Salmonella Induced Dat-Negative Autoimmune Haemolytic Anemia in a Pregnant Woman Complicated by Fetal Loss. Case Report and Literature Review

Salmonella Induced Dat-Negative Autoimmune Haemolytic Anemia in a Pregnant Woman Complicated by Fetal Loss. Case Report and Literature Review | 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 Case Report Salmonella Induced Dat-Negative Autoimmune Haemolytic Anemia in a Pregnant Woman Complicated by Fetal Loss. Case Report and Literature Review Sarah A. Elkourashy, Jassim Ahmed Khan, Dina Soliman, Sulieman Abujarir, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7113962/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Infections during pregnancy present unique diagnostic and therapeutic challenges, particularly when rare immune complications arise during gestation. Haemolytic anaemia induced by Salmonella infection is a seldom-reported phenomenon, especially during gestation. We describe a 28-year-old previously healthy primigravida who presented at 32 weeks with acute gastroenteritis caused by Salmonella Group B and was subsequently diagnosed with direct antiglobulin test-negative (DAT-negative) autoimmune haemolytic anaemia (AIHA). Despite supportive care, antibiotics, and immunosuppressive therapy, the patient experienced an unexplained intrauterine fetal death (IUFD) at 36 weeks. This case underscores the importance of early recognition of atypical infectious sequelae in pregnancy, the diagnostic challenge of DAT-negative AIHA, and the potential feto-maternal consequences. We review the immunopathologic mechanisms, diagnostic considerations, and implications for antenatal care, advocating for heightened clinical vigilance and interdisciplinary management. Autoimmune hemolytic anemia (AIHA) DAT-negative hemolysis Salmonella infection Pregnancy complications Intrauterine fetal demise (IUFD) Infectious hemolysis Third trimester pregnancy Hematologic disorders in pregnancy Immunohematology Case report Introduction Salmonella infection in pregnancy can pose various threats to the pregnancy. However, its association with events leading to haemolytic anaemia is poorly understood and yet to be researched. Pregnancy loss, septic abortion, IUFD, preterm labour are anecdotally documented complications of Typhi infections (George F Guirguis 1, 2017) ( 1 ) . Although Salmonella is widely regarded as a treatable infection, its role in inducing hemolysis, particularly in pregnancy, remains poorly understood. While febrile illness with haemolysis in pregnancy usually provokes a suspicion of chorioamnionitis, viral infection and pyelonephritis (Brion Gluck 1, 1994) ( 2 ) seldom do the Obstetricians and haematologists contemplate on Salmonella typhi infection. The outcomes of infections in pregnancy could possibly include preterm birth, chorioamnionitis, meningitis, hydrocephaly, developmental delays, microcephaly, and sepsis (MY Chan 1, 2017) ( 3 ) (Roll, 1995) ( 4 ) . Salmonella infections are commonly acquired from raw/undercooked eggs, raw meat, poultry, seafood, raw milk, dairy products. The factors impacting such infections in pregnancy could possibly link to the systematic shift from T-helper 1 (Th1) to T-helper 2 (Th2) cell-mediated responses in the mother. In a Th1-dominated response, the Th1-type T lymphocytes and proinflammatory cytokines amplify cell-mediated immunity allowing for recognition of the body’s own cells that engulf the pathogen and express pathogen-related antigens on their surfaces. When shifting to the Th2 cell-mediated response, the Th2-stimulating cytokines dominate and suppress the Th1 T cell responses probably diminishes self-recognition mechanism while the cell-mediated immunity is compromised (Jessica E Thaxton 1, 2013) ( 5 ) . During pregnancy, the maternal immune system undergoes functional adaptations, particularly a bias toward Th2-dominant responses, facilitating tolerance of the semi-allogenic fetus. While this shift supports fetal survival, it may compromise the ability to mount effective responses against intracellular organisms like Salmonella , potentially leading to heightened severity or unusual presentations of infections. (MY Chan 1, 2017) ( 3 ) . Epidemiologically, autoimmunity complicates 0.9–10% of pregnancies (Jacqueline R Lim 1, 2021) ( 6 ) . The differential diagnosis of DAT-negative AIHA in pregnancy is complex and requires the exclusion of other possible causes of haemolysis (physiologic conditions such as haemodilution, nutrient deficiency; chronic pre-existing ones, hemoglobinopathies, congenital haemolytic anaemias and acute severe forms, such as pre-eclamptic syndromes and microangiopathies). Case presentation A 28-year-old primigravida, previously healthy, presented at 32 weeks of gestation with a 3-day history of sudden-onset diarrhoea, vomiting, and low-grade fever. She was not on any medication apart from prenatal vitamins and iron supplements. She had more than 10 episodes of greenish diarrhoea per day, accompanied by nausea, vomiting (3–4 episodes daily), and progressive pallor. Over the preceding few days, she had also noticed dark-coloured urine and increasing fatigue. She noticed her skin colour turned pale, and the urine turned dark colour over the last few days. She had no cough or any URTI symptoms. Clinical and Laboratory Findings Haemoglobin (Hb): 7.6 g/dL (macrocytic anemia, MCV 112) Reticulocyte count: 293 ×10⁹/L (elevated, suggestive of hemolysis) Peripheral smear: Leucoerythroblastic picture with macrocytosis Direct Antiglobulin Test (DAT): Negative Liver Function Tests: Mild elevation in direct bilirubin, LDH 267 Sepsis Workup: Negative blood/urine cultures, positive stool culture for Salmonella group B, yet negative for stool ova parasite and Clostridium difficile. Infectious Workup: Negative for viral hepatitis, TORCH screen Initial management of the patient included initiation of intravenous (IV) ceftriaxone (2g daily) and metronidazole (500 mg three times daily). She was transfused with packed RBCs, achieving an Hb increase to 8 g/dL, which later dropped to 6.6 g/dL despite ongoing therapy. Yet again after 4 days, she was re- transfused with packed RBCs; Haemolysis secondary to Acute GI infection was concluded and the patient kept on the same antimicrobials. After seven-day course of antimicrobials, she presented again with generalised fatigue and shortness of breath. Her labs showed Hb of 7.2 g/dL, retic count raised up to 625 and persistent positive stool culture for Salmonella group B. An ultrasound abdomen was executed, which showed mild splenomegaly (14.6cm). In view of persistent haemolysis, IV methylprednisolone (60 mg daily) and IV immunoglobulin (0.5 g/kg for 4 days) were started, leading to Hb stabilization (9.3 g/dL). Later, she was discharged on oral prednisolone (60 mg daily, tapered gradually). Unfortunately, seven days later, patient presented with complaints of decreased fetal movements with progressive decline for the last 2 days. At 36 weeks gestation, she presented with reduced fetal movements for two days, and USG revealed intrauterine foetal death (IUFD). She was completely asymptomatic with no features of recent infection. No history of sexual transmitted disease and upon examination; no oral or genital vesicles. IUFD Workup: TORCH screen: HSV IgM positive, HSV Type I IgG positive, HSV Type II IgG negative. Cytomegalovirus/Rubella serology were negative Thrombophilia panel: normal levels of Protein C, S and antithrombin III, no mutation detected for Prothrombin c.*97G > A variant or Factor V Leiden variant c.1601G > A (p.R534Q) as genetic risk factor for pregnancy loss, Lupus Anticoagulants and antibodies for antiphospholipid syndrome were not detected. Autoimmune screen: Negative Placental histopathology: No significant pathology. She was induced for vaginal delivery, and post-delivery care focused mainly on good psychological support. She was discharged on prednisolone 30mg daily with tapering doses for the next 3 weeks with other supportive measures. On the following year, the patient conceived spontaneously and delivered uneventfully. Viral serology for Herpes simplex virus was repeated at 1 year from the event of IUFD and showed HSV IgM negative, HSV Type I IgG positive, HSV Type II IgG negative which confirmed no previous infection of HSV Type II and previous detection of HSV IgM during the workup of fetal demise was just false positive result. Discussion and Conclusion Salmonella infection in pregnancy occurs with similar frequency as in the general population, with an incidence of 0.2% positive rectal cultures at the time of delivery (Neelam Kaistha 1, 2013) ( 7 ) . In a retrospective study on Relapse and De novo AIHA along with its treatment outcomes conducted by (Bruno Fattizzo, 2013) ( 8 ) spanning 12 tertiary haematology centres across Italy, Denmark, France, the Netherlands, the United Kingdom, the United States, and Spain, ranging from 1997–2002,they concluded that amongst the 33 women - the 20 women were diagnosed with AIHA before pregnancy, 10 had a relapse. An additional 13 patients developed de novo AIHA during gestation/puerperium (2 patients had AIHA relapse during a second pregnancy). Among 24 haemolytic events, anaemia was uniformly severe (median Hb, 6.4 