Cost effectiveness of thiamine supplementation in pregnant and post-partum women to prevent infantile beriberi deaths in Northeast India

Cost effectiveness of thiamine supplementation in pregnant and post-partum women to prevent infantile beriberi deaths in Northeast India | 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 Research Article Cost effectiveness of thiamine supplementation in pregnant and post-partum women to prevent infantile beriberi deaths in Northeast India Carinthia Balabet Nengnong, Roshine Koshy, Thangmaism Bikram Singha, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7813280/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Thiamine deficiency can be fatal if untreated. Lack of affordable confirmatory tests contribute to preventable infant mortality from thiamine deficiency, otherwise known as beriberi. We calculated the potential cost-effectiveness of a thiamine supplementation program among pregnant and postpartum women to prevent infantile beriberi deaths in Northeast India. Methods A decision-tree model was constructed to estimate the lifetime costs and outcomes associated with implementing a 12-month thiamine supplementation program for pregnant and postpartum women, with a primary outcome of prevention of infantile deaths due to beriberi. The model was populated using both primary and secondary data sources including real world evidence from a secondary care hospital in a rural Northeast Indian setting. Results Results of the model indicate that a routine of 6 months antenatal and 6 months postnatal thiamine supplementation program via one multivitamin per day containing 10 milligrams of thiamine is likely to be highly cost effective with an incremental cost effectiveness ratio (ICER) of INR 2386 (USD 27.81 ) per life year saved at a WTP threshold of INR 1, 72,000 (USD 2004.84) (1 x GDP per capita). Conclusion These results indicate that a thiamine supplementation program among pregnant and postpartum women represents a highly cost-effective use of local resources by substantially reducing infantile morbidity and mortality rates associated with beriberi in the northeastern region of India. The study also provides an example of using locally available data in performing CEA in LMIC settings, where high quality cost and effectiveness data are often unavailable. thiamine supplementation cost effectiveness analysis intersectionality Northeast India Figures Figure 1 Figure 2 Introduction Thiamine, also known as vitamin B1, is an essential micronutrient that is metabolised to thiamine pyrophosphate (TPP), a coenzyme necessary for the metabolism of carbohydrates. It is crucial for the optimal functioning of the heart, skeletal muscles and the nervous system ( 1 ). It is water-soluble and primarily obtained from foods like whole grains, legumes, nuts, beef, and pork ( 1 , 2 ). Since the body cannot store large amounts of thiamine due to its short half-life, consistent dietary intake is necessary to maintain adequate levels ( 1 , 3 ). Thiamine deficiency can cause disorders affecting the nervous, cardiovascular, and gastrointestinal systems ( 1 ), and is potentially fatal if left untreated, especially in babies born to and breastfed by thiamine deficient mothers ( 4 , 5 ). The global prevalence of thiamine deficiency is poorly documented due to lack of data to establish definitive biochemical levels indicative of symptomatic thiamine deficiency ( 3 , 4 , 6 ). Thiamine deficiency is an issue of intersectionality and is deeply rooted in inequity, where it is primarily documented in pregnant and postpartum women, in poor households, or in high-risk isolated populations such as prisoners, refugee camps and in conflict settings where there is a poor dietary diversity and limited access to vitamin-rich foods ( 2 , 5 , 7 – 9 ). In high-income countries, wheat flour and cereals are often fortified with thiamine ( 3 ) and thiamine deficiency is thought to be rare and predominantly linked to alcoholism. In low- and middle-income countries (LMICs), thiamine fortification of foods is relatively rare and thiamine deficiency is often associated with culturally dictated dietary habits and undernutrition, particularly due to reliance on polished rice, which lacks thiamine ( 1 ). For example, infantile thiamine deficiency has been reported as endemic in Indian Kashmir ( 10 ) where customary postpartum dietary restrictions that dictate a diet of polished rice and chicken soup were found to contribute to thiamine deficiency in mothers and their exclusively breastfed infants ( 10 ). Thiamine deficiency cases have more recently been reported in the northeast region (NER) of India ( 11 – 13 ). Several suspected and confirmed cases of thiamine deficiency disorder have been documented in the three northeastern states of Assam, Mizoram and Tripura ( 11 – 13 ). Infants from low socio-economic backgrounds who were exclusively breastfed and later diagnosed with thiamine deficiency, known as infantile beriberi, were documented to have either died or developed serious illness in one cohort study ( 12 ). A micronutrient assessment study by the National Institute of Nutrition revealed that daily thiamine intake was significantly lower in the NER Indian states, including Manipur (0.5 mg), Meghalaya (0.57 mg), and Assam (0.66 mg) when compared to the national average of 1.15 mg ( 11 ). There is increasing concern among clinicians from rural areas in the NER that the prevalence of thiamine deficiency is rising ( 11 – 14 ), and the lack of reliable diagnostic tools to identify thiamine deficiency at the point of care presents a particular challenge to timely treatment intervention ( 11 ). In the absence of public policies to provide thiamine rich foods to those most vulnerable to thiamine deficiency, and the catastrophic outcomes in infants born to thiamine deficient mothers, this study was commissioned by the Department of Health Research, Ministry of Health & Family Welfare (MoHFW) of India to assess whether a publicly-subsidised thiamine supplementation program in pregnant and post-partum women would be a cost-effective public investment to reduce deaths caused by infantile beriberi. Methods A cost-effectiveness analysis (CEA) was conducted to assess the impact of thiamine supplementation among pregnant and postpartum women in the Northeast Region (NER) of India to reduce infantile beriberi and associated mortality. The study employed a decision-tree model to estimate lifetime costs and health outcomes of implementing a 12-month thiamine supplementation program (six months antenatal and six months postnatal) compared to no supplementation. The model was populated using primary and secondary data sources. A systematic review to evaluate the clinical efficacy of thiamine supplementation during pregnancy and postpartum for preventing infantile beriberi was conducted, however no data was available on the clinical and cost effectiveness of this type of supplementation. Further details from this review are available in a second publication (under review). In short, we identified published evidence from 16 studies in six LMICs to indicate that thiamine deficiency if left untreated resulted in infantile death, and that timely intervention with high dose thiamine injection could completely reverse any clinical symptoms within 24 hours. This provided important information to inform assumptions within our counterfactual, or ‘do nothing’ arm of the decision tree. To address data gaps in the published literature, real-world evidence from a discrete hospital-based dataset from one hospital in Northeast India was incorporated into the model, alongside estimates for additional parameters that were obtained from clinical expert interviews (supplementary file 2). Alongside hospital-based data, prevalence estimates (7.25%) from the sole published evidence available, a refugee cohort from Thailand (5), were also modelled to estimate cost effectiveness. Ethics approval and consent to participate Ethical approval for the study was obtained from the Indian Institute of Public Health Shillong–Institutional Ethics Committee (IIPHS-IEC) (Reference No: IIPHS-IEC/2021-22/056). The study adhered to the Indian Council of Medical Research (ICMR) National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, 2017. Written informed consent was obtained from all participating clinical experts prior to the interviews. Secondary data used in the analysis were anonymised and handled in accordance with ethical standards. Data Sources Table 2 illustrates the parameters and values used in the model. Published literature A systematic review of published literature was conducted and data relevant to the efficacy of thiamine supplementation in pregnant and lactating women was extracted to estimate averted cases and mortality parameters in the model. No studies were identified that reported on the efficacy of thiamine supplementation in comparison to no supplementation to prevent infantile beriberi and associated mortality. Due to this data gap, real world evidence from a local hospital-based data (described below) was used to populate key parameter values, as were clinical expert interviews. Expert Opinion interviews Clinicians who have experience in managing and documenting cases of thiamine deficiency at secondary care facilities located in four states of Northeast India (Assam, Meghalaya, Tripura, and Mizoram), were targeted for key informant interviews to inform model parameters for which no data were available or to inform clinical assumptions underpinning the model structure and/or parameter values. One facility in rural Assam was targeted based on its clinicians reporting a rise in confirmed cases of thiamine deficiency to the research team, the hospital maintained systematic records of maternal and infant cases that resulted in changes in their practice and their direct request to conduct further research into this area. The