Fever of unknown origin in pregnancy: A case report

Abstract

Systemic lupus erythematosus is an autoimmune disease that primarily affects women of reproductive age. In pregnancy, it can lead to maternal and fetal complications. However, diagnosis in pregnancy is challenging since the disease mimics many features associated with other disorders and some complications related to pregnancy.

Here we report a 24-year-old woman at 26 weeks gestation who presented with a fever of unknown origin. She developed tachycardia, nausea, fatigue, rigors, and pancytopenia. Once sepsis and other chronic conditions were ruled out, rheumatology was consulted. Following the diagnosis of systemic lupus erythematosus, a combination of hydroxychloroquine, azathioprine, and corticosteroids was started, and the patient showed rapid improvement. She had an uncomplicated delivery at term.

This case report highlights a unique presentation of new-onset systemic lupus erythematous in pregnancy. Delay in diagnosis can lead to maternal and fetal complications; however, prompt diagnosis and treatment can improve symptoms and lead to a favorable pregnancy outcome.

Highlights

• •This case highlights a unique presentation of new-onset systemic lupus erythematosus (SLE) in pregnancy.
• •SLE shares clinical features similar to disorders and complications related to pregnancy; making SLE difficult to diagnose.
• •Although rare, suspicion for SLE should be present, especially when initial treatment for suspected differentials fails.
• •Prompt recognition and management of SLE can prevent possible adverse outcomes.

1. Introduction

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease that primarily affects women of childbearing age [1]. Disease flares are common during pregnancy, and SLE in pregnancy is associated with significant adverse maternal and fetal outcomes such as hypertension, preeclampsia, lupus nephritis, spontaneous abortion, preterm birth, neonatal death, and intrauterine growth restriction [1]. To improve morbidity and mortality, a multidisciplinary approach is important for early diagnosis and management [2]. However, the diagnosis of SLE in pregnancy can be challenging due to the overlapping symptoms and abnormal laboratory tests shared with other diagnoses and complications seen in pregnancy. Currently, there is limited literature for the guidance of new-onset SLE in pregnancy. Here, we present a case of new-onset SLE in pregnancy and the challenges that accompanied the diagnosis. Through this case report we hope to provide insight for making the diagnosis to prevent delay and adverse maternal and fetal outcomes in pregnancies complicated by SLE.

2. Case Presentation

A 24-year-old primigravida, without significant past medical history, presented to hospital at 26 weeks of gestation with complaints of headaches, fevers, chills, nausea, and vomiting for one week. She was noted to have a fever of 103° Fahrenheit (39.4° Celsius) and maternal and fetal tachycardia. She was given intravenous fluids for hydration, treated for a urinary tract infection (UTI) based on her initial workup, and discharged home. Following her discharge, she continued to maintain a fever. Upon further workup, she was noted to have pancytopenia. She continued to have cyclic fevers, and she was subsequently transferred to another hospital for a higher level of care.

Upon arrival, she appeared pale and diaphoretic. Her blood pressure was 95/50 mmHg, her temperature was 102.9° Fahrenheit (39.4° Celsius), and she was tachycardic. Her abnormal vital signs were concerning for sepsis; therefore, aggressive hydration was initiated, blood and urine cultures were obtained, and broad-spectrum antibiotics were started. Chest X-ray and computed tomography (CT) scan were both normal, ruling out pulmonary embolism. The initial infectious workup included: Streptococcus, influenza, COVID-19, human immunodeficiency virus (HIV), and a hepatitis profile, and all tests were negative. Laboratory results (Table 1) showed pancytopenia, a result that was concerning for an autoimmune etiology, specifically SLE; therefore, anti-nuclear antibody (ANA) and anti-DNA antibody double-stranded (anti-DNA Ab, double-stranded) were added to the workup. A detailed physical exam showed no oral ulcers or cutaneous lupus signs.

Table 1.

Blood tests results.