g/dL; range, 3.1–8.7) and required treatment in all cases (96% steroids ± intravenous immunoglobulin, IVIG, 58% transfusions). Response was achieved in all patients and was complete in 65% of the cases. Antithrombotic prophylaxis was administered to 8 patients (33%). After delivery, rituximab was administered to 4 patients, and cyclosporine was added to 1 patient. The rate of maternal complications, including premature rupture of membranes, placental detachment, and preeclampsia, was 15%. Early miscarriages occurred in 13% of the pregnancies. Fetal adverse events (22% of cases) included respiratory distress, fetal growth restriction, preterm birth, AIHA of the newborn, and 2 perinatal deaths. They also advocated on use of Rituximab in severe refractory cases after weighing risk vs benefit. However, its use during pregnancy induces B-cell depletion in foetus. Hence, we advise that prior to starting Rituximab, the decision should be judicious. The interplay between Salmonella infection and hemolysis has been studied, particularly in regions endemic to both malaria and non-typhoidal Salmonella (NTS) infections. Salmonella initially invade epithelial and M cells of the intestine within Peyer's patches and bacteria are then phagocytosed by macrophages and dendritic cells in the intestinal wall. This facilitates dissemination via the lymphatic system and blood to other tissues. In the absence of haemolysis, the spleen and liver are the major sites of Salmonella replication, where bacteria are predominately found within macrophages. L-Arginine plays a crucial role in limiting intestinal permeability and translocation of both E. coli and NTS. At the level of invasion across the intestinal mucosa, one potential mechanism is haemolysis-related depletion of L-arginine; the substrate for nitric oxide synthesis. Arginase, an arginine degrading enzyme, is released from RBCs during intravascular haemolysis with free Hb. The latter also drives L-arginine depletion by scavenging nitric oxide. Thus, it’s clear that diminished levels of L-Arginine could possibly provide facile access to invade and disseminate infection. Impaired neutrophil oxidative burst has also been observed in sickle cell disease, which is characterized by severe haemolysis and dramatically increased susceptibility to NTS infection, indicating this mechanism may be a general consequence of haemolysis. Thus, in the setting of concurrent intravascular, granulocytes entering the circulation in response to infection are able to phagocytose S. typhimurium but, owing to their reduced oxidative burst capacity, fail to kill them, providing instead an innocuous niche for bacterial replication and dissemination (Cunnington AJ, 2012) ( 9 ) . An interesting case published(Marguerite B Vigliani 1, 2013) ( 10 ) in 2013 depicting first trimester loss due to Salmonella typhii infection found Salmonella in fetal tissues at autopsy. They also drew S. Typhi and L. monocytogenes to develop a plausible hypothesis to explain how this organism was able to cross the placenta in the first trimester to cause abruption, inflammation, and expulsion of the foetus and placenta. An interesting facet is non-typhoidal Salmonella is still a cause of morbidity in Western countries. This infection can result in rapid-onset fetal demise and septic abortion (LoriAnn Zettell 1, 1995) ( 11 ) . Salmonella Mississippi, Salmonella enteritidis Oranienburg, S. Virchow, Group C1, S .Dublin are rare species which have been anecdotally documented to cause 1st and 2nd trimester abortions. S serovar Montevideo has been exceptional from other variants as it has been documented to cause Neonatal meningitides, cultures from placenta were found to be positive (Birendra Rai 1, 2014) ( 12 ) . Appropriate and timely cultures obtained prior to the initiation of antibiotic therapy are essential for confirming the diagnosis. Blood cultures are positive early in the course of infection, while stool cultures are positive later in the course of the infection. Cultures of multiple sites (urine, amniotic fluid, skin scrapings, bone marrow) improve the yield of a positive culture (Brion Gluck 1, 1994) ( 2 ) . Ampicillin 8g/day and Ceftriaxone 75mg/kg/day for 5 days have been the cornerstone in treating Salmonella Infections in pregnancy in today’s time. The Vi capsular polysaccharide vaccine provides effective immunity for two years with a single dose. It is safe to use during pregnancy. However, the duration of protection is relatively short; hence frequent travellers or long-term residents in high-risk areas need boosters every third year (Faraj Touchan *, 2009) ( 13 ) . This case is further complicated by DAT-negative, AIHA in pregnancy can have variable outcomes with an estimated incidence of 0.8–3/100,000/year (Lefkou, 2010) ( 14 ) . AIHA could be primary or secondary (Systemic Lupus Erythematosus, malignancies, infections or immunodeficiency). The blood indices need to wisely monitor throughout the pregnancy. In a retrospective descriptive study performed between 2011–2016 by Rao Preethi Venkatachala (Rao Preethi Venkatachala, 2021) ( 15 ) and her colleagues in South India on AIHA in pregnancy, they found DAT negative pregnancies required higher number of intrapartum transfusions, fever, abortions, anaemia and jaundice and few required Azathioprine and steroids. In a cohort study of clinical course of pregnancy with AIHA and their perinatal outcomes, published by Irina Murakhovskaya and colleagues in 2021, they found shorter duration of postpartum haemolysis in DAT negative cases while steroid and transfusions were given in both settings. In steroid refractory cases, IV Ig is used. Intravenous immunoglobulin helps to block the macrophages that work to destroy platelets prematurely and improves platelet survival time. Second-line treatment options include rituximab (category C drug) and splenectomy (MM, 2017) ( 16 ) . Negative DAT may be due to a small quantity of IgG on their red blood cells (RBCs) (below detectable levels), or when low-affinity anti-IgG is present, or when the autoantibodies are IgA or IgM in nature. Nevertheless, early identification of DAT negative anaemia in pregnancy and substantial response to steroid have led to excellent maternal and fetal outcomes. Foetal monitoring with serial ultrasonography should be initiated from 20 weeks of gestation to assess foetal growth and Doppler assessment of foetal middle cerebral artery (MCA) peak systolic velocity to assess for foetal anaemia (Rao Preethi Venkatachala, 2021) ( 15 ) (S J Pretlove, 2009) ( 17 ) (Ulrich Jäger, 2020) ( 18 ) . In our opinion, DAT negative AIHA is perhaps a diagnostic challenge since it requires an extensive negative work-up to rule out any other cause of congenital or acquired haemolytic anaemia. Next Generation Sequencing analyses are now increasingly used to detect the presence of relevant variants and somatic mutations and may be helpful to find some previously unexplained haemolytic anaemia. The management of DN-AIHA is not standardized and mostly extrapolated from the one of AIHA. Steroids, splenectomy and/or the treatment of an underlying disease may lead to a complete and durable remission (Rodberg, 2022) ( 19 ) . (Table 1 .) Table 1 Literature Review Summary Study AIHA in Pregnancy Key Outcomes Clinical Implications Fattizzo et al. (2023) 33 cases of AIHA 22% had fetal complications (IUFD, preterm birth) AIHA in pregnancy requires aggressive management and fetal monitoring Vigliani et al. (2013) Salmonella & early pregnancy loss Found Salmonella in fetal tissues Highlights placental invasion as a risk factor for IUFD Murakhovskaya et al. (2021) DAT-negative AIHA Better postpartum recovery, but required steroids & IVIG DAT-negative AIHA can be managed effectively with steroids and IVIG Bougioukas et al. (2021) HSV in late pregnancy 50% IUFD rate in disseminated cases Routine HSV screening may be needed in unexplained fetal loss The workup of IUFD revealed positive HSV IgM results raising suspicion for concurrent HSV infection. In asymptomatic pregnant women, a positive HSV IgM result, coupled with the absence of vesicular rash, and a subsequent negative result after pregnancy, alongside persistent negative HSV-2 IgG during and after pregnancy, makes the possibility of disseminated HSV unlikely. It is important to note that positive HSV IgM results during pregnancy are not uncommon, and it is generally not recommended to rely on HSV IgM testing during pregnancy due to its lack of specificity and potential for false positives (Ting-Li Shi 1, 2018) ( 20 ) . Theoretically, the presence of HSV IgM at 36 weeks, despite an absence of clinical symptoms or lesions, raises concerns regarding asymptomatic viral shedding and transplacental transmission. HSV IgM testing is discouraged during pregnancy due to its low specificity and high false-positive rate (ACOG 2017) ( 21 ) . CDC also advises against HSV IgM testing, recommending type-specific serologic assays instead (CDC 2021) ( 22 ) . Disseminated HSV-2 has a predilection for late pregnancy, with up to 65% of cases occurring in the third trimester and an overall 50% risk of transplacental infection (Lauren Bougioukas a, 2021) ( 23 ) . Vertical transmission during pregnancy is rare occurring in less