database of the German Federal Statistical Office. Childbearing age was defined as between 15 and 50 years of age. The data were extracted by federal state and per year for the period 2010\u0026ndash;2024. (supplementary material: data sources)\u003c/p\u003e \u003cp\u003eAs the number of live births per woman, also known as total fertility rate (TFR), can vary widely between countries-of-origin, it was necessary to include it when estimating the risk of an inherited condition with high geographical variation in carrier frequency, such as haemoglobinopathies. Here we used the TFRs published by the World Bank for the year 2023 as a reference for all countries-of-origin included in our analysis (supplementary material: data sources). Existing data on Turkish migrants in Germany describe many factors that influence immigrants' fertility behaviour after arrival including length of stay in the country, age, and marital status at the time of migration.\u003csup\u003e\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e To reflect the uncertainty in our estimate, we assessed the effect of the TFR on the number of pregnancy in non-German women in two ways: First, we used a simple ratio between the share of births from non-German mothers and the share of non-German women of childbearing age. This approach assumes a homogeneous fertility behaviour among all non-German nationalities. As this assumption is unrealistic, we adjusted the results by using a country-specific fertility rate weighting in the second approach. Here we added a multiplier calculated by dividing the TFR of a country by the median of all TFRs reported for all countries-of-origin of all foreign women living in Germany (supplementary material: applied equations). This approach is expected to reflect the heterogeneity of fertility behaviour between nationalities more accurately, as we assume that women from countries with higher TFRs are likely to have a higher number of children and vice versa.\u003c/p\u003e \u003cp\u003eFor carrier frequencies of haemoglobinopathies, we used the published estimates by Modell and Darlison as a reference (supplementary material: data sources). We included data on carrier frequencies among pregnancies by country-of-origin for two categories: all variants and only significant haemoglobin variants, where the coexistence of α- and β-globin variants is allowed. Significant haemoglobin variants represent genetic changes that can cause severe clinical phenotypes in homozygosity and compound heterozygosity, which include haemoglobin S, -C, -E, -D, β-thalassaemia, and α\u003csup\u003e0\u003c/sup\u003e-thalassaemia. No measures of uncertainty were available for any of the datasets used. By combining the carrier frequencies with the two approaches described above for the probability of pregnancy in non-German women of childbearing age, we estimated the number of those at risk for carrying a haemoglobinopathy. We stratified the results by including or excluding the country-specific fertility rate weighting (results in figures are indicated as \u0026ldquo;(cw)\u0026rdquo;: country-weighted fertility rate) for both abovementioned categories. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates data collection and processing.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eOur analysis revealed a significant increase in the share of births by non-German mothers along with a substantial increase in the proportion of non-German women of childbearing age. On average, mothers lacking German heritage had about 32% more children than German nationals during the period analysed (supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). These averages varied considerably between German federal states, highlighting the different fertility patterns within the non-German population (supplementary tables S2-17). Our analysis indicates an increased proportion of pregnancies at risk of carrying a haemoglobinopathy in all federal states up to over 500%. The dominant increase was between 2014 and 2016, coinciding with the large influx of refugees into Germany mainly from Middle Eastern, Central Asian, and African countries (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, supplementary tables S2-17).\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e To highlight the clinical relevance, we stratified our results into carriers of significant and any haemoglobin variants and used different fertility rate weighting approaches to demonstrate the local evolution of significant haemoglobin variant carriers (supplementary material: applied equations). Bremen, Hamburg, Berlin, and Hesse had the highest estimated proportions in 2024, whereas federal states in East Germany: Saxony, Saxony-Anhalt, Brandenburg, and Thuringia, experienced the strongest increase in the estimated proportions of pregnancies at risk of carrying a haemoglobinopathy between 2010 and 2024 (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, supplementary tables S18-20). In conclusion, our analysis indicates a strong development to the proportion of mothers at risk for carrying a haemoglobinopathy in the current population of Germany, with a high degree of regional heterogeneity across all German federal states.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAccording to the micro-census in 2024, 30.4% (=\u0026thinsp;25,164,000) of the population living in Germany were individuals with a migration background.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e More than half of these individuals (51.7%) were German nationals, with or without migration experience. Among the main countries-of-origin, of all individuals with a migration background, were Turkey (12%), Syria (4,9%), Romania (4,4%) and Italy (3,4%; supplementary table S21). Given the significantly higher carrier rates for haemoglobinopathies in pregnancies reported in these countries (2.1%, 6.0%, 1.0%, and 3.5% for significant variants respectively; supplementary tables S1-17) compared to Germany (0.54%), our results likely underestimate the proportion of pregnancies at risk, particularly by excluding German women with a migration background defined as natives in available statistical data. Despite this, we expect a 104% increase in the proportion of pregnancies at risk of carrying haemoglobinopathy with significant variants at national level between 2010 and 2024. An estimated annual increase of 0.04% arose, mainly due to mutations affecting the beta-globin chain (supplementary table S22).\u003c/p\u003e \u003cp\u003eComparing our results with data from regional pilot studies of the universal newborn screening for SCD in Germany from 2011 to 2019, we observed similar results (supplementary table S23). In these studies, approximately one child in 250 (0.4%) was found to have a sickle cell trait, which suggests an average probability of haemoglobin S carriage of 0.2% for pregnant women in Germany. Our estimates closely align with these findings, showing an average haemoglobin S carrier frequency of 0.23% for the same period (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Furthermore, our current findings are consistent with a previous study in which we examined thalassaemia carriage probability in blood count data from 35,717 randomly selected pregnant women in Berlin between 2014 and 2020 (dissertation data Hakimeh).