Unexplained Recurrent Maternal Fever Leading To Fetal Demise: Role of Empirical Therapy For Successful Outcome

Annals of Case Reports and Clinical Studies Case Report (ISSN: 2834-5673) Annal Cas Rep Clin Stud (ACRCS) 2025 | Volume 4 | Issue 12 Unexplained Recurrent Maternal Fever Leading To Fetal Demise: Role of Empirical Therapy For Successful Outcome Malini Sukayogula*, Tarakeswari Surapaneni, HemaMalini Vadlamani Maternal and Fetal Medicine, Fernandez Hospital, Hyderabad, Telangana, India Citation: Malini Sukayogula, Tarakeswari Surapaneni, HemaMalini Vadlamani. Unexplained Recurrent Maternal Fever Leading To Fetal Demise: Role of Empirical Therapy For Successful Outcome. Ann Case Rep Clin Stud. 2025;4(12):1-6. Received Date: 15 December 2025; Accepted Date: 17 December 2025; Published Date: 19 December 2025 *Corresponding author: Malini Sukayogula, Maternal and Fetal Medicine, Fernandez Hospital, Hyderabad, Telangana, India Copyright: © Malini Sukayogula, Open Access 2025. This article, published in Ann Case Rep Clin Stud (ACRCS) (Attribution 4.0 International), as described by http://creativecommons.org/licenses/by/4.0/ ABSTRACT Background: Pyrexia of unknown origin (PUO) during pregnancy is uncommon and poses significant diagnostic and management challenges. It may reflect underlying immune dysregulation, contributing to adverse fetal outcomes. Case Presentation: We report a 26-year-old woman with recurrent mid-trimester high-grade fevers during two consecutive pregnancies, both ending in intrauterine fetal demise (IUFD). Extensive investigations failed to identify an infectious, malignant, or inflammatory cause. Placental histopathology revealed inflammatory changes. Lupus anticoagulant was later found to be positive. In her third pregnancy, early initiation of empirical immunosuppressive therapy—azathioprine, low-dose steroids, low-molecular-weight heparin, and aspirin— resulted in a successful outcome with delivery of a healthy infant. Conclusion: PUO in pregnancy may be a manifestation of immune dysregulation or fetal allograft rejection. In select cases, empirical immunomodulatory therapy instituted preconceptionally or early in pregnancy may improve outcomes. A high index of suspicion and multidisciplinary management are crucial in such scenarios. Keywords: Pyrexia of unknown origin, PUO, IUFD, Intrauterine fetal demise, Empirical treatment INTRODUCTION Fever in pregnancy is a common clinical problem with implications on the maternal and fetal health. Hyperthermia-induced fetal damage can be due to cell death, membrane disruption, vascular disruption or placental infarction [1]. There is a linear association between duration of fever and fetal outcomes which can rarely result in Intrauterine fetal demise. Most fevers during pregnancy are due to infectious causes such as Urinary Tract Infection, Respiratory tract infection, Malaria, Dengue or Hepatitis. Pyrexia of unknown origin (PUO) defined as clinically documented temperature >101°f or higher on several occasions with no etiology Annals of Case Reports and Clinical Studies Case Report (ISSN: 2834-5673) Annal Cas Rep Clin Stud (ACRCS) 2025 | Volume 4 | Issue 12 revealed after workup contributes to almost 14.5% (2).Causes for PUO include infections, malignancies, inflammatory disease and miscellaneous. We report a case of recurrent unexplained maternal fever during mid-trimester in two pregnancies, culminating in Intrauterine fetal demise (IUFD). A third pregnancy managed with early empirical immunomodulatory therapy resulted in a successful live birth. CASE HISTORY 26yrs old G2P1L1, in a non-consanguineous marriage, presented at 23+2 weeks of gestation with fever of one week duration. First Pregnancy She had developed fever at 22 weeks’ gestation. Details of evaluation are presented in (Table 1). Her urinary tract infection was treated with antibiotics as per sensitivity, and repeat cultures were sterile. Abdominal ultrasound was normal. Despite treatment, fever