probability of survival for thiamine-deficient infants was conservatively set at 0.50. Clinical experts reported the condition was completely reversible if treated on time, however considering access to care and discrepancies in diagnosis, this likely represents a simplification of real-world experiences of beriberi survival and death in Northeast India. Survival was set at 50% to simultaneously account for low clinical suspicion of infantile beriberi and extremely high rates of mortality associated with this condition if untreated, balanced with high rates of survival in those cases that are detected early and treated with high dose, parenteral thiamine. Cohort data from a single hospital facility Data from a hospital cohort of 988 mothers who delivered at a secondary care hospital in the Northeastern Indian state of Assam was used to inform key prevalence parameter values in supplemented and unsupplemented arms of the model. The hospital data had information on the health outcomes of infants at birth, and survival at one year of age. The first group included 499 mothers who delivered at the hospital but did not attend routine Antenatal Care (ANC) at the facility nor receive thiamine supplementation intervention. The second group comprised 489 mothers who attended at least four ANC visits and were prescribed six months of a multi-B vitamin (Brand Name: Becosules) containing 10mg of thiamine during pregnancy and six months post-partum. Hospital data records from this cohort were used to inform the probability ratios of clinical endpoints in the decision tree model. All mothers and their infants were followed up for one year at the community level. No cases of beriberi nor infant deaths attributed to thiamine deficiency were reported in the supplemented mothers’ group. Among those who received no thiamine supplementation, four infant deaths within six months of birth were attributed to thiamine deficiency by verbal autopsy conducted by clinicians. Based on this data, the prevalence of beriberi was calculated to be 0.008. The prevalence estimates in supplemented and unsupplemented mothers were used to populate the probability values of each arm of the decision tree. To avoid division by zero in the model and account for the possibility of thiamine deficiency penetrance in supplemented mothers, the probability of thiamine deficient infants who were born to multivitamin supplemented mothers was set at 0.0001. The probability of thiamine deficient infants born to un-supplemented high-risk mothers was set at 0.008 in line with the Assam hospital data. Corresponding parameter probability values were set at p2 = (1-p1), where p2= probability of the corresponding arm of the decision tree and p1= the completed probability value. Table 2: Parameter values and corresponding data sources Parameters Values Source Probabilities (Prevalence rate of Thiamine def in infants) 0.008 Assam Hospital Data 2023 Duration of multi-B vitamin* supplements 6 months antenatal and 6 months postnatal Clinical experts Primary Outcome Life Years Gained (70.8 years) Life Expectancy at birth for the year (WHO) Mortality Rate 50% Clinical experts Willingness To Pay Threshold ₹172000 (USD1965.19) HTAIn Reference Case (One Time Gross Domestic Product of India, 2023) Time Horizon Lifetime HTAIn Reference Case Study Perspective Health System HTAIn Reference Case Cost data The cost data was sourced from various reliable databases and expert consultations. The National Health System Cost Database (NHSCD) provided the baseline costs. Table 3 outlines the specific cost parameters used. Unit costs of the Multi-B tablets that delivered the thiamine supplementation were obtained from India MART (15), the source of intervention procurement in the Assam hospital. Table 3: Cost parameters and values Cost Parameters used in the model Values Source Intervention Costs Unit Cost of one pack of 20 tablets (in INR (USD)) 43 (0.49) India MART Unit Cost of ANC Visit (in INR(in INR (USD)) 403 (4.60) NHSCD Number of Multi-B packs required for intervention 12 Assam Hospital Data Number of ANC visits required for intervention 4 Assam Hospital Data Total cost of intervention (in INR) 2128(24.31) - Standard of Care costs Unit cost ANC visit (in INR) 403(4.60) NHSCD Number of ANC visits assumed for standard of care 3 Clinical Expert Total costs of standard of care (in INR) (0.053) Costs per thiamine deficient case Unit cost of OPD for beriberi presentation (in INR) 403 (4.60) NHSCD Unit cost intensive thiamine treatment (in INR) 360 (4.11) NHSCD Unit cost NICU Admission Charges per day (in INR) 5109 (58.37) NHSCD Unit cost Discharge Medicine for Home Management (in INR) 360 (4.11) NHSCD Unit cost follow-up appointment (in INR) 403 (4.60) NHSCD Number of OPD visits per case 1 Clinical Experts Number of intensive treatment courses per thiamine case 1 Clinical Experts Average number of days in NICU per case 7 Clinical Experts Number of follow-up appointments per case 2 Clinical Experts Total cost per case of thiamine deficient infant (in INR) 37692 (430.65) - The Decision Tree Model A decision tree model (Figure 1) was developed to measure the incremental cost-effectiveness ratio of thiamine supplementation as an intervention to prevent infantile thiamine deficiency and related mortality. The decision tree model was initially constructed in Microsoft Excel and later imported into TreeAge software to assess the costs and outcomes of the two treatment strategies: thiamine supplementation (10mg thiamine daily for 12 months) and no supplementation. The first chance node in the tree illustrates two alternate pathways -Thiamine supplementation and no thiamine supplementation. These two pathways are further divided into thiamine deficient infants and healthy infants for both supplemented and un-supplemented arms. Terminal nodes (i.e. endpoints of the model) are infantile survival in full health and death Outcome Measures The primary outcome measure was defined as life years saved, calculated from a baseline of the average life expectancy of a healthy person in India, 70.8 years as per 2019 estimates from the World Health Organization (WHO). This metric allows for a clear comparison between the expected lifespan of a healthy individual and the actual lifespan achieved through the intervention, highlighting the impact on longevity. Base-Case Analysis Based on best practice guidelines set by the WHO and the HTAIn reference case, one-time gross domestic product per capita of India (2023) which is INR 172,000 was used as the cost-effectiveness willingness to pay (WTP) threshold. An incremental cost effectiveness ratio (ICER) below the WTP threshold was considered cost-effective. A health system costing perspective was adopted, and a lifetime horizon was considered for the study. Key Assumptions of the model Full adherence to the daily thiamine supplement regimen was assumed, based on adherence rates reported in the Assam hospital data. Slightly higher ANC attendance in the supplementation arm was also assumed wherein the routine care in this arm was structured to include 4 ANC visits per pregnant woman, as observed in the pregnancy cohort. The usual care arm was structured to incorporate 3 ANC visits, as was found to be standard among those availing ANC through the Meghalaya Health Insurance Scheme (16). An assumption was made that any infant who developed beriberi would do so in the first 6 months of life as is reported in the literature (2) and verified by the clinicians interviewed. Those infants who develop beriberi were assumed to be treated and survive in full health with no lasting morbidity, as clinical experts informed was the case, or to die of complications directly associated with this deficiency. To adequately capture cost per case of beriberi in this model, each case is costed from the health system perspective where outpatient assessment, inpatient admission, high-dose thiamine treatment administration, and follow-up care is provided. Results Expert opinion interviews The clinical expert interviews highlighted that despite the efficacy of thiamine treatment in deficient states, the low index of suspicion among clinicians of thiamine deficiency disorders contributes to high case fatality due to delayed diagnosis and initiation of treatment. Clinicians working in rural areas observed that infants with beriberi presenting with cardiac and neurological symptoms had 100% case fatality if left untreated. Along with affected infants, hospitals also documented peripartum women with features of both peripheral neuropathy and cardiac failure showing remarkable improvement with parenteral thiamine supplementation. Diagnosis of all thiamine deficiency disorders was cited as challenging due to the lack of affordable tests, often prompting empirical thiamine administration as a diagnostic measure. Contributing factors to thiamine deficiency were cited to include low socio-economic status and poor dietary diversity. Cost Effectiveness Analysis The results from the base case analysis indicates that an intervention involving six months of antenatal and six months of postnatal thiamine supplementation, administered via a daily multivitamin containing 10mg of thiamine, is likely to be highly cost-effective. The Incremental Cost-Effectiveness Ratio (ICER) was calculated at INR 2386 (USD 27.81) per life year saved. This can be considered highly cost-effective using a Willingness to Pay (WTP) threshold of INR 172,000 (USD 2004.84) (equivalent to 1 x GDP per capita of India in 2023), which is in line with best practice guidelines from WHO and HTAIn. The base case results are detailed in Table 4 and represented in the cost-effectiveness plane in Figure 2. Table 4: Results of the Base Case Analysis Intervention Cost Incre. Cost Effectiveness Incremental Effectiveness ICER No Supplementation 1510.5 70.52 Thiamine Supplementation 2174.7 664.2 70.80 0.278 2386.119 Sensitivity