than 1% of cases but for those with active lesions or shedding the virus asymptomatically the risk of vertical transmission intrapartum is high (Ting-Li Shi 1, 2018) ( 20 ) (Nawar Younis Hussain 1, 2014) ( 24 ) . In fact, Routine HSV screening is not included in antenatal care (ANC), but targeted testing through vaginal swabs, PCR, and obstetric scans is essential in suspected cases (Wafaa Ali Belail Hammad 1, 2021) ( 25 ) . This case demonstrates a rare but clinically significant progression of Salmonella infection during pregnancy. Immune modulation in pregnancy predisposes women to disseminated infections that may pose serious risks to maternal and fetal health. Infections caused by Salmonella have been linked to adverse outcomes such as spontaneous abortion, premature delivery, and intrauterine fetal demise. Moreover, the nonspecific or mild symptoms seen in some cases may hinder early recognition and timely intervention. Salmonella 's invasion of intestinal epithelium and macrophages can trigger a hyperinflammatory response and immune-mediated haemolysis. L-Arginine depletion secondary to haemolysis may impair nitric oxide synthesis, predisposing to vascular dysfunction and placental insufficiency. The absence of standard guidelines for managing DAT-negative AIHA in pregnancy further underscores the need for heightened clinical suspicion and individualized management strategies. Next-generation sequencing may aid in identifying underlying genetic predispositions to hemolytic disorders. The potential for HSV reactivation and its contribution to fetal compromise, although considered, remains less supported in this case due to the lack of clinical lesions and the low specificity of IgM serology in pregnant lady who can be considered immunocompromised as well due to high dose steroids received in the previous 4 weeks. In addition to repeated viral testing the next year which revealed negative results for HSV Type II IgM and IgG. A multidisciplinary approach, including hematology, obstetrics, infectious disease, and clinical pharmacy, was pivotal. Timely use of antimicrobials, transfusion support, and immunosuppressive therapy stabilized maternal condition but could not reverse fetal outcome (Quentin A Hill 1, 2017) ( 26 ) . This case underscores the necessity of expanded maternal screening protocols and earlier fetal monitoring in immune-mediated anemia in unexplained hemolysis and sepsis-like presentations. In future cases, consideration for early immunomodulatory therapy, extended fetal surveillance, and even prophylactic transfusions may be warranted. Conclusion This case highlights the importance of recognizing Salmonella -induced AIHA as a potential contributor to IUFD. Given the multifactorial nature of fetal loss, we propose further research into the interplay between infection-induced hemolysis, immune dysregulation, and placental insufficiency. Clinicians should maintain a high index of suspicion for DAT-negative AIHA in pregnant patients presenting with unexplained hemolysis along with infection. We recommend inclusion of Typhoid IgM/IgG and HSV-PCR in unexplained maternal hemolysis during pregnancy, particularly in endemic regions as part of routine ANCsa. In addition, establishing serologies for Rubella and Syphilis, may facilitate early diagnosis and intervention, which ultimately improves maternal and fetal outcomes. Abbreviations Abbreviation Definition AIHA Autoimmune Hemolytic Anemia DAT Direct Antiglobulin Test IUFD Intrauterine Fetal Demise Hb Hemoglobin RBC Red Blood Cell IVIG Intravenous Immunoglobulin IV Intravenous LDH Lactate Dehydrogenase TORCH Toxoplasmosis, Other (syphilis, varicella-zoster, parvovirus B19), Rubella, Cytomegalovirus, Herpes simplex HSV Herpes Simplex Virus PCR Polymerase Chain Reaction NTS Non-typhoidal Salmonella Th1/Th2 T-helper cell type 1 / type 2 Tdap Tetanus, diphtheria, and acellular pertussis vaccine ANCsa Antenatal Care Serological Assessments Declarations This Manuscript is original work and has not been submitted or under consideration for publication elsewhere. All authors have reviewed and approved the manuscript. Ethical approval The case report was approved by the Hamad Medical Corporation’s Medical Research Centre under the number (MRC—04-24-788) Department and Institution: Clinical Haematology Department, NCCCR Consent for publication Inormed consent was obtained from all the participant for the publication of anonymized clinical information, including any potentially identifying images. Documentation of consent is available from the corresponding author upon reasonable request. Data availability statement The data supporting the findings of this case report are not publicly available due to concerns regarding patient confidentiality. De-identified data may be made available from the corresponding author upon reasonable request and with appropriate institutional approvals, where applicable. Conflict of interest The authors have no known competing interests that could have influenced this paper Funding information Qatar National Library (QNL) open-access forum Authors and Affiliations SE (corresponding author) a Department of Hematology and Bone Marrow Transplant, National Centre for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar; b Weill Cornell Medicine – Qatar (WCM-Q), Doha, Qatar ORCID: 0000-0002-5066–0125 [email protected] JK Clinical Haematology Department, National Centre for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar DS b Weill Cornell Medicine – Qatar (WCM-Q), Doha, Qatar; c Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, Doha, Qatar SA Infectious Disease Department, Communicable Disease Centre, Hamad Medical Corporation, Doha, Qatar NE (corresponding author) Department of Clinical Pharmacy and Pharmacology, Hamad Medical Corporation, Doha, Qatar [email protected] Acknowledgments Authors’ contributions: SAE and JAK contributed to manuscript writing and literature review. DS reviewed and contributed to the hematopathological content. NE reviewed and contributed to the pharmacological content. The authors thank the clinical teams involved in patient care. The authors would like to acknowledge Qatar National Library for funding this Open access article. References Guirguis GF, Patel K, Gittens-Williams L, Apuzzio JJ, Martimucci K, Williams SF. Salmonella enterica Serotype Typhi Bacteremia Complicating Pregnancy in the Third Trimester. Case Reports in Obstetrics and Gynecology [Internet]. 2017 Jan 19 [cited 2022 Nov 18];2017:e4018096. Availablefrom: https://www.hindawi.com/journals/criog/2017/4018096/ Gluck B, Ramin KD, Ramin SM. Salmonella typhi and Pregnancy: A Case Report. Infectious Diseases in Obstetrics and Gynecology [Internet]. 1994 [cited 2022 Nov 14];2(4):186–9. Available from: https://downloads.hindawi.com/journals/idog/1994/531470.pdf Chan MY, Smith MA. Infections in Pregnancy. Comprehensive Toxicology [Internet]. 2018;232–49. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152168/ ROLL C, SCHMID E, MENKEN U, HANSSLER L. Fatal sepsis acquired prenatally in a premature infant. Obstetrics & Gynecology. 1996 Oct;88(4):692–3. Thaxton JE, Sharma S. Interleukin-10: A Multi-Faceted Agent of Pregnancy. American Journal of Reproductive Immunology. 2010 Feb 16;63(6):482–91. Lim JR, Nielsen TC, Dale RC, Jones HF, Beech A, Nassar N, et al. Prevalence of autoimmune conditions in pregnant women in a tertiary maternity hospital: A cross-sectional survey and maternity database review. Obstetric Medicine. 2020 Nov 3;1753495X2096468. Singla N. Salmonella Typhi Isolation in a Pregnant Woman: Determining the Importance. JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH. 2013; Fattizzo B, Bortolotti M, Fantini NN, Glenthøj A, Michel M, Napolitano M, et al. Autoimmune hemolytic anemia during pregnancy and puerperium: an international multicenter experience. Blood [Internet]. 2023 Apr 20 [cited 2023 Nov 21];141(16):2016–21. Available from: https://pubmed.ncbi.nlm.nih.gov/36706358/ Cunnington AJ, de Souza JB, Walther M, et al. . Nat Med. 2011;18:120-127. Vigliani MB, Bakardjiev AI. First Trimester Typhoid Fever with Vertical Transmission of Salmonella Typhi, an Intracellular Organism. Case Reports in Medicine [Internet]. 2013 [cited 2024 Jan 23];2013:1–5. Available from: https://www.semanticscholar.org/paper/First-Trimester-Typhoid-Fever-with-Vertical-of-an-Vigliani-Bakardjiev/f44be0b1e795cafc94f7e500b69d09bcaefcb028 Zettell L, Jelsema RD, Isada NB. First-trimester Septic Abortion Due to Salmonella enteritidis Oranienburg. Infectious Diseases in Obstetrics and Gynecology. 1995;2(5):239–41. Rai B, Utekar T, Ray R. Preterm delivery and neonatal meningitis due to transplacental acquisition of non-typhoidal Salmonella serovar montevideo. Case Reports [Internet]. 2014 May 29 [cited 2024 Jan 29];2014:bcr2014205082. Available from: https://casereports.bmj.com/content/2014/bcr-2014-205082 Touchan F, Hall JD, Lee RV. Typhoid fever during pregnancy: case report and review. Obstetric Medicine. 2009 Nov 30;2(4):161–3. Lefkou E, Nelson-Piercy C, Hunt BJ. Evans’ syndrome in pregnancy: a systematic literature review and two new cases. European Journal of Obstetrics, Gynecology, and Reproductive Biology [Internet]. 