persisted, and she had IUFD at 27 weeks. A stillborn male baby (700 g, small for gestational age) was delivered. Placental histopathology showed acute necrotizing villitis, while fetal autopsy was not performed. Fever subsided within three days postpartum. Second Pregnancy She again developed high grade fever at 22 weeks and admitted with us at 23 +2 weeks. At presentation: Pulse rate 125 bpm, Mean Arterial Pressure was 82 mmHg, temperature 102°f. She did not have any localising signs or symptoms nor a history of exposure. The investigations are detailed in (Table 1). She was treated empirically with Ampicillin and later stepped up to Inj Meropenem when she developed hypotension. After discussion with obstetric medicine team, considering autoimmune etiology, started on parenteral steroids followed by oral prednisolone 30mg/day. She was afebrile for two days following parenteral steroids, but fever recurred on third day followed by IUFD at 25 weeks. She birthed a stillborn boy baby (620 grams, appropriate for gestation). Placenta weighed 235 grams, calcified (Figure 1). Fever subsided within 24 hours of delivery. Placental membrane culture was sterile and histopathology was suggestive of Chorioamnionitis. Fetal autopsy was unremarkable. Chromosomal microarray revealed no pathogenic copy number variants. Annals of Case Reports and Clinical Studies Case Report (ISSN: 2834-5673) Annal Cas Rep Clin Stud (ACRCS) 2025 | Volume 4 | Issue 12 Figure 1: Image of the placenta after 2nd delivery which ended in IUFD Table 1: Details of workup during the 1st and 2nd pregnancies -both ended in IUFD 1st Pregnancy September 2022 2nd Pregnancy June 2023 Work up for Infectious Etiology Total Leucocyte count 24,290 10,500 Complete Urine examination Normal Smear for Malaria Parasite and Parasite F Negative Negative Dengue NS1 Negative Negative High vaginal Swab Sterile Blood Culture: no growth Urine Culture Klebsiellatreated; Repeat Culture -sterile No growth Lumbar punctureCerebrospinal Fluid evaluation Normal COVID-19 RTPCR Negative Listeria IgM Negative Scrub Typhus IgM Negative Negative WIDAL Negative Negative Brucella IgM Negative Negative S. Procalcitonin: Normal Workup for Inflammatory markers C Reactive Protein 5.16 (0.0-0.5) S. Ferritin Normal S. Triglycerides Normal Annals of Case Reports and Clinical Studies Case Report (ISSN: 2834-5673) Annal Cas Rep Clin Stud (ACRCS) 2025 | Volume 4 | Issue 12 Evaluation in the interval period showed positive Lupus anticoagulant, and negative Anticardiolipin antibody, Beta 2 glycoprotein and screening for hereditary thrombophilia Couple Karyotype was normal. Autoimmune etiology or fetal allograft rejection was considered the most likely culprit. Third Pregnancy and Outcome Preconception counselling was done, and she conceived before repeat lupus anticoagulant testing. On confirmation of viability, she was started on azathioprine 50 mg twice daily, prednisolone 10 mg/day, aspirin 150 mg/day, and low-molecular-weight heparin 40 mg/day. She was closely monitored with blood counts, liver function, and urine cultures. Serial Fetal Growth scans showed an appropriately grown baby. At 29 weeks, she was diagnosed with intrahepatic cholestasis of pregnancy -total bile acids were 98µmol/L, with normal transaminases. She responded to ursodeoxycholic acid 300 mg TDS, and bile acids fell to 21µmol/L after two weeks. In view of early onset IHCP and previous history, labour was induced at 34 weeks. Emergency caesarean was done for cord presentation, delivered a baby girl 1950gms, 30th centile. Placenta weighed 350gms and histopathology showed appropriate villous maturation with no evidence of inflammation or villitis. Both mother and baby remained well at six-week follow-up DISCUSSION Early evaluation, identification and localization of the cause of fever in pregnancy is important to improve maternal and fetal outcomes. A comprehensive history and physical examination should include history of travel, medication/drug use, contact