Analysis One Way Deterministic Sensitivity Analysis (OWSA) was used to check the robustness of the model findings under different cost and baseline prevalence or ‘untreated’ conditions. The cost of the supplementation regimen was inflated by 10 times the current value and remained highly cost-effective under the HTA India-recommended WTP threshold, with an ICER of INR 72580 (USD 846) per life year gained. A shift in the baseline prevalence value to 7.25% in the untreated arm based on published literature from Thailand (5) resulted in an ICER value of INR 117 (USD 1.36) per life-year gained. Discussion This study aimed to assess the incremental cost-effectiveness of thiamine supplementation as compared to the standard of care for pregnant and postpartum women in preventing infantile beriberi. A mix of methods including a systematic review (ref in press), clinical expert opinions, and cost-effectiveness analysis, was used to model the lifetime costs and outcomes of a 12-month thiamine supplementation programme in the Northeast Region (NER) of India. The findings suggest that thiamine supplementation is likely to be a highly cost-effective strategy for preventing beriberi and associated deaths, with an ICER of INR 2386 (USD 27.81) per life year saved at a WTP threshold of INR 1,72,000 (USD 2004.84). This research sought to provide evidence for policy decision-making for a problem that was identified locally by clinicians. They had often changed their own prescription patterns to include supplementation but articulated the need to support the implementation of the same for pregnant and postpartum women across the NER of India, to address immediate health needs and promote long-term public health benefits for women and their babies in the wider population. After exposing a lack of peer-reviewed literature to support the parameterization of our decision tree model, we adopted a mix of methods to answer this important public health question. In the expert interviews, the clinicians we interviewed spoke about the clinical manifestations of beriberi that they encounter, highlighting the severity and rapid progression of infantile cardiac beriberi as a cause for major concern. Clinicians reported that the window from the onset of symptoms to severe complications can be very short, leading to rapid deterioration and mortality if left untreated. This aligns with other case studies on cardiac beriberi, which report rapid deterioration and high rates of mortality(5,11–13). Clinicians proposed low clinical suspicion and absence of a point of care test impeding timely diagnosis in addition to the lack of community awareness as explanatory factors for mortality related to the disease. Clinicians also reported the dramatic and rapid response to thiamine treatment in clinically suspected cases, a finding corroborated by numerous studies conducted in Northeast India involving both women and children (13,14). Infantile beriberi can often present with pneumonia-like respiratory symptoms (but is usually afebrile), which is noteworthy as pneumonia is an oft documented cause of infant deaths in the 2-6 months age group. Thiamine deficiency is an issue of intersectionality, with strong correlation to socioeconomic status, dietary practices, and cultural and religious practices in pregnancy and postpartum. In northwestern Thailand, high rates of infantile beriberi were documented in a socially disadvantaged group of refugees belonging to the Karen ethnic minority (5). The symptoms reported by clinicians interviewed in the current study as being observed in affected infants, like their age group and response to treatment, were similar to those documented in the Karen refugee population (5). Dietary practices also overlapped, for example, the polished rice consumed by the Karen refugees in relief camps was similar to that provided through the Public Distribution System in rural northeast India. In addition, the consumption of known anti-thiamine factors such as fermented fish, betel nut and tea leaves (17), were found in both contexts. Secondary to location, ethnicity or income, populations affected by micronutrient deficiencies are often marginalised groups in society, illustrating the role of socioeconomic disadvantage in shaping nutritional vulnerability (18). These parallels in dietary patterns and symptomatology, despite differences in time and geography, favour adapting the prevalence estimates from the Karen refugee study in constructing the additional cost-effectiveness model. Those populations on the margins of society are known to have particularly high prevalence of thiamine deficiency. This is likely one of the drivers of high rates of thiamine deficiency in the NER of India in particular, where refugees and tribal groups make up 27.7% of the total population in the country and 85% % percent of in NER (19). Thiamine-related infant mortality was reported to be as high as 7.25% in the Karen refugee population in Thailand (5). This is nine times higher than the estimated probability in the NER used in the model gained from the sample of 489 women in Assam that accessed antenatal care in public health facilities. When using the Thailand estimate within our deterministic sensitivity analysis, the ICER came down to INR 258.79 (USD2.96) per life-year gained, indicating the ICER to be sensitive to underlying prevalence and therefore overarching life years to be gained from prevention of thiamine deficiency. Considering the higher number of infant deaths reported before thiamine supplementation in the North East Indian state of Mizoram (12) along with the figures for thiamine deficiency detected across different age groups in the Assam hospital (see Supplementary Data), and a very high prevalence of thiamine deficiency of 33-34% in pregnant and lactating women documented in a recent study in the region by the National Institute of Nutrition (20), we suspect that the prevalence estimate used in this study is likely to be a gross underestimate and therefore that the true ICER value is far lower than the base case estimate. As diet is the primary source of thiamine, particular attention should be paid to nutritional practices and accessibility of nutrient rich food. Across various studies conducted in India, particularly in the Northeast region, a common dietary pattern has emerged in the literature relation to thiamine deficiency, characterised by the consumption of polished rice, fermented fish, and tea (14). Similarly, research conducted in Laos also identified a similar dietary pattern, where the intake of fermented fish, tea, and betel nut served as contributory factors for beriberi (21). Similar evidence is also reported from Kashmir, where the predominantly Muslim community adhere to specific dietary restrictions (particularly during pregnancy) and a higher consumption of staple polished white rice and tea (22,23). The lack of accessible, affordable diagnostic tests is a significant challenge in detecting and managing beriberi. To address this issue, the World Health Organisation (WHO) recommends adopting clinical criteria for diagnosis in settings where diagnostic tests are unavailable (2). This approach is similar to practices adopted by health facilities in low-resource settings across Asia, where the administration of thiamine serves as a crucial method to identify suspected cases of thiamine deficiency (10–13,22). In our analysis, a regimen of six months antenatal and six months postnatal thiamine supplementation of one multi-B vitamin containing 10mg of thiamine per day was found to be highly cost-effective use of local resources. This finding is consistent with another study on multiple micronutrient supplementation instead of only iron and folic acid in three high-burden Asian countries including India , which demonstrated cost-effectiveness at approximately INR 2,638 (USD 30.75) per DALY averted (24). To our knowledge, this economic evaluation is one of the first studies to demonstrate the cost-effectiveness of a supplementation intervention for thiamine deficiency. This study illustrates how a mix of methods incorporating locally available data can supplement quantitative and qualitative findings to strengthen the understanding of thiamine deficiency and infant mortality in India. The main limitation of this study is that there was a dearth of published data in relation to population prevalence of thiamine deficiency and associated probability of death in infants due to thiamine deficiency. In the absence of this important data, all available published and unpublished local data along with clinical expert opinions were used to inform a number of parameter values. This form of data, while not ideal, also presents a case for how available data could be used especially in LMIC settings for conducting studies that have potential policy implications. While a real-world longitudinal trial of thiamine supplementation is desirable to monitor and evaluate its effectiveness, this study provides evidence in the interim for working towards eliminating beriberi in infants and their mothers in the NER and across India. Conclusion and recommendations The results of this study demonstrate that a regimen of six months antenatal and six months postnatal thiamine supplementation, providing 10 mg of thiamine daily through a multi-B vitamin, is highly cost-effective, with an ICER of INR 2386 (USD 27.81) per life year saved at a WTP threshold of INR 1,72,000 (USD 2004.84). The findings provide policy recommendations for investment in a thiamine supplementation programme for pregnant and lactating mothers in Northeast India, to be integrated into routine antenatal care provided through the public health system. Investment in this intervention has the potential to save thousands of infants and mother’s lives across the region, representing a highly cost-effective use of local resources for health. Declarations Contributors CBN lead the study and drafted the manuscript. TJ, RK, BSK served as clinical experts and supported in manuscript development. TBS supported the systematic review and analysis. SA and LD contributed to the study design, analysis, and manuscript drafting. All authors reviewed and approved the final version of the manuscript. Conflict of Interest The authors report no conflicts of interest. Funding The study was funded by the Department of Health Research (DHR), Ministry of Health and Family Welfare, Government of India References Martel JL, Kerndt CC, Doshi H, Franklin DS. Vitamin B1 (Thiamine). StatPearls Publishing; 2023. World Health Organisation. Thiamine deficiency and its prevention and control in major emergencies [Internet]. 