\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Higher carrier rates calculated from blood count data underscore the relevance of carrier risk among German nationals, who were not included in our present analysis.\u003c/p\u003e \u003cp\u003eDue to the elevated flow of migration to Germany, haemoglobin disorders are on the steady rise. Our findings highlight the need for targeted interventions to address the increasing carrier risk of haemoglobinopathies. As the estimated proportion of pregnancies at risk of carrying significant variants was at 1% or more in six federal states (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, supplementary table S24), a non-targeted prenatal screening including a blood smear and a haemoglobin analysis at least on regional level seems to be appropriate. These additional screenings would ensure comprehensive testing, reliable counselling, informed decision-making, and specialized care for pregnant women at risk in Germany.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWhile regional and national policies are largely lacking, we see a high need for prospective studies to confirm our findings and to extend the current German maternity guidelines regarding the implementation of a screening algorithm for haemoglobin disorders in antenatal care in accordance with the World Health Organization\u0026rsquo;s prevention recommendations.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e Since comparable carrier rates in other European countries with developed health care systems, such as the UK, Denmark, France and the Netherlands have prompted the establishment of national screening programmes, we see an urgent need for expansion of counselling services including multilingual and culturally competent education programmes, community involvement to support patient empowerment, healthcare professional education, and thematic research funding along with the expansion of testing offer and specialized care facilities. \u003csup\u003e7,12,13\u003c/sup\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cu\u003eAuthors\u0026rsquo; contributions:\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eDH: designed the methodology, analysed and interpreted the data and principally wrote the manuscript; JLN: contributed to the development of the manuscript; DBH, MAD, LH, ASS, NN: discussed the results and contributed to manuscript finalisation; UG: performed regression analysis and discussed the methodology; CE and LO: discussed the methodology and results and contributed to the development of the manuscript.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBrandon Michael Schultz has contributed to the improvement of the scientific language of this manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGBD 2021 Sickle Cell Disease Collaborators. Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000\u0026ndash;2021: a systematic analysis from the Global Burden of Disease Study 2021. The Lancet Haematology, 2023;10(8):e585\u0026ndash;e599.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood. 2010;115(22):4331\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThe Lancet Global Health Editorial. Homing in on haemoglobinopathies. Lancet Glob Health. 2022;10(1):e1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWebsite of Eurostat, an official website of the European Union, Luxembourg. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://ec.europa.eu/eurostat/web/interactive-publications/demography-2024\u003c/span\u003e\u003cspan address=\"https://ec.europa.eu/eurostat/web/interactive-publications/demography-2024\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. 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Access date: 11.09.2025\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOnline database of the German Federal Statistical Office (GENESIS): \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www-genesis.destatis.de/genesis/online\u003c/span\u003e\u003cspan address=\"https://www-genesis.destatis.de/genesis/online\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Table number: 12211-0202. Title: \u0026ldquo;Personen mit Migrationshintergrund (i.w.S.) aus Hauptwohnsitzhaushalten: Deutschland, Jahre, Geschlecht, Geburtsland bzw. Geburtsland der Eltern\u0026rdquo;. Access date: 11.09.2025\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHakimeh D. Der Einfluss von Migration auf die Pr\u0026auml;valenz der Thalass\u0026auml;mie in einer Kohorte von Schwangeren in Berlin. Refubium: Charit\u0026eacute; - Universit\u0026auml;tsmedizin Berlin; 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEXECUTIVE BOARD 118th Session (EB118/5), World Health Organization. Thalassaemia and other haemoglobinopathies. WHO 2006.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7935231/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7935231/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn recent years, Germany has become one of the most popular destinations for international migrants and refugees, mostly from countries with a high prevalence of haemoglobinopathies. The concurrent lack of awareness among healthcare professionals, of systematic data, and of targeted screening carry the risk of disparities in patient care. In this context, a change in public health policy is urgently needed. In this article, we argue for a tailored prenatal screening algorithm supported by an analysis of open-source data showing a significant increase in pregnancies at risk of carrying a haemoglobinopathy. We also advocate for multifaceted interventions including the expansion of counselling services, healthcare professional education, community engagement and dedicated research funding to establish a robust framework for the management of haemoglobinopathies in Germany.\u003c/p\u003e","manuscriptTitle":"Demographic modelling of haemoglobinopathies incidence in Germany: A call for targeted public health policy responses","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-13 10:32:29","doi":"10.21203/rs.3.rs-7935231/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e284938c-e704-4c12-9b54-f44ac360ffc9","owner":[],"postedDate":"January 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":60983457,"name":"Health sciences/Health care/Public health/Epidemiology"},{"id":60983458,"name":"Health sciences/Diseases/Haematological diseases/Anaemia"}],"tags":[],"updatedAt":"2026-01-13T10:32:29+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-13 10:32:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7935231","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7935231","identity":"rs-7935231","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}