2010 Mar 1;149(1):10–7. Available from: https://pubmed.ncbi.nlm.nih.gov/20031296/ Venkatachala RP, Sheela CN, Anandram S, Ross CR. Autoimmune Hemolytic Anaemias in Pregnancy: Experience in a Tertiary Care Hospital in South India. The Journal of Obstetrics and Gynecology of India. 2021 Mar 4;71(4):379–85. Czarina MM. Evans syndrome complicated by chronic hypertension with superimposed pre-eclampsia with HELLP syndrome in pregnancy: a case report. Philipp J Obstet Gynecol. 2017;41(1):32–37 Pretlove SJ, Fox CE, Khan KS, Kilby MD. Noninvasive methods of detecting fetal anaemia: a systematic review and meta-analysis. BJOG. 2009;116(12):1558–1567. doi: 10.1111/j.1471-0528.2009.02255.x. Jäger U, Barcellini W, Broome CM, Gertz MA, Hill A, Hill QA, Jilma B, Kuter DJ, Michel M, Montillo M, Röth A. Diagnosis and treatment of autoimmune hemolytic anemia in adults: recommendations from the First International Consensus Meeting. Blood Rev. 2020;1(41):100648. doi: 10.1016/j.blre.2019.100648. Rodberg K. DAT-Negative Autoimmune Hemolytic Anemia. Hematology/Oncology Clinics of North America. 2022 Apr;36(2):307–13. Shi TL, Huang LJ, Xiong Y, Zhong YY, Yang J, Fu T, et al. The risk of herpes simplex virus and human cytomegalovirus infection during pregnancy upon adverse pregnancy outcomes: A meta-analysis. Journal of Clinical Virology. 2018 Jul 1;104:48–55. American College of Obstetricians and Gynecologists (ACOG). Management of herpes in pregnancy. Obstet Gynecol. 2017;130(5):e251-e260. [ACOG Practice Bulletin No. 82, revised]. Centres for Disease Control and Prevention (CDC). Genital Herpes - CDC Fact Sheet (Detailed). Atlanta, GA: U.S. Department of Health and Human Services; 2022. Available from: https://www.cdc.gov/std/herpes/stdfact-herpes-detailed.htm Bougioukas L, Psoinos RBC, Jones DC, Morris EA, Hale AJ. Disseminated herpes simplex virus 2 as a complication of pregnancy. IDCases [Internet]. 2021 Jan 1 [cited 2024 Feb 8];24:e01107. Available from: https://www.sciencedirect.com/science/article/pii/S2214250921000639 Hussain NY, Uriel A, Mammen C, Bonington A. Disseminated herpes simplex infection during pregnancy, rare but important to recognise. Qatar Medical Journal. 2014 Jul 1;2014(1). Hammad WAB, Konje JC. Herpes simplex virus infection in pregnancy – An update. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2021 Apr;259:38–45. Hill QA, Stamps R, Massey E, Grainger JD, Provan D. Hill A The diagnosis and management of primary autoimmune haemolytic anaemia. Br J Haematol. 2017;176(3):395–411. doi: 10.1111/bjh.14478. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7113962","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":500167560,"identity":"a3fb1fbc-8765-4b1c-b252-ca70f1eda6ce","order_by":0,"name":"Sarah A. Elkourashy","email":"","orcid":"","institution":"National Centre for Cancer Care and Research (NCCCR), Hamad Medical Corporation (HMC)","correspondingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"A.","lastName":"Elkourashy","suffix":""},{"id":500167561,"identity":"19c51d2b-f6d8-4ccd-bed0-2eb51ab1295d","order_by":1,"name":"Jassim Ahmed Khan","email":"","orcid":"","institution":"National Centre for Cancer Care and Research (NCCCR), Hamad Medical Corporation (HMC)","correspondingAuthor":false,"prefix":"","firstName":"Jassim","middleName":"Ahmed","lastName":"Khan","suffix":""},{"id":500167562,"identity":"3393e91e-b53d-4592-89cd-fb7bf07c56f3","order_by":2,"name":"Dina Soliman","email":"","orcid":"","institution":"Weill Cornell Medicine-Qatar (WCM-Q)","correspondingAuthor":false,"prefix":"","firstName":"Dina","middleName":"","lastName":"Soliman","suffix":""},{"id":500167563,"identity":"6ab8686c-68ab-471d-b760-56d1f4f415af","order_by":3,"name":"Sulieman Abujarir","email":"","orcid":"","institution":"Hamad Medical Corporation","correspondingAuthor":false,"prefix":"","firstName":"Sulieman","middleName":"","lastName":"Abujarir","suffix":""},{"id":500167564,"identity":"01b3e5c2-6c9c-4e23-9101-e0b8e9d27243","order_by":4,"name":"Nurhan Elshafey","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIie3NPwrCMBTH8SeFusTOSqB6hCcFRXoZi4NLFA8gWBEyibPeokeoFOwScI10UA/gYsFFEf+hY1M3wXyX5A0ffgA63U9m+AaADVCcPq88pPAgDgARX5Myy0maxfEkHQzRxs1heZRDF6w4zCat6ZLT+QodTPodylZdqIh2NkHpcYOYFy9IGFJmRoChimz3k5RccRRshHNm1ztZ71QrBZ+WOLZRkgbt8TuRqhXhcVqaYX0hWMPtzbqkIlUrcRSl5IRVKxZOwk6uba0VK59q4eslEOYUUPXfv9xEp9Pp/qUba3tJEv01I/AAAAAASUVORK5CYII=","orcid":"","institution":"HMC","correspondingAuthor":true,"prefix":"","firstName":"Nurhan","middleName":"","lastName":"Elshafey","suffix":""}],"badges":[],"createdAt":"2025-07-13 14:38:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7113962/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7113962/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91533591,"identity":"b1da5cde-1705-4130-b71b-39b0edc0c250","added_by":"auto","created_at":"2025-09-17 12:32:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":535553,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7113962/v1/aa9a3f4d-f1f0-4031-be56-c6075956db3a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eSalmonella Induced Dat-Negative Autoimmune Haemolytic Anemia in a Pregnant Woman Complicated by Fetal Loss. Case Report and Literature Review\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003e\u003cem\u003eSalmonella\u003c/em\u003e infection in pregnancy can pose various threats to the pregnancy. However, its association with events leading to haemolytic anaemia is poorly understood and yet to be researched. Pregnancy loss, septic abortion, IUFD, preterm labour are anecdotally documented complications of \u003cem\u003eTyphi\u003c/em\u003e infections (George F Guirguis 1, 2017)\u003csup\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/sup\u003e. Although Salmonella is widely regarded as a treatable infection, its role in inducing hemolysis, particularly in pregnancy, remains poorly understood. While febrile illness with haemolysis in pregnancy usually provokes a suspicion of chorioamnionitis, viral infection and pyelonephritis (Brion Gluck 1, 1994)\u003csup\u003e(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/sup\u003e seldom do the Obstetricians and haematologists contemplate on \u003cem\u003eSalmonella\u003c/em\u003e typhi infection. The outcomes of infections in pregnancy could possibly include preterm birth, chorioamnionitis, meningitis, hydrocephaly, developmental delays, microcephaly, and sepsis (MY Chan 1, 2017)\u003csup\u003e(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/sup\u003e (Roll, 1995)\u003csup\u003e(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/sup\u003e. \u003cem\u003eSalmonella\u003c/em\u003e infections are commonly acquired from raw/undercooked eggs, raw meat, poultry, seafood, raw milk, dairy products. The factors impacting such infections in pregnancy could possibly link to the systematic shift from T-helper 1 (Th1) to T-helper 2 (Th2) cell-mediated responses in the mother. In a Th1-dominated response, the Th1-type T lymphocytes and proinflammatory cytokines amplify cell-mediated immunity allowing for recognition of the body’s own cells that engulf the pathogen and express pathogen-related antigens on their surfaces. When shifting to the Th2 cell-mediated response, the Th2-stimulating cytokines dominate and suppress the Th1 T cell responses probably diminishes self-recognition mechanism while the cell-mediated immunity is compromised (Jessica E Thaxton 1, 2013)\u003csup\u003e(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/sup\u003e. During pregnancy, the maternal immune system undergoes functional adaptations, particularly a bias toward Th2-dominant responses, facilitating tolerance of the semi-allogenic fetus. While this shift supports fetal survival, it may compromise the ability to mount effective responses against intracellular organisms like \u003cem\u003eSalmonella\u003c/em\u003e, potentially leading to heightened severity or unusual presentations of infections. (MY Chan 1, 2017)\u003csup\u003e(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eEpidemiologically, autoimmunity complicates 0.9–10% of pregnancies (Jacqueline R Lim 1, 2021)\u003csup\u003e(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/sup\u003e. The differential diagnosis of DAT-negative AIHA in pregnancy is complex and requires the exclusion of other possible causes of haemolysis (physiologic conditions such as haemodilution, nutrient deficiency; chronic pre-existing ones, hemoglobinopathies, congenital haemolytic anaemias and acute severe forms, such as pre-eclamptic syndromes and microangiopathies).\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 28-year-old primigravida, previously healthy, presented at 32 weeks of gestation with a 3-day history of sudden-onset diarrhoea, vomiting, and low-grade fever. She was not on any medication apart from prenatal vitamins and iron supplements. She had more than 10 episodes of greenish diarrhoea per day, accompanied by nausea, vomiting (3–4 episodes daily), and progressive pallor. Over the preceding few days, she had also noticed dark-coloured urine and increasing fatigue. She noticed her skin colour turned pale, and the urine turned dark colour over the last few days. She had no cough or any URTI symptoms.