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Shoshin beriberi-thiamine responsive pulmonary hypertension in exclusively breastfed infants: A study from northern India. Indian Heart J. 2017 Jan;69(1):24–7. Kareem O, Mufti S, Nisar S, Tanvir M, Muzaffer U, Ali N, et al. Prevalence of Thiamine Deficiency in Pregnancy and its impact on fetal outcome in an area endemic for thiamine deficiency. Tickell KD, editor. PLoS Negl Trop Dis. 2023 May 30;17(5):e0011324. Kashi B, M Godin C, Kurzawa ZA, Verney AM, Busch-Hallen JF, De-Regil LM. Multiple Micronutrient Supplements Are More Cost-effective Than Iron and Folic Acid: Modeling Results from 3 High-Burden Asian Countries. J Nutr. 2019 Jul;149(7):1222–9. Additional Declarations No competing interests reported. Supplementary Files SupplementaryFile1ThiamineDeficiencyinKarmganjDistrict.docx SupplementaryFile2InterviewGuideclinicalExperts.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 13 Nov, 2025 Editor assigned by journal 11 Nov, 2025 Editor invited by journal 16 Oct, 2025 Submission checks completed at journal 16 Oct, 2025 First submitted to journal 16 Oct, 2025 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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1","display":"","copyAsset":false,"role":"figure","size":175612,"visible":true,"origin":"","legend":"\u003cp\u003eDecision Tree Model for Cost Effectiveness of Thiamine Supplementation in Preventing Infantile Beriberi\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7813280/v1/1413c694ea3d7534c54caa22.png"},{"id":96917596,"identity":"5f37993a-e269-4f92-9fa7-cac89bbc1a80","added_by":"auto","created_at":"2025-11-27 14:10:11","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":146033,"visible":true,"origin":"","legend":"\u003cp\u003eCost-effectiveness plane illustrating the results of the thiamine supplementation intervention as a cost-effective measure\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7813280/v1/0e4e2a80d4f891d9bb70a280.png"},{"id":97135463,"identity":"c70e531c-e8c8-45ba-bc01-d55f413beffc","added_by":"auto","created_at":"2025-12-01 09:47:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":955295,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7813280/v1/7c0625a4-df75-49f4-8d81-74930d828b9d.pdf"},{"id":96789749,"identity":"334cf1d7-ec28-45ff-b530-5ab65d8a3ab3","added_by":"auto","created_at":"2025-11-26 06:44:49","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":16920,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFile1ThiamineDeficiencyinKarmganjDistrict.docx","url":"https://assets-eu.researchsquare.com/files/rs-7813280/v1/4ed50460b8e857e1f81fd25e.docx"},{"id":96789751,"identity":"31afacd9-ade0-4528-a5bd-cd155eb45d92","added_by":"auto","created_at":"2025-11-26 06:44:49","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":39413,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFile2InterviewGuideclinicalExperts.docx","url":"https://assets-eu.researchsquare.com/files/rs-7813280/v1/dd1322f2e2c9946c6bb5c507.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cost effectiveness of thiamine supplementation in pregnant and post-partum women to prevent infantile beriberi deaths in Northeast India","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThiamine, also known as vitamin B1, is an essential micronutrient that is metabolised to thiamine pyrophosphate (TPP), a coenzyme necessary for the metabolism of carbohydrates. It is crucial for the optimal functioning of the heart, skeletal muscles and the nervous system (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). It is water-soluble and primarily obtained from foods like whole grains, legumes, nuts, beef, and pork (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Since the body cannot store large amounts of thiamine due to its short half-life, consistent dietary intake is necessary to maintain adequate levels (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Thiamine deficiency can cause disorders affecting the nervous, cardiovascular, and gastrointestinal systems (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), and is potentially fatal if left untreated, especially in babies born to and breastfed by thiamine deficient mothers (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe global prevalence of thiamine deficiency is poorly documented due to lack of data to establish definitive biochemical levels indicative of symptomatic thiamine deficiency (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Thiamine deficiency is an issue of intersectionality and is deeply rooted in inequity, where it is primarily documented in pregnant and postpartum women, in poor households, or in high-risk isolated populations such as prisoners, refugee camps and in conflict settings where there is a poor dietary diversity and limited access to vitamin-rich foods (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn high-income countries, wheat flour and cereals are often fortified with thiamine (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) and thiamine deficiency is thought to be rare and predominantly linked to alcoholism. In low- and middle-income countries (LMICs), thiamine fortification of foods is relatively rare and thiamine deficiency is often associated with culturally dictated dietary habits and undernutrition, particularly due to reliance on polished rice, which lacks thiamine (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). For example, infantile thiamine deficiency has been reported as endemic in Indian Kashmir (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) where customary postpartum dietary restrictions that dictate a diet of polished rice and chicken soup were found to contribute to thiamine deficiency in mothers and their exclusively breastfed infants (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThiamine deficiency cases have more recently been reported in the northeast region (NER) of India (\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Several suspected and confirmed cases of thiamine deficiency disorder have been documented in the three northeastern states of Assam, Mizoram and Tripura (\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Infants from low socio-economic backgrounds who were exclusively breastfed and later diagnosed with thiamine deficiency, known as infantile beriberi, were documented to have either died or developed serious illness in one cohort study (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). A micronutrient assessment study by the National Institute of Nutrition revealed that daily thiamine intake was significantly lower in the NER Indian states, including Manipur (0.5 mg), Meghalaya (0.57 mg), and Assam (0.66 mg) when compared to the national average of 1.15 mg (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThere is increasing concern among clinicians from rural areas in the NER that the prevalence of thiamine deficiency is rising (\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), and the lack of reliable diagnostic tools to identify thiamine deficiency at the point of care presents a particular challenge to timely treatment intervention (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). In the absence of public policies to provide thiamine rich foods to those most vulnerable to thiamine deficiency, and the catastrophic outcomes in infants born to thiamine deficient mothers, this study was commissioned by the Department of Health Research, Ministry of Health \u0026amp; Family Welfare (MoHFW) of India to assess whether a publicly-subsidised thiamine supplementation program in pregnant and post-partum women would be a cost-effective public investment to reduce deaths caused by infantile beriberi.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eA cost-effectiveness analysis (CEA) was conducted to assess the impact of thiamine supplementation among pregnant and postpartum women in the Northeast Region (NER) of India to reduce infantile beriberi and associated mortality. The study employed a decision-tree model to estimate lifetime costs and health outcomes of implementing a 12-month thiamine supplementation program (six months antenatal and six months postnatal) compared to no supplementation.\u003c/p\u003e\n\u003cp\u003eThe model was populated using primary and secondary data sources. A systematic review to evaluate the clinical efficacy of thiamine supplementation during pregnancy and postpartum for preventing infantile beriberi was conducted, however no data was available on the clinical and cost effectiveness of this type of supplementation. Further details from this review are available in a second publication (under review). In short, we identified published evidence from 16 studies in six LMICs to indicate that thiamine deficiency if left untreated resulted in infantile death, and that timely intervention with high dose thiamine injection could completely reverse any clinical symptoms within 24 hours. This provided important information to inform assumptions within our counterfactual, or \u0026lsquo;do nothing\u0026rsquo; arm of the decision tree. \u0026nbsp;To address data gaps in the published literature, real-world evidence from a discrete hospital-based dataset from one hospital in Northeast India was incorporated into the model, alongside estimates for additional parameters that were obtained from clinical expert interviews (supplementary file 2). Alongside hospital-based data, prevalence estimates (7.25%) from the sole published evidence available, a refugee cohort from Thailand (5), were also modelled to estimate cost effectiveness.