with animals and personal and family history of malignancies and inflammatory disorders. Evaluation of PUO is detailed in (Figure 2). LDH Normal ANA Negative cANCA Negative Negative p-ANCA Borderline positive Negative Imaging USG abdomen Mild Hepatomegaly Mild Right Hydronephrosis Normal Chest X Ray PA view Normal 2D echo normal Normal Normal Others LFT, Creatinine Normal Annals of Case Reports and Clinical Studies Case Report (ISSN: 2834-5673) Annal Cas Rep Clin Stud (ACRCS) 2025 | Volume 4 | Issue 12 Figure 2. Workup for fever during pregnancy (ADH: antidiuretic hormone; ALP: alkaline phosphatase; ANCA: antineutrophil cytoplasmic antibody; CBC: complete blood count; CRP: C reactive protein; CXR: Chest X ray; DNA: deoxyribonucleic acid; RFT: Renal function test; LFT: Liver function test; RT-PCR: reverse transcription polymerase chain reaction; TEE transesophageal echo cardiogram) The adverse effects of fever on the fetus have been reported in various animal studies and case series [2]. The fetus and placenta are semi allografts to the mother. Fetal allograft rejection can manifest, in the extreme form, as intra uterine fetal demise, with the placenta showing features of chronic chorioamnionitis in the absence of amniotic fluid infection .In their study of placentas in cases of fetal deaths, Lannaman et al observed Chronic inflammatory lesions of the placenta in 57% of cases of fetal death after exclusion of infectious causes and also noted that amniotic fluid concentration of CXCL-10 (a chemokine elevated in transplant rejection) was significantly higher in patients with chronic inflammatory lesions than those without these lesions and propose that fetal demise can be caused by a breakdown of maternal-fetal tolerance [3].The placental histopathology in our case also showed features of necrotizing villitis in the first pregnancy and chorioamnionitis with negative culture for microorganisms in the second pregnancy, which could be a manifestation of allograft rejection. Nardi E et al found significantly increased expression of placental interleukin 6, vascular endothelial growth factor receptor 2 mRNA, sphingosine 1-phosphate receptors and sphingosine kinase 2 in the placentas obtained after IUFD, whereas expression of activin A and of selected ATP binding cassette transporters is reduced, suggesting derangement in inflammatory and protective factors as the cause for fetal demise [4]. Annals of Case Reports and Clinical Studies Case Report (ISSN: 2834-5673) Annal Cas Rep Clin Stud (ACRCS) 2025 | Volume 4 | Issue 12 At present, confirmatory tests for fetal allograft rejection are in research stage, the treatment needs to be started on empirical basis after ruling out other causes for PUO and intrauterine fetal demise. This case highlights the need to think beyond infection when managing persistent fever in pregnancy. We initiated empirical immunosuppressive therapy in this mother early in her third pregnancy and we had a successful outcome. The woman did not develop pyrexia during her pregnancy and had a healthy baby. CONCLUSION Unexplained fetal demise can be a consequence of fetal allograft rejection and deranged inflammatory and protective factors. PUO in pregnancy may be a consequence of the same. We propose a role for empirical immunosuppressive therapy in selected cases for successful outcomes. REFERENCES 1. Prakash, Jay & Kumar, Tushar. Pyrexia of Unknown Origin During Pregnancy. 2023. 2. Mewada BN, Gandhi D, Diwan F, Panchal PN. Prospective Study of Pyrexia with Pregnancy. Ann Afr Med. 2023;22(1):1–4. 3. Lannaman K, Romero R, Chaemsaithong P, Ahmed A, Yeo L, Hassan S, et al. 497: Fetal death: an extreme form of maternal anti-fetal rejection. Am J Obstet Gynecol. 2015;212(1):S251. 4. Nardi E, Seidita I, Abati I, Donati C, Bernacchioni C, Castiglione F, et al. The placenta in fetal death: molecular evidence of dysregulation of inflammatory, proliferative, and fetal protective pathways. Am J Obstet Gynecol. 2025;232(3):328.e1-328.e9.