\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical and Laboratory Findings\u003c/b\u003e\u003c/p\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eHaemoglobin (Hb): 7.6 g/dL (macrocytic anemia, MCV 112)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eReticulocyte count: 293 ×10⁹/L (elevated, suggestive of hemolysis)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003ePeripheral smear: Leucoerythroblastic picture with macrocytosis\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eDirect Antiglobulin Test (DAT): Negative\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eLiver Function Tests: Mild elevation in direct bilirubin, LDH 267\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eSepsis Workup: Negative blood/urine cultures, positive stool culture for \u003cem\u003eSalmonella\u003c/em\u003e group B, yet negative for stool ova parasite and Clostridium difficile.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eInfectious Workup: Negative for viral hepatitis, TORCH screen\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003cp\u003eInitial management of the patient included initiation of intravenous (IV) ceftriaxone (2g daily) and metronidazole (500 mg three times daily). She was transfused with packed RBCs, achieving an Hb increase to 8 g/dL, which later dropped to 6.6 g/dL despite ongoing therapy. Yet again after 4 days, she was re- transfused with packed RBCs; Haemolysis secondary to Acute GI infection was concluded and the patient kept on the same antimicrobials. After seven-day course of antimicrobials, she presented again with generalised fatigue and shortness of breath. Her labs showed Hb of 7.2 g/dL, retic count raised up to 625 and persistent positive stool culture for \u003cem\u003eSalmonella\u003c/em\u003e group B. An ultrasound abdomen was executed, which showed mild splenomegaly (14.6cm). In view of persistent haemolysis, IV methylprednisolone (60 mg daily) and IV immunoglobulin (0.5 g/kg for 4 days) were started, leading to Hb stabilization (9.3 g/dL). Later, she was discharged on oral prednisolone (60 mg daily, tapered gradually). Unfortunately, seven days later, patient presented with complaints of decreased fetal movements with progressive decline for the last 2 days. At 36 weeks gestation, she presented with reduced fetal movements for two days, and USG revealed intrauterine foetal death (IUFD).\u003c/p\u003e\u003cp\u003eShe was completely asymptomatic with no features of recent infection. No history of sexual transmitted disease and upon examination; no oral or genital vesicles.\u003c/p\u003e\u003cp\u003eIUFD Workup:\u003c/p\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eTORCH screen: HSV IgM positive, HSV Type I IgG positive, HSV Type II IgG negative. Cytomegalovirus/Rubella serology were negative\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eThrombophilia panel: normal levels of Protein C, S and antithrombin III, no mutation detected for Prothrombin c.*97G \u0026gt; A variant or Factor V Leiden variant c.1601G \u0026gt; A (p.R534Q) as genetic risk factor for pregnancy loss, Lupus Anticoagulants and antibodies for antiphospholipid syndrome were not detected.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAutoimmune screen: Negative\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003ePlacental histopathology: No significant pathology.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003cp\u003eShe was induced for vaginal delivery, and post-delivery care focused mainly on good psychological support. She was discharged on prednisolone 30mg daily with tapering doses for the next 3 weeks with other supportive measures.\u003c/p\u003e\u003cp\u003eOn the following year, the patient conceived spontaneously and delivered uneventfully. Viral serology for Herpes simplex virus was repeated at 1 year from the event of IUFD and showed HSV IgM negative, HSV Type I IgG positive, HSV Type II IgG negative which confirmed no previous infection of HSV Type II and previous detection of HSV IgM during the workup of fetal demise was just false positive result.\u003c/p\u003e"},{"header":"Discussion and Conclusion","content":"\u003cp\u003e\u003cem\u003eSalmonella\u003c/em\u003e infection in pregnancy occurs with similar frequency as in the general population, with an incidence of 0.2% positive rectal cultures at the time of delivery (Neelam Kaistha 1, 2013)\u003csup\u003e(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn a retrospective study on Relapse and De novo AIHA along with its treatment outcomes conducted by (Bruno Fattizzo, 2013)\u003csup\u003e(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/sup\u003e spanning 12 tertiary haematology centres across Italy, Denmark, France, the Netherlands, the United Kingdom, the United States, and Spain, ranging from 1997–2002,they concluded that amongst the 33 women - the 20 women were diagnosed with AIHA before pregnancy, 10 had a relapse. An additional 13 patients developed de novo AIHA during gestation/puerperium (2 patients had AIHA relapse during a second pregnancy). Among 24 haemolytic events, anaemia was uniformly severe (median Hb, 6.4 g/dL; range, 3.1–8.7) and required treatment in all cases (96% steroids ± intravenous immunoglobulin, IVIG, 58% transfusions). Response was achieved in all patients and was complete in 65% of the cases. Antithrombotic prophylaxis was administered to 8 patients (33%). After delivery, rituximab was administered to 4 patients, and cyclosporine was added to 1 patient. The rate of maternal complications, including premature rupture of membranes, placental detachment, and preeclampsia, was 15%. Early miscarriages occurred in 13% of the pregnancies. Fetal adverse events (22% of cases) included respiratory distress, fetal growth restriction, preterm birth, AIHA of the newborn, and 2 perinatal deaths. They also advocated on use of Rituximab in severe refractory cases after weighing risk vs benefit. However, its use during pregnancy induces B-cell depletion in foetus. Hence, we advise that prior to starting Rituximab, the decision should be judicious.\u003c/p\u003e\u003cp\u003eThe interplay between \u003cem\u003eSalmonella\u003c/em\u003e infection and hemolysis has been studied, particularly in regions endemic to both malaria and non-typhoidal \u003cem\u003eSalmonella\u003c/em\u003e (NTS) infections. \u003cem\u003eSalmonella\u003c/em\u003e initially invade epithelial and M cells of the intestine within Peyer's patches and bacteria are then phagocytosed by macrophages and dendritic cells in the intestinal wall. This facilitates dissemination via the lymphatic system and blood to other tissues. In the absence of haemolysis, the spleen and liver are the major sites of \u003cem\u003eSalmonella\u003c/em\u003e replication, where bacteria are predominately found within macrophages. L-Arginine plays a crucial role in limiting intestinal permeability and translocation of both \u003cem\u003eE. coli\u003c/em\u003e and NTS. At the level of invasion across the intestinal mucosa, one potential mechanism is haemolysis-related depletion of L-arginine; the substrate for nitric oxide synthesis. Arginase, an arginine degrading enzyme, is released from RBCs during intravascular haemolysis with free Hb. The latter also drives L-arginine depletion by scavenging nitric oxide. Thus, it’s clear that diminished levels of L-Arginine could possibly provide facile access to invade and disseminate infection. Impaired neutrophil oxidative burst has also been observed in sickle cell disease, which is characterized by severe haemolysis and dramatically increased susceptibility to NTS infection, indicating this mechanism may be a general consequence of haemolysis. Thus, in the setting of concurrent intravascular, granulocytes entering the circulation in response to infection are able to phagocytose \u003cem\u003eS. typhimurium\u003c/em\u003e but, owing to their reduced oxidative burst capacity, fail to kill them, providing instead an innocuous niche for bacterial replication and dissemination (Cunnington AJ, 2012)\u003csup\u003e(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAn interesting case published(Marguerite B Vigliani 1, 2013) \u003csup\u003e(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/sup\u003e in 2013 depicting first trimester loss due to \u003cem\u003eSalmonella\u003c/em\u003e typhii infection found \u003cem\u003eSalmonella\u003c/em\u003e in fetal tissues at autopsy. They also drew \u003cem\u003eS.\u003c/em\u003e Typhi and \u003cem\u003eL. monocytogenes\u003c/em\u003e to develop a plausible hypothesis to explain how this organism was able to cross the placenta in the first trimester to cause abruption, inflammation, and expulsion of the foetus and placenta. An interesting facet is non-typhoidal \u003cem\u003eSalmonella\u003c/em\u003e is still a cause of morbidity in Western countries. This infection can result in rapid-onset fetal demise and septic abortion (LoriAnn Zettell 1, 1995)\u003csup\u003e(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/sup\u003e.\u003cem\u003eSalmonella\u003c/em\u003e Mississippi, \u003cem\u003eSalmonella\u003c/em\u003e enteritidis Oranienburg, \u003cem\u003eS.