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval for the study was obtained from the Indian Institute of Public Health Shillong\u0026ndash;Institutional Ethics Committee (IIPHS-IEC) (Reference No: IIPHS-IEC/2021-22/056). The study adhered to the Indian Council of Medical Research (ICMR) National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, 2017. Written informed consent was obtained from all participating clinical experts prior to the interviews. Secondary data used in the analysis were anonymised and handled in accordance with ethical standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 2 illustrates the parameters and values used in the model.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublished literature\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA systematic review of published literature was conducted and data relevant to the efficacy of thiamine supplementation in pregnant and lactating women was extracted to estimate averted cases and mortality parameters in the model. No studies were identified that reported on the efficacy of thiamine supplementation in comparison to no supplementation to prevent infantile beriberi and associated mortality. Due to this data gap, real world evidence from a local hospital-based data (described below) was used to populate key parameter values, as were clinical expert interviews.\u0026nbsp;\u003c/p\u003e\u003ch2\u003eExpert Opinion interviews\u003c/h2\u003e\n\u003cp\u003e\u0026nbsp;Clinicians who have experience in managing and documenting cases of thiamine deficiency at secondary care facilities located in four states of Northeast India (Assam, Meghalaya, Tripura, and Mizoram), were targeted for key informant interviews to inform model parameters for which no data were available or to inform clinical assumptions underpinning the model structure and/or parameter values. One facility in rural Assam was targeted based on its clinicians reporting a rise in confirmed cases of thiamine deficiency to the research team, the hospital maintained systematic records of maternal and infant cases that resulted in changes in their practice and their direct request to conduct further research into this area.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe probability of survival for thiamine-deficient infants was conservatively set at 0.50. Clinical experts reported the condition was completely reversible if treated on time, however considering access to care and discrepancies in diagnosis, this likely represents a simplification of real-world experiences of beriberi survival and death in Northeast India. Survival was set at 50% to simultaneously account for low clinical suspicion of infantile beriberi and extremely high rates of mortality associated with this condition if untreated, balanced with high rates of survival in those cases that are detected early and treated with high dose, parenteral thiamine.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCohort data from a single hospital facility\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData from a hospital cohort of 988 mothers who delivered at a secondary care hospital in the Northeastern Indian state of Assam was used to inform key prevalence parameter values in supplemented and unsupplemented arms of the model. The hospital data had information on the health outcomes of infants at birth, and survival at one year of age. The first group included 499 mothers who delivered at the hospital but did not attend routine Antenatal Care (ANC) at the facility nor receive thiamine supplementation intervention. The second group comprised 489 mothers who attended at least four ANC visits and were prescribed six months of a multi-B vitamin (Brand Name: Becosules) containing 10mg of thiamine during pregnancy and six months post-partum. Hospital data records from this cohort were used to inform the probability ratios of clinical endpoints in the decision tree model.\u003c/p\u003e\n\u003cp\u003eAll mothers and their infants were followed up for one year at the community level. No cases of beriberi nor infant deaths attributed to thiamine deficiency were reported in the supplemented mothers\u0026rsquo; group. Among those who received no thiamine supplementation, four infant deaths within six months of birth were attributed to thiamine deficiency by verbal autopsy conducted by clinicians. Based on this data, the prevalence of beriberi was calculated to be 0.008. The prevalence estimates in supplemented and unsupplemented mothers were used to populate the probability values of each arm of the decision tree. To avoid division by zero in the model and account for the possibility of thiamine deficiency penetrance in supplemented mothers, the probability of thiamine deficient infants who were born to multivitamin supplemented mothers was set at 0.0001. The probability of thiamine deficient infants born to un-supplemented high-risk mothers was set at 0.008 in line with the Assam hospital data. Corresponding parameter probability values were set at p2 = (1-p1), where p2= probability of the corresponding arm of the decision tree and p1= the completed probability value.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2: Parameter values and corresponding data sources\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eParameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eValues\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSource\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eProbabilities (Prevalence rate of Thiamine def in infants)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e0.008\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eAssam Hospital Data 2023\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eDuration of multi-B vitamin* supplements\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e6 months antenatal and 6 months postnatal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eClinical experts\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003ePrimary Outcome\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003eLife Years Gained (70.8 years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eLife Expectancy at birth for the year (WHO)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eMortality Rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eClinical experts\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eWillingness To Pay Threshold\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e₹172000 (USD1965.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eHTAIn Reference Case (One Time Gross Domestic Product of India, 2023)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eTime Horizon\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003eLifetime\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eHTAIn Reference Case\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eStudy Perspective\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003eHealth System\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eHTAIn Reference Case\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eCost data\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe cost data was sourced from various reliable databases and expert consultations. The National Health System Cost Database (NHSCD) provided the baseline costs. Table 3 outlines the specific cost parameters used. Unit costs of the Multi-B tablets that delivered the thiamine supplementation were obtained from India MART (15), the source of intervention procurement in the Assam hospital.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3: Cost parameters and values\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCost Parameters used in the model\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eValues\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSource\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eIntervention Costs\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eUnit Cost of one pack of 20 tablets (in INR (USD))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e43 (0.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003eIndia MART\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eUnit Cost of ANC Visit (in INR(in INR (USD))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e403 (4.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003eNHSCD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eNumber of Multi-B packs required for intervention\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e12\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003eAssam Hospital Data\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eNumber of ANC visits required for intervention\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003eAssam Hospital Data\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eTotal cost of intervention (in INR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e2128(24.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e-\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eStandard of Care costs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eUnit cost ANC visit (in INR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e403(4.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003eNHSCD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eNumber of ANC visits assumed for standard of care\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003eClinical Expert\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eTotal costs of standard of care (in INR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003col start=\"1209\"\u003e\n \u003cli\u003e(0.053)\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"10\" valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eCosts per thiamine deficient case\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eUnit cost of OPD for beriberi presentation (in INR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e403 (4.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003eNHSCD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eUnit cost intensive thiamine treatment (in INR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e360 (4.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003eNHSCD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eUnit cost NICU Admission Charges per day (in INR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e5109 (58.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003eNHSCD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eUnit cost Discharge Medicine for Home Management (in INR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e360 (4.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003eNHSCD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eUnit cost follow-up appointment (in INR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e403 (4.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003eNHSCD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eNumber of OPD visits per case\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003eClinical Experts\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eNumber of intensive treatment courses per thiamine case\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003eClinical Experts\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eAverage number of days in NICU per case\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e7\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003eClinical Experts\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eNumber of follow-up appointments per case\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e2\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003eClinical Experts\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eTotal cost per case of thiamine deficient infant (in INR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e37692 (430.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e-\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eThe Decision Tree Model\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA decision tree model (Figure 1) was developed to measure the incremental cost-effectiveness ratio of thiamine supplementation as an intervention to prevent infantile thiamine deficiency and related mortality. The decision tree model was initially constructed in Microsoft Excel and later imported into TreeAge software to assess the costs and outcomes of the two treatment strategies: thiamine supplementation (10mg thiamine daily for 12 months) and no supplementation. The first chance node in the tree illustrates two alternate pathways -Thiamine supplementation and no thiamine supplementation. These two pathways are further divided into thiamine deficient infants and healthy infants for both supplemented and un-supplemented arms. Terminal nodes (i.e. endpoints of the model) are infantile survival in full health and death\u003c/p\u003e\n\u003cp id=\"_Toc168262390\"\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Measures\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome measure was defined as life years saved, calculated from a baseline of the average life expectancy of a healthy person in India, 70.8 years as per 2019 estimates from the World Health Organization (WHO). This metric allows for a clear comparison between the expected lifespan of a healthy individual and the actual lifespan achieved through the intervention, highlighting the impact on longevity.\u003c/p\u003e\n\u003cp id=\"_Toc171584003\"\u003e\u003cstrong\u003eBase-Case Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on best practice guidelines set by the WHO and the HTAIn reference case, one-time gross domestic product per capita of India (2023) which is INR 172,000 was used as the cost-effectiveness willingness to pay (WTP) threshold. An incremental cost effectiveness ratio (ICER) below the WTP threshold was considered cost-effective. A health system costing perspective was adopted, and a lifetime horizon was considered for the study.\u003c/p\u003e\n\u003cp id=\"_Toc168262392\"\u003e\u003cstrong\u003eKey Assumptions\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;of the model\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFull adherence to the daily thiamine supplement regimen was assumed, based on adherence rates reported in the Assam hospital data. Slightly higher ANC attendance in the supplementation arm was also assumed wherein the routine care in this arm was structured to include 4 ANC visits per pregnant woman, as observed in the pregnancy cohort. \u0026nbsp; The usual care arm was structured to incorporate 3 ANC visits, as was found to be standard among those availing ANC through the Meghalaya Health Insurance Scheme (16). An assumption was made that any infant who developed beriberi would do so in the first 6 months of life as is reported in the literature (2) and verified by the clinicians interviewed. Those infants who develop beriberi were assumed to be treated and survive in full health with no lasting morbidity, as clinical experts informed was the case, or to die of complications directly associated with this deficiency. To adequately capture cost per case of beriberi in this model, each case is costed from the health system perspective where outpatient assessment, inpatient admission, high-dose thiamine treatment administration, and follow-up care is provided.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eExpert opinion interviews\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe clinical expert interviews highlighted that despite the efficacy of thiamine treatment in deficient states, the low index of suspicion among clinicians of thiamine deficiency disorders contributes to high case fatality due to delayed diagnosis and initiation of treatment. Clinicians working in rural areas observed that infants with beriberi presenting with cardiac and neurological symptoms had 100% case fatality if left untreated. Along with affected infants, hospitals also documented peripartum women with features of both peripheral neuropathy and cardiac failure showing remarkable improvement with parenteral thiamine supplementation. Diagnosis of all thiamine deficiency disorders was cited as challenging due to the lack of affordable tests, often prompting empirical thiamine administration as a diagnostic measure. Contributing factors to thiamine deficiency were cited to include low socio-economic status and poor dietary diversity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCost Effectiveness Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results from the base case analysis indicates that an intervention involving six months of antenatal and six months of postnatal thiamine supplementation, administered via a daily multivitamin containing 10mg of thiamine, is likely to be highly cost-effective. The Incremental Cost-Effectiveness Ratio (ICER) was calculated at INR 2386 (USD 27.81) per life year saved. This can be considered highly cost-effective using a Willingness to Pay (WTP) threshold of INR 172,000 (USD 2004.84) (equivalent to 1 x GDP per capita of India in 2023), which is in line with best practice guidelines from WHO and HTAIn. The base case results are detailed in Table 4 and represented in the cost-effectiveness plane in Figure 2.\u003c/p\u003e\n\u003cp id=\"_Toc171584039\"\u003eTable\u0026nbsp;4: Results of the Base Case Analysis\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"91%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCost\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cspan id=\"_Toc149552510\"\u003e\u003cstrong\u003eIncre. Cost\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cspan id=\"_Toc149552511\"\u003e\u003cstrong\u003eEffectiveness\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cspan id=\"_Toc149552512\"\u003e\u003cstrong\u003eIncremental Effectiveness\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cspan id=\"_Toc149552513\"\u003e\u003cstrong\u003eICER\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003eNo Supplementation\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1510.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e70.52\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003eThiamine Supplementation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2174.7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e664.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e70.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e0.278\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e2386.119\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch2\u003eSensitivity Analysis\u003c/h2\u003e\n\u003cp\u003eOne Way Deterministic Sensitivity Analysis (OWSA) was used to check the robustness of the model findings under different cost and baseline prevalence or \u0026lsquo;untreated\u0026rsquo; conditions. The cost of the supplementation regimen was inflated by 10 times the current value and remained highly cost-effective under the HTA India-recommended WTP threshold, with an ICER of INR 72580 (USD 846) per life year gained. A shift in the baseline prevalence value to 7.25% in the untreated arm based on published literature from Thailand (5) resulted in an ICER value of INR 117 (USD 1.36) per life-year gained.