\u003c/em\u003eVirchow, Group C1, \u003cem\u003eS\u003c/em\u003e .Dublin are rare species which have been anecdotally documented to cause 1st and 2nd trimester abortions. \u003cem\u003eS\u003c/em\u003e serovar Montevideo has been exceptional from other variants as it has been documented to cause Neonatal meningitides, cultures from placenta were found to be positive (Birendra Rai 1, 2014)\u003csup\u003e(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAppropriate and timely cultures obtained prior to the initiation of antibiotic therapy are essential for confirming the diagnosis. Blood cultures are positive early in the course of infection, while stool cultures are positive later in the course of the infection. Cultures of multiple sites (urine, amniotic fluid, skin scrapings, bone marrow) improve the yield of a positive culture (Brion Gluck 1, 1994) \u003csup\u003e(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/sup\u003e. Ampicillin 8g/day and Ceftriaxone 75mg/kg/day for 5 days have been the cornerstone in treating \u003cem\u003eSalmonella\u003c/em\u003e Infections in pregnancy in today’s time.\u003c/p\u003e\u003cp\u003eThe Vi capsular polysaccharide vaccine provides effective immunity for two years with a single dose. It is safe to use during pregnancy. However, the duration of protection is relatively short; hence frequent travellers or long-term residents in high-risk areas need boosters every third year (Faraj Touchan *, 2009)\u003csup\u003e(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThis case is further complicated by DAT-negative, AIHA in pregnancy can have variable outcomes with an estimated incidence of 0.8–3/100,000/year (Lefkou, 2010)\u003csup\u003e(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/sup\u003e. AIHA could be primary or secondary (Systemic Lupus Erythematosus, malignancies, infections or immunodeficiency). The blood indices need to wisely monitor throughout the pregnancy. In a retrospective descriptive study performed between 2011–2016 by \u003cem\u003eRao Preethi Venkatachala\u003c/em\u003e (Rao Preethi Venkatachala, 2021) \u003csup\u003e(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/sup\u003e and her colleagues in South India on AIHA in pregnancy, they found DAT negative pregnancies required higher number of intrapartum transfusions, fever, abortions, anaemia and jaundice and few required Azathioprine and steroids. In a cohort study of clinical course of pregnancy with AIHA and their perinatal outcomes, published by \u003cem\u003eIrina Murakhovskaya and\u003c/em\u003e colleagues in 2021, they found shorter duration of postpartum haemolysis in DAT negative cases while steroid and transfusions were given in both settings. In steroid refractory cases, IV Ig is used. Intravenous immunoglobulin helps to block the macrophages that work to destroy platelets prematurely and improves platelet survival time. Second-line treatment options include rituximab (category C drug) and splenectomy (MM, 2017) \u003csup\u003e(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eNegative DAT may be due to a small quantity of IgG on their red blood cells (RBCs) (below detectable levels), or when low-affinity anti-IgG is present, or when the autoantibodies are IgA or IgM in nature. Nevertheless, early identification of DAT negative anaemia in pregnancy and substantial response to steroid have led to excellent maternal and fetal outcomes. Foetal monitoring with serial ultrasonography should be initiated from 20 weeks of gestation to assess foetal growth and Doppler assessment of foetal middle cerebral artery (MCA) peak systolic velocity to assess for foetal anaemia (Rao Preethi Venkatachala, 2021) \u003csup\u003e(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/sup\u003e (S J Pretlove, 2009)\u003csup\u003e(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/sup\u003e (Ulrich Jäger, 2020)\u003csup\u003e(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/sup\u003e. In our opinion, DAT negative AIHA is perhaps a diagnostic challenge since it requires an extensive negative work-up to rule out any other cause of congenital or acquired haemolytic anaemia. Next Generation Sequencing analyses are now increasingly used to detect the presence of relevant variants and somatic mutations and may be helpful to find some previously unexplained haemolytic anaemia. The management of DN-AIHA is not standardized and mostly extrapolated from the one of AIHA. Steroids, splenectomy and/or the treatment of an underlying disease may lead to a complete and durable remission (Rodberg, 2022) \u003csup\u003e(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/sup\u003e. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.)\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eLiterature Review Summary\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAIHA in Pregnancy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eKey Outcomes\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eClinical Implications\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFattizzo et al. (2023)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33 cases of AIHA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22% had fetal complications (IUFD, preterm birth)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAIHA in pregnancy requires aggressive management and fetal monitoring\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVigliani et al. (2013)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eSalmonella\u003c/em\u003e \u0026amp; early pregnancy loss\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFound \u003cem\u003eSalmonella\u003c/em\u003e in fetal tissues\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHighlights placental invasion as a risk factor for IUFD\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMurakhovskaya et al. (2021)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDAT-negative AIHA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBetter postpartum recovery, but required steroids \u0026amp; IVIG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDAT-negative AIHA can be managed effectively with steroids and IVIG\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBougioukas et al. (2021)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHSV in late pregnancy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50% IUFD rate in disseminated cases\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRoutine HSV screening may be needed in unexplained fetal loss\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003eThe workup of IUFD revealed positive HSV IgM results raising suspicion for concurrent HSV infection. In asymptomatic pregnant women, a positive HSV IgM result, coupled with the absence of vesicular rash, and a subsequent negative result after pregnancy, alongside persistent negative HSV-2 IgG during and after pregnancy, makes the possibility of disseminated HSV unlikely. It is important to note that positive HSV IgM results during pregnancy are not uncommon, and it is generally not recommended to rely on HSV IgM testing during pregnancy due to its lack of specificity and potential for false positives (Ting-Li Shi 1, 2018) \u003csup\u003e(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eTheoretically, the presence of HSV IgM at 36 weeks, despite an absence of clinical symptoms or lesions, raises concerns regarding asymptomatic viral shedding and transplacental transmission. HSV IgM testing is discouraged during pregnancy due to its low specificity and high false-positive rate (ACOG 2017) \u003csup\u003e(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/sup\u003e. CDC also advises against HSV IgM testing, recommending type-specific serologic assays instead (CDC 2021) \u003csup\u003e(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/sup\u003e. Disseminated HSV-2 has a predilection for late pregnancy, with up to 65% of cases occurring in the third trimester and an overall 50% risk of transplacental infection (Lauren Bougioukas a, 2021)\u003csup\u003e(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/sup\u003e. Vertical transmission during pregnancy is rare occurring in less than 1% of cases but for those with active lesions or shedding the virus asymptomatically the risk of vertical transmission intrapartum is high (Ting-Li Shi 1, 2018) \u003csup\u003e(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/sup\u003e (Nawar Younis Hussain 1, 2014) \u003csup\u003e(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e)\u003c/sup\u003e. In fact, Routine HSV screening is not included in antenatal care (ANC), but targeted testing through vaginal swabs, PCR, and obstetric scans is essential in suspected cases (Wafaa Ali Belail Hammad 1, 2021) \u003csup\u003e(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThis case demonstrates a rare but clinically significant progression of \u003cem\u003eSalmonella\u003c/em\u003e infection during pregnancy. Immune modulation in pregnancy predisposes women to disseminated infections that may pose serious risks to maternal and fetal health. Infections caused by \u003cem\u003eSalmonella\u003c/em\u003e have been linked to adverse outcomes such as spontaneous abortion, premature delivery, and intrauterine fetal demise. Moreover, the nonspecific or mild symptoms seen in some cases may hinder early recognition and timely intervention.