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study aimed to assess the incremental cost-effectiveness of thiamine supplementation as compared to the standard of care for pregnant and postpartum women in preventing infantile beriberi. A mix of methods including a systematic review (ref in press), clinical expert opinions, and cost-effectiveness analysis, was used to model the lifetime costs and outcomes of a 12-month thiamine supplementation programme in the Northeast Region (NER) of India. The findings suggest that thiamine supplementation is likely to be a highly cost-effective strategy for preventing beriberi and associated deaths, with an ICER of INR 2386 (USD 27.81) per life year saved at a WTP threshold of INR 1,72,000 (USD 2004.84).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis research sought to provide evidence for policy decision-making for a problem that was identified locally by clinicians. They had often changed their own prescription patterns to include supplementation but articulated the need to support the implementation of the same for pregnant and postpartum women across the NER of India, to address immediate health needs and promote long-term public health benefits for women and their babies in the wider population. After exposing a lack of peer-reviewed literature to support the parameterization of our decision tree model, we adopted a mix of methods to answer this important public health question.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the expert interviews, the clinicians we interviewed spoke about the clinical manifestations of beriberi that they encounter, highlighting the severity and rapid progression of infantile cardiac beriberi as a cause for major concern. Clinicians reported that the window from the onset of symptoms to severe complications can be very short, leading to rapid deterioration and mortality if left untreated. This aligns with other case studies on cardiac beriberi, which report rapid deterioration and high rates of mortality(5,11\u0026ndash;13). Clinicians proposed low clinical suspicion and absence of a point of care test impeding timely diagnosis in addition to the lack of community awareness as explanatory factors for mortality related to the disease. Clinicians also reported the dramatic and rapid response to thiamine treatment in clinically suspected cases, a finding corroborated by numerous studies conducted in Northeast India involving both women and children\u0026nbsp;(13,14). Infantile beriberi can often present with pneumonia-like respiratory symptoms (but is usually afebrile), which is noteworthy as pneumonia is an oft documented cause of infant deaths in the 2-6 months age group.\u003c/p\u003e\n\u003cp\u003eThiamine deficiency is an issue of intersectionality, with strong correlation to socioeconomic status, dietary practices, and cultural and religious practices in pregnancy and postpartum. In northwestern Thailand, high rates of infantile beriberi were documented in a socially disadvantaged group of refugees belonging to the Karen ethnic minority\u0026nbsp;(5). The symptoms reported by clinicians interviewed in the current study as being observed in affected infants, like their age group and response to treatment, were similar to those documented in the Karen refugee population\u0026nbsp;(5). Dietary practices also overlapped, for example, the polished rice consumed by the Karen refugees in relief camps was similar to that provided through the Public Distribution System in rural northeast India. In addition, the consumption of known anti-thiamine factors such as fermented fish, betel nut and tea leaves\u0026nbsp;(17), were found in both contexts. Secondary to location, ethnicity or income, populations affected by micronutrient deficiencies are often marginalised groups in society, illustrating the role of socioeconomic disadvantage in shaping nutritional vulnerability\u0026nbsp;(18). These parallels in dietary patterns and symptomatology, despite differences in time and geography, favour adapting the prevalence estimates from the Karen refugee study in constructing the additional cost-effectiveness model.\u0026nbsp;Those populations on the margins of society are known to have particularly high prevalence of thiamine deficiency. This is likely one of the drivers of high rates of thiamine deficiency in the NER of India in particular, where refugees and tribal groups make up\u0026nbsp;27.7% of the total population in the country and 85%\u0026nbsp;% percent of in NER\u0026nbsp;(19). Thiamine-related infant mortality was reported to be as high as 7.25% in the Karen refugee population in Thailand\u0026nbsp;(5). This is nine times higher than the estimated probability in the NER used in the model gained from the sample of 489 women in Assam that accessed antenatal care in public health facilities. When using the Thailand\u0026nbsp;estimate within our deterministic sensitivity analysis, the ICER came down to\u0026nbsp;INR 258.79 (USD2.96)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eper life-year gained, indicating the ICER to be sensitive to underlying prevalence and therefore overarching life years to be gained from prevention of thiamine deficiency. Considering the higher number of infant deaths reported before thiamine supplementation in the North East Indian state of Mizoram\u0026nbsp;(12)\u0026nbsp;along with the figures for thiamine deficiency detected across different age groups in the Assam hospital (see Supplementary Data), and a very\u0026nbsp;high prevalence of thiamine deficiency of 33-34% in pregnant and lactating women documented in a recent study in the region by the National Institute of Nutrition\u0026nbsp;(20), we suspect that the prevalence estimate used in this study is likely to be a gross underestimate and therefore that the true ICER value is far lower than the base case estimate.\u003c/p\u003e\n\u003cp\u003eAs diet is the primary source of thiamine, particular attention should be paid to nutritional practices and accessibility of nutrient rich food. \u0026nbsp;Across various studies conducted in India, particularly in the Northeast region, a common dietary pattern has emerged in the literature relation to thiamine deficiency, characterised by the consumption of polished rice, fermented fish, and tea (14).\u0026nbsp;Similarly, research conducted in Laos also identified a similar dietary pattern, where the intake of fermented fish, tea, and betel nut served as contributory factors for beriberi\u0026nbsp;(21).\u0026nbsp;Similar evidence is also reported from Kashmir, where the predominantly Muslim community adhere to specific dietary restrictions (particularly during pregnancy) and a higher consumption of staple polished white rice and tea\u0026nbsp;(22,23).\u003c/p\u003e\n\u003cp\u003eThe lack of accessible, affordable diagnostic tests is a significant challenge in detecting and managing beriberi. To address this issue, the World Health Organisation (WHO) recommends adopting clinical criteria for diagnosis in settings where diagnostic tests are unavailable\u0026nbsp;(2). This approach is similar to practices adopted by health facilities in low-resource settings across Asia, where the administration of thiamine serves as a crucial method to identify suspected cases of thiamine deficiency\u0026nbsp;(10\u0026ndash;13,22).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn our analysis, a regimen of six months antenatal and six months postnatal thiamine supplementation of one multi-B vitamin containing 10mg of thiamine per day was found to be highly cost-effective use of local resources. This finding is consistent with another study on multiple micronutrient supplementation instead of only iron and folic acid in three high-burden Asian countries including India , which demonstrated cost-effectiveness at approximately INR 2,638 (USD 30.75) per DALY averted (24). To our knowledge, this economic evaluation is one of the first studies to demonstrate the cost-effectiveness of a supplementation intervention for thiamine deficiency. This study illustrates how a mix of methods incorporating locally available data can supplement quantitative and qualitative findings to strengthen the understanding of thiamine deficiency and infant mortality in India.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe main limitation of this study is that there was a dearth of published data in relation to population prevalence of thiamine deficiency and associated probability of death in infants due to thiamine deficiency. In the absence of this important data, all available published and unpublished local data along with clinical expert opinions were used to inform a number of parameter values. This form of data, while not ideal, also presents a case for how available data could be used especially in LMIC settings for conducting studies that have potential policy implications. While a real-world longitudinal trial of thiamine supplementation is desirable to monitor and evaluate its effectiveness, this study provides evidence in the interim for working towards eliminating beriberi in infants and their mothers in the NER and across India.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion and recommendations","content":"\u003cp\u003eThe results of this study demonstrate that a regimen of six months antenatal and six months postnatal thiamine supplementation, providing 10 mg of thiamine daily through a multi-B vitamin, is highly cost-effective, with an ICER of INR 2386 (USD 27.81) per life year saved at a WTP threshold of INR 1,72,000 (USD 2004.84). The findings provide policy recommendations for investment in a thiamine supplementation programme for pregnant and lactating mothers in Northeast India, to be integrated into routine antenatal care provided through the public health system. Investment in this intervention has the potential to save thousands of infants and mother\u0026rsquo;s lives across the region, representing a highly cost-effective use of local resources for health.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eContributors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCBN lead the study and drafted the manuscript. TJ, RK, BSK served as clinical experts and supported in manuscript development. TBS supported the systematic review and analysis. SA and LD contributed to the study design, analysis, and manuscript drafting. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors report no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was funded by the Department of Health Research (DHR), Ministry of Health and Family Welfare, Government of India\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMartel JL, Kerndt CC, Doshi H, Franklin DS. Vitamin B1 (Thiamine). StatPearls Publishing; 2023. \u003c/li\u003e\n\u003cli\u003eWorld Health Organisation. Thiamine deficiency and its prevention and control in major emergencies [Internet]. World Health Organisation; 1999 [cited 2021 May 10] p. 1\u0026ndash;52. Available from: https://www.who.int/nutrition/publications/en/thiamine_in_emergencies_eng.pdf\u003c/li\u003e\n\u003cli\u003eWhitfield KC, Smith G, Chamnan C, Karakochuk CD, Sophonneary P, Kuong K, et al. High prevalence of thiamine (vitamin B1) deficiency in early childhood among a nationally representative sample of Cambodian women of childbearing age and their children. Tickell KD, editor. PLoS Negl Trop Dis. 2017 Sep 5;11(9):e0005814. \u003c/li\u003e\n\u003cli\u003eJohnson CR, Fischer PR, Thacher TD, Topazian MD, Bourassa MW, Combs GF. Thiamin deficiency in low- and middle-income countries: Disorders, prevalences, previous interventions and current recommendations. Nutr Health. 2019 Jun;25(2):127\u0026ndash;51. \u003c/li\u003e\n\u003cli\u003eLuxemburger C, White NJ, Ter Kuile F, Singh HM, Allier-Frachon I, Ohn M, et al. Beri-beri: the major cause of infant mortality in Karen refugees. Trans R Soc Trop Med Hyg. 2003 Mar;97(2):251\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eNazir M, Lone R, Charoo BA. Infantile Thiamine Deficiency: New Insights into an Old Disease. Indian Pediatr. 2019 Aug;56(8):673\u0026ndash;81. \u003c/li\u003e\n\u003cli\u003eAhoua L, Etienne W, Fermon F, Godain G, Brown V, Kadjo K, et al. Outbreak of Beriberi in a Prison in C\u0026ocirc;te D\u0026rsquo;Ivoire. Food Nutr Bull. 2007 Sep;28(3):283\u0026ndash;90. \u003c/li\u003e\n\u003cli\u003eTiamkao S, Boonsong A, Saepeung K, Kasemsap N, Apiwattanakul M, Suanprasert N, et al. An Outbreak of Peripheral Neuropathy in a Prison. Case Rep Neurol. 2019 Feb 26;11(1):53\u0026ndash;60. \u003c/li\u003e\n\u003cli\u003eWatson JT, El Bushra H, Lebo EJ, Bwire G, Kiyengo J, Emukule G, et al. Outbreak of Beriberi among African Union Troops in Mogadishu, Somalia. Morgan D, editor. PLoS ONE. 2011 Dec 21;6(12):e28345. \u003c/li\u003e\n\u003cli\u003eQureshi UA, Sami A, Altaf U, Ahmad K, Iqbal J, Wani NA, et al. Thiamine responsive acute life threatening metabolic acidosis in exclusively breast-fed infants. Nutrition. 2016 Feb;32(2):213\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eKoshy RM, Thankaraj S, Ismavel VA, Solomi CV. The rediscovery of thiamine deficiency disorders at a secondary level mission hospital in Northeast India. Ann N Y Acad Sci. 2021 Aug;1498(1):96\u0026ndash;107. \u003c/li\u003e\n\u003cli\u003eMalsawma J. Infantile Beri Beri: The Mizoram Experience. Indian Pediatr. 2020 Apr 15;57:376\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eThangkaraj S, Koshy R, Ismavel V. Infantile Cardiac Beri beri in Rural Northeast India. Indian Pediatr. 2020 Sep 15;57:859\u0026ndash;60. \u003c/li\u003e\n\u003cli\u003eKoshy RM, Ismavel VA, Sharma H, Jacob PM. Suspected Thiamine Deficiency Presenting as Peripheral Neuropathy among Peripartum Women in a Hospital in Rural Assam: A Neglected Public Health Problem. Ann N Y Acad Sci. 2018 Sep;5(3):178\u0026ndash;81. \u003c/li\u003e\n\u003cli\u003eIndiaMART InterMESH Ltd. IndiaMART. IndiaMart. Available from: https://www.indiamart.com/?srsltid=AfmBOoqH9508DWBOqR3YegNxawqqxCiWl8q6HbLzLKO4sxnWNbbB6P4J\u003c/li\u003e\n\u003cli\u003eDutta EK, Kumar S, Venkatachalam S, Downey LE, Albert S. An analysis of government-sponsored health insurance enrolment and claims data from Meghalaya: Insights into the provision of health care in North East India. Sharma GA, editor. PLOS ONE. 2022 Jun 3;17(6):e0268858. \u003c/li\u003e\n\u003cli\u003eVimokesant SL, Hilker DM, Nakornchai S, Rungruangsak K, Dhanamitta S. Effects of betel nut and fermented fish on the thiamin status of northeastern Thais. Am J Clin Nutr. 1975 Dec 1;28(12):1458\u0026ndash;63. \u003c/li\u003e\n\u003cli\u003eBayati M, Arkia E, Emadi M. Socio-economic inequality in the nutritional deficiencies among the world countries: evidence from global burden of disease study 2019. J Health Popul Nutr. 2025 Jan 13;44(1):8. \u003c/li\u003e\n\u003cli\u003eMinistry of Development of North Eastern Region. NorthEast Region facts [Internet]. Ministry of Development of North Eastern Region; Available from: https://mdoner.gov.in/dashboard/files/nerfacts.pdf\u003c/li\u003e\n\u003cli\u003eNational Institute of Nutrition. Prevalence of thiamine deficiency in Pregnant and Lactating wome in Northeast India. In 2023. \u003c/li\u003e\n\u003cli\u003eSoukaloun D, Kounnavong S, Pengdy B, Boupha B, Durondej S, Olness K, et al. Dietary and socio-economic factors associated with beriberi in breastfed Lao infants. Ann Trop Paediatr. 2003 Sep;23(3):181\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eBhat JI, Rather HA, Ahangar AA, Qureshi UA, Dar P, Ahmed QI, et al. Shoshin beriberi-thiamine responsive pulmonary hypertension in exclusively breastfed infants: A study from northern India. Indian Heart J. 2017 Jan;69(1):24\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eKareem O, Mufti S, Nisar S, Tanvir M, Muzaffer U, Ali N, et al. Prevalence of Thiamine Deficiency in Pregnancy and its impact on fetal outcome in an area endemic for thiamine deficiency. Tickell KD, editor. PLoS Negl Trop Dis. 2023 May 30;17(5):e0011324. \u003c/li\u003e\n\u003cli\u003eKashi B, M Godin C, Kurzawa ZA, Verney AM, Busch-Hallen JF, De-Regil LM. Multiple Micronutrient Supplements Are More Cost-effective Than Iron and Folic Acid: Modeling Results from 3 High-Burden Asian Countries. J Nutr. 2019 Jul;149(7):1222\u0026ndash;9. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-public-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pubh","sideBox":"Learn more about [BMC Public Health](http://bmcpublichealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pubh/default.aspx","title":"BMC Public Health","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"thiamine supplementation, cost effectiveness analysis, intersectionality, Northeast India","lastPublishedDoi":"10.21203/rs.3.rs-7813280/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7813280/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eThiamine deficiency can be fatal if untreated. Lack of affordable confirmatory tests contribute to preventable infant mortality from thiamine deficiency, otherwise known as beriberi. We calculated the potential cost-effectiveness of a thiamine supplementation program among pregnant and postpartum women to prevent infantile beriberi deaths in Northeast India.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA decision-tree model was constructed to estimate the lifetime costs and outcomes associated with implementing a 12-month thiamine supplementation program for pregnant and postpartum women, with a primary outcome of prevention of infantile deaths due to beriberi. The model was populated using both primary and secondary data sources including real world evidence from a secondary care hospital in a rural Northeast Indian setting.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eResults of the model indicate that a routine of 6 months antenatal and 6 months postnatal thiamine supplementation program via one multivitamin per day containing 10 milligrams of thiamine is likely to be highly cost effective with an incremental cost effectiveness ratio (ICER) of INR 2386 (USD 27.81 ) per life year saved at a WTP threshold of INR 1, 72,000 (USD 2004.84) (1 x GDP per capita).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThese results indicate that a thiamine supplementation program among pregnant and postpartum women represents a highly cost-effective use of local resources by substantially reducing infantile morbidity and mortality rates associated with beriberi in the northeastern region of India. The study also provides an example of using locally available data in performing CEA in LMIC settings, where high quality cost and effectiveness data are often unavailable.\u003c/p\u003e","manuscriptTitle":"Cost effectiveness of thiamine supplementation in pregnant and post-partum women to prevent infantile beriberi deaths in Northeast India","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-26 06:44:44","doi":"10.21203/rs.3.rs-7813280/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2025-11-13T15:01:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-11T08:59:52+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-16T09:14:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-16T05:51:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Public Health","date":"2025-10-16T05:47:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-public-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pubh","sideBox":"Learn more about [BMC Public Health](http://bmcpublichealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pubh/default.aspx","title":"BMC Public Health","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"68cbeaeb-a483-4e5a-8fa4-88d3c362150c","owner":[],"postedDate":"November 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-11-26T06:44:44+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-26 06:44:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7813280","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7813280","identity":"rs-7813280","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}