\u003c/p\u003e\u003cp\u003e\u003cem\u003eSalmonella\u003c/em\u003e's invasion of intestinal epithelium and macrophages can trigger a hyperinflammatory response and immune-mediated haemolysis. L-Arginine depletion secondary to haemolysis may impair nitric oxide synthesis, predisposing to vascular dysfunction and placental insufficiency. The absence of standard guidelines for managing DAT-negative AIHA in pregnancy further underscores the need for heightened clinical suspicion and individualized management strategies. Next-generation sequencing may aid in identifying underlying genetic predispositions to hemolytic disorders.\u003c/p\u003e\u003cp\u003eThe potential for HSV reactivation and its contribution to fetal compromise, although considered, remains less supported in this case due to the lack of clinical lesions and the low specificity of IgM serology in pregnant lady who can be considered immunocompromised as well due to high dose steroids received in the previous 4 weeks. In addition to repeated viral testing the next year which revealed negative results for HSV Type II IgM and IgG.\u003c/p\u003e\u003cp\u003eA multidisciplinary approach, including hematology, obstetrics, infectious disease, and clinical pharmacy, was pivotal. Timely use of antimicrobials, transfusion support, and immunosuppressive therapy stabilized maternal condition but could not reverse fetal outcome (Quentin A Hill 1, 2017) \u003csup\u003e(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThis case underscores the necessity of expanded maternal screening protocols and earlier fetal monitoring in immune-mediated anemia in unexplained hemolysis and sepsis-like presentations. In future cases, consideration for early immunomodulatory therapy, extended fetal surveillance, and even prophylactic transfusions may be warranted.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case highlights the importance of recognizing \u003cem\u003eSalmonella\u003c/em\u003e-induced AIHA as a potential contributor to IUFD. Given the multifactorial nature of fetal loss, we propose further research into the interplay between infection-induced hemolysis, immune dysregulation, and placental insufficiency. Clinicians should maintain a high index of suspicion for DAT-negative AIHA in pregnant patients presenting with unexplained hemolysis along with infection. We recommend inclusion of Typhoid IgM/IgG and HSV-PCR in unexplained maternal hemolysis during pregnancy, particularly in endemic regions as part of routine ANCsa. In addition, establishing serologies for Rubella and Syphilis, may facilitate early diagnosis and intervention, which ultimately improves maternal and fetal outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.2097%;\"\u003e\n \u003cp\u003eAbbreviation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72.7903%;\"\u003e\n \u003cp\u003eDefinition\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.2097%;\"\u003e\n \u003cp\u003eAIHA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72.7903%;\"\u003e\n \u003cp\u003eAutoimmune Hemolytic Anemia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.2097%;\"\u003e\n \u003cp\u003eDAT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72.7903%;\"\u003e\n \u003cp\u003eDirect Antiglobulin Test\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.2097%;\"\u003e\n \u003cp\u003eIUFD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72.7903%;\"\u003e\n \u003cp\u003eIntrauterine Fetal Demise\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.2097%;\"\u003e\n \u003cp\u003eHb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72.7903%;\"\u003e\n \u003cp\u003eHemoglobin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.2097%;\"\u003e\n \u003cp\u003eRBC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72.7903%;\"\u003e\n \u003cp\u003eRed Blood Cell\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.2097%;\"\u003e\n \u003cp\u003eIVIG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72.7903%;\"\u003e\n \u003cp\u003eIntravenous Immunoglobulin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.2097%;\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72.7903%;\"\u003e\n \u003cp\u003eIntravenous\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.2097%;\"\u003e\n \u003cp\u003eLDH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72.7903%;\"\u003e\n \u003cp\u003eLactate Dehydrogenase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.2097%;\"\u003e\n \u003cp\u003eTORCH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72.7903%;\"\u003e\n \u003cp\u003eToxoplasmosis, Other (syphilis, varicella-zoster, parvovirus B19), Rubella, Cytomegalovirus, Herpes simplex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.2097%;\"\u003e\n \u003cp\u003eHSV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72.7903%;\"\u003e\n \u003cp\u003eHerpes Simplex Virus\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.2097%;\"\u003e\n \u003cp\u003ePCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72.7903%;\"\u003e\n \u003cp\u003ePolymerase Chain Reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.2097%;\"\u003e\n \u003cp\u003eNTS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72.7903%;\"\u003e\n \u003cp\u003eNon-typhoidal Salmonella\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.2097%;\"\u003e\n \u003cp\u003eTh1/Th2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72.7903%;\"\u003e\n \u003cp\u003eT-helper cell type 1 / type 2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.2097%;\"\u003e\n \u003cp\u003eTdap\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72.7903%;\"\u003e\n \u003cp\u003eTetanus, diphtheria, and acellular pertussis vaccine\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.2097%;\"\u003e\n \u003cp\u003eANCsa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72.7903%;\"\u003e\n \u003cp\u003eAntenatal Care Serological Assessments\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003eThis Manuscript is original work and has not been submitted or under consideration for publication elsewhere. All authors have reviewed and approved the manuscript.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\n \u003cul\u003e\n \u003cli\u003eThe case report was approved by the Hamad Medical Corporation\u0026rsquo;s Medical Research Centre under the number (MRC\u0026mdash;04-24-788)\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDepartment and Institution: Clinical Haematology Department, NCCCR\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eInormed consent was obtained from all the participant for the publication of anonymized clinical information, including any potentially identifying images. Documentation of consent is available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\n \u003cul\u003e\n \u003cli\u003eThe data supporting the findings of this case report are not publicly available due to concerns regarding patient confidentiality.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDe-identified data may be made available from the corresponding author upon reasonable request and with appropriate institutional approvals, where applicable.\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\n \u003cul\u003e\n \u003cli\u003eThe authors have no known competing interests that could have influenced this paper\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eFunding information\u0026nbsp;\u003c/strong\u003e\n \u003cul\u003e\n \u003cli\u003eQatar National Library (QNL) open-access forum\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAuthors and Affiliations\u003c/strong\u003e\n \u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eSE (corresponding author)\u003c/strong\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003ea Department of Hematology and Bone Marrow Transplant, National Centre for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar;\u0026nbsp;\u003cbr\u003e\u0026nbsp;b Weill Cornell Medicine \u0026ndash; Qatar (WCM-Q), Doha, Qatar\u003cbr\u003e\u0026nbsp; ORCID: 0000-0002-5066\u0026ndash;0125\u003c/p\u003e\n\u003cp\[email protected]\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eJK\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Clinical Haematology Department, National Centre for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDS\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;b Weill Cornell Medicine \u0026ndash; Qatar (WCM-Q), Doha, Qatar;\u0026nbsp;\u003cbr\u003e\u0026nbsp;c Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, Doha, Qatar\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eSA\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Infectious Disease Department, Communicable Disease Centre, Hamad Medical Corporation, Doha, Qatar\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eNE (corresponding author)\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Department of Clinical Pharmacy and Pharmacology, Hamad Medical Corporation, Doha, Qatar\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\[email protected]\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\n \u003cul\u003e\n \u003cli\u003eAuthors\u0026rsquo; contributions: SAE and JAK contributed to manuscript writing and literature review. DS reviewed and contributed to the hematopathological content. NE reviewed and contributed to the pharmacological content.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe authors thank the clinical teams involved in patient care.\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe authors would like to acknowledge Qatar National Library for funding this Open access article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGuirguis GF, Patel K, Gittens-Williams L, Apuzzio JJ, Martimucci K, Williams SF. Salmonella enterica Serotype Typhi Bacteremia Complicating Pregnancy in the Third Trimester. Case Reports in Obstetrics and Gynecology [Internet]. 2017 Jan 19 [cited 2022 Nov 18];2017:e4018096. Availablefrom: https://www.hindawi.com/journals/criog/2017/4018096/\u003c/li\u003e\n\u003cli\u003eGluck B, Ramin KD, Ramin SM. Salmonella typhi and Pregnancy: A Case Report. Infectious Diseases in Obstetrics and Gynecology [Internet]. 1994 [cited 2022 Nov 14];2(4):186\u0026ndash;9. Available from: https://downloads.hindawi.com/journals/idog/1994/531470.pdf\u003c/li\u003e\n\u003cli\u003eChan MY, Smith MA. Infections in Pregnancy. Comprehensive Toxicology [Internet]. 2018;232\u0026ndash;49. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152168/\u003c/li\u003e\n\u003cli\u003eROLL C, SCHMID E, MENKEN U, HANSSLER L. Fatal sepsis acquired prenatally in a premature infant. Obstetrics \u0026amp; Gynecology. 1996 Oct;88(4):692\u0026ndash;3.\u003c/li\u003e\n\u003cli\u003eThaxton JE, Sharma S. Interleukin-10: A Multi-Faceted Agent of Pregnancy. American Journal of Reproductive Immunology. 2010 Feb 16;63(6):482\u0026ndash;91.\u003c/li\u003e\n\u003cli\u003eLim JR, Nielsen TC, Dale RC, Jones HF, Beech A, Nassar N, et al. Prevalence of autoimmune conditions in pregnant women in a tertiary maternity hospital: A cross-sectional survey and maternity database review. Obstetric Medicine. 2020 Nov 3;1753495X2096468.\u003c/li\u003e\n\u003cli\u003eSingla N. Salmonella Typhi Isolation in a Pregnant Woman: Determining the Importance. JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH. 2013;\u003c/li\u003e\n\u003cli\u003eFattizzo B, Bortolotti M, Fantini NN, Glenth\u0026oslash;j A, Michel M, Napolitano M, et al. Autoimmune hemolytic anemia during pregnancy and puerperium: an international multicenter experience. Blood [Internet]. 2023 Apr 20 [cited 2023 Nov 21];141(16):2016\u0026ndash;21. Available from: https://pubmed.ncbi.nlm.nih.gov/36706358/\u003c/li\u003e\n\u003cli\u003eCunnington AJ, de Souza JB, Walther M, et al. . Nat Med. 2011;18:120-127.\u003c/li\u003e\n\u003cli\u003eVigliani MB, Bakardjiev AI. First Trimester Typhoid Fever with Vertical Transmission of Salmonella Typhi, an Intracellular Organism. Case Reports in Medicine [Internet]. 2013 [cited 2024 Jan 23];2013:1\u0026ndash;5. Available from: https://www.semanticscholar.org/paper/First-Trimester-Typhoid-Fever-with-Vertical-of-an-Vigliani-Bakardjiev/f44be0b1e795cafc94f7e500b69d09bcaefcb028\u003c/li\u003e\n\u003cli\u003eZettell L, Jelsema RD, Isada NB. First-trimester Septic Abortion Due to Salmonella enteritidis Oranienburg. Infectious Diseases in Obstetrics and Gynecology. 1995;2(5):239\u0026ndash;41.\u003c/li\u003e\n\u003cli\u003eRai B, Utekar T, Ray R. Preterm delivery and neonatal meningitis due to transplacental acquisition of non-typhoidal Salmonella serovar montevideo. Case Reports [Internet]. 2014 May 29 [cited 2024 Jan 29];2014:bcr2014205082. Available from: https://casereports.bmj.com/content/2014/bcr-2014-205082\u003c/li\u003e\n\u003cli\u003eTouchan F, Hall JD, Lee RV. Typhoid fever during pregnancy: case report and review. Obstetric Medicine. 2009 Nov 30;2(4):161\u0026ndash;3.\u003c/li\u003e\n\u003cli\u003eLefkou E, Nelson-Piercy C, Hunt BJ. Evans\u0026rsquo; syndrome in pregnancy: a systematic literature review and two new cases. European Journal of Obstetrics, Gynecology, and Reproductive Biology [Internet]. 2010 Mar 1;149(1):10\u0026ndash;7. Available from: https://pubmed.ncbi.nlm.nih.gov/20031296/\u003c/li\u003e\n\u003cli\u003eVenkatachala RP, Sheela CN, Anandram S, Ross CR. Autoimmune Hemolytic Anaemias in Pregnancy: Experience in a Tertiary Care Hospital in South India. The Journal of Obstetrics and Gynecology of India. 2021 Mar 4;71(4):379\u0026ndash;85.\u003c/li\u003e\n\u003cli\u003eCzarina MM. Evans syndrome complicated by chronic hypertension with superimposed pre-eclampsia with HELLP syndrome in pregnancy: a case report. \u003cem\u003ePhilipp J Obstet Gynecol. \u003c/em\u003e2017;41(1):32\u0026ndash;37\u003c/li\u003e\n\u003cli\u003ePretlove SJ, Fox CE, Khan KS, Kilby MD. Noninvasive methods of detecting fetal anaemia: a systematic review and meta-analysis. \u003cem\u003eBJOG. \u003c/em\u003e2009;116(12):1558\u0026ndash;1567. doi: 10.1111/j.1471-0528.2009.02255.x.\u003c/li\u003e\n\u003cli\u003eJ\u0026auml;ger U, Barcellini W, Broome CM, Gertz MA, Hill A, Hill QA, Jilma B, Kuter DJ, Michel M, Montillo M, R\u0026ouml;th A. Diagnosis and treatment of autoimmune hemolytic anemia in adults: recommendations from the First International Consensus Meeting. \u003cem\u003eBlood Rev. \u003c/em\u003e2020;1(41):100648. doi: 10.1016/j.blre.2019.100648.\u003c/li\u003e\n\u003cli\u003eRodberg K. DAT-Negative Autoimmune Hemolytic Anemia. Hematology/Oncology Clinics of North America. 2022 Apr;36(2):307\u0026ndash;13.\u003c/li\u003e\n\u003cli\u003eShi TL, Huang LJ, Xiong Y, Zhong YY, Yang J, Fu T, et al. The risk of herpes simplex virus and human cytomegalovirus infection during pregnancy upon adverse pregnancy outcomes: A meta-analysis. Journal of Clinical Virology. 2018 Jul 1;104:48\u0026ndash;55.\u003c/li\u003e\n\u003cli\u003eAmerican College of Obstetricians and Gynecologists (ACOG). Management of herpes in pregnancy. Obstet Gynecol. 2017;130(5):e251-e260. [ACOG Practice Bulletin No. 82, revised].\u003c/li\u003e\n\u003cli\u003eCentres for Disease Control and Prevention (CDC). Genital Herpes - CDC Fact Sheet (Detailed). Atlanta, GA: U.S. Department of Health and Human Services; 2022. Available from: https://www.cdc.gov/std/herpes/stdfact-herpes-detailed.htm\u003c/li\u003e\n\u003cli\u003eBougioukas L, Psoinos RBC, Jones DC, Morris EA, Hale AJ. Disseminated herpes simplex virus 2 as a complication of pregnancy. IDCases [Internet]. 2021 Jan 1 [cited 2024 Feb 8];24:e01107. Available from: https://www.sciencedirect.com/science/article/pii/S2214250921000639\u003c/li\u003e\n\u003cli\u003eHussain NY, Uriel A, Mammen C, Bonington A. Disseminated herpes simplex infection during pregnancy, rare but important to recognise. Qatar Medical Journal. 2014 Jul 1;2014(1).\u003c/li\u003e\n\u003cli\u003eHammad WAB, Konje JC. Herpes simplex virus infection in pregnancy \u0026ndash; An update. European Journal of Obstetrics \u0026amp; Gynecology and Reproductive Biology. 2021 Apr;259:38\u0026ndash;45.\u003c/li\u003e\n\u003cli\u003eHill QA, Stamps R, Massey E, Grainger JD, Provan D. Hill A The diagnosis and management of primary autoimmune haemolytic anaemia. \u003cem\u003eBr J Haematol. \u003c/em\u003e2017;176(3):395\u0026ndash;411. doi: 10.1111/bjh.14478.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":", Autoimmune hemolytic anemia (AIHA), DAT-negative hemolysis, Salmonella infection, Pregnancy complications, Intrauterine fetal demise (IUFD), Infectious hemolysis, Third trimester pregnancy, Hematologic disorders in pregnancy, Immunohematology, Case report","lastPublishedDoi":"10.21203/rs.3.rs-7113962/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7113962/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eInfections during pregnancy present unique diagnostic and therapeutic challenges, particularly when rare immune complications arise during gestation. Haemolytic anaemia induced by Salmonella infection is a seldom-reported phenomenon, especially during gestation. We describe a 28-year-old previously healthy primigravida who presented at 32 weeks with acute gastroenteritis caused by Salmonella Group B and was subsequently diagnosed with direct antiglobulin test-negative (DAT-negative) autoimmune haemolytic anaemia (AIHA). Despite supportive care, antibiotics, and immunosuppressive therapy, the patient experienced an unexplained intrauterine fetal death (IUFD) at 36 weeks. This case underscores the importance of early recognition of atypical infectious sequelae in pregnancy, the diagnostic challenge of DAT-negative AIHA, and the potential feto-maternal consequences. We review the immunopathologic mechanisms, diagnostic considerations, and implications for antenatal care, advocating for heightened clinical vigilance and interdisciplinary management.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e","manuscriptTitle":"Salmonella Induced Dat-Negative Autoimmune Haemolytic Anemia in a Pregnant Woman Complicated by Fetal Loss. Case Report and Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-19 09:00:06","doi":"10.21203/rs.3.rs-7113962/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"73442d6c-0d2c-4e24-aa0c-7a45b1df0a15","owner":[],"postedDate":"August 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-17T12:24:05+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-19 09:00:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7113962","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7113962","identity":"rs-7113962","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}