Laboratory Parameter	Results	Reference Range Value
Total Bilirubin (mg/dL)	0.39	0.15–1.00
Direct Bilirubin (mg/dL)	<0.20	0.00–0.30
Urine Protein Creatinine Ratio (mg/mg)	0.48	<0.02
Urine Protein (mg/12 h)	265	0–75
White Blood Cells (TH/cmm)	2.4	4–10
Hemoglobin (g/dL)	6.7	12–15
Hematocrit (%)	20.3	36–43
Platelet Count (TH/cmm)	109	109
Lactate Dehydrogenase (U/L)	519	135–214
Haptoglobin (mg/dL)	<10	30–200
Ferritin (ng/mL)	509	13–150
Erythrocyte Sedimentation Rate (mm/h)	65	2–37
C-Reactive Protein (mg/dL)	11.67	0–0.5
Procalcitonin (μg/L)	0.96	0–0.5
Lactate (mmol/L)	2.3	0.7–2.1
C3 Complement (mg/dL)	131	90–180
C4 Complement (mg/dL)	39	10–40
ANA HEp-2 Substrate	Positive (Speckled)	Negative <1:80
ANA Titer	1:320	Negative <1:80
SSA/RO IGG (U)	>8	Negative <1
SSB/LA IGG	<0.2	Negative <1
RNP Ab IgG	0.3	Negative <1
Smith Ab IgG	<0.2	Negative <1
DNA, DS Ab IgG (IU/mL)	<12.3	Negative <30
Direct Antiglobulin Test	Polydat 2+ Positive DATIgG 1+ Positive	Negative
Beta-2 Glycoprotein 1 Ab, IgG (SGU)	<10	<20
Beta-2 Glycoprotein 1 Ab, IgA (SAU)	<10	<20
Beta-2 Glycoprotein 1 Ab, IgM (SMU)	<10	<20
Cardiolipin Ab IgG (GPL)	<10	<14
Cardiolipin Ab IgA (APL)	<10	<11
Cardiolipin Ab IgM (MPL)	<10	<12
HIV RNA Quant (Viral Load)	Not Detected	Not detected
HSV 1 PCR	Not Detected	Not detected
HSV 2 PCR	Not Detected	Not detected
Syphilis Antibody	Non-reactive	Not detected
Histoplasma Antigen Urine	Not Detected	Not detected
Blastomyces Antigen	Not Detected	Not detected
EBV PCR	Not Detected	Not detected
CMV PCR	Not Detected	Not detected
TB Gold Results	Not Detected	Not detected
Parvovirus B19 IgG	Positive	Negative
Parvovirus B19 IgM	Negative	Negative
Rapid Strep A Screen	Negative	Negative
Blood Culture, Right	No growth after 5 days	No growth
Blood Culture Left	No growth after 5 days	No growth
Urine Culture	No growth	No growth

Legend: ANA: Antinuclear antibody, SSA/RO: anti–Sjögren's-syndrome-related antigen A autoantibodies, SSB/LA: anti–Sjögren's-syndrome-related antigen B autoantibodies, IgG/IGG: immunoglobulin G, RNP: Ribonucleprotein, Ab: antibody, DNA, DS: Double stranded DNA, HIV RNA: human immunodeficiency virus ribonucleic acid, HSV PCR: herpes simplex virus polymerase chain reaction, EBV: Epstein-Barr virus, CMV: cytomegalovirus, TB: tuberculosis, U: Units, IU: International Units.

Results and reference values are as denoted by The University of Mississippi Medical Center reporting laboratory, Mayo Clinic Lab and ARUP Laboratories.

The patient was transfused two units of packed red blood cells, with little improvement in her anemia. She maintained cyclical fevers of unknown origin occurring approximately every eight hours for over 48 h, rigors, fatigue, and fetal tachycardia, which only improved temporarily with aggressive hydration and acetaminophen. Although autoimmune disease was high on the differential, additional infectious etiologies workup and renal function testing were initiated (Table 1). All tests returned negative (Table 1). Amniocentesis was discussed for possible chorioamnionitis; however, the patient declined.

Due to the patient's critical state, betamethasone was given for fetal lung maturity. The fever and maternal tachycardia subsided within 24 h after treatment. Her response to the corticosteroids made the diagnosis of systemic autoimmune disease more favorable. At the same time, results of her autoimmune workup were notable for positive antinuclear antibody (ANA) (Table 1). Anti-Sjögren's-syndrome-related antigen A autoantibodies (SSA) and Coombs immunoglobulin G (IgG) were also added to the workup; both results were positive (Table 1), and rheumatology was consulted. In addition to her constitutional symptoms (fever) and hematologic abnormalities (leukopenia and hemolysis), the patient also had serositis based on having pericardial and pleural effusions. According to the 2019 European Alliance of Associations for Rheumatology (EULAR) and American College of Rheumatology (ACR) classification criteria, she met the diagnosis for SLE. In addition, she also had presumed Evans syndrome due to the findings of autoimmune hemolytic anemia and immune neutropenia.

After a multidisciplinary discussion between maternal fetal medicine and hematology, four doses 6 mg dexamethasone were completed every 12 h. The patient was then switched to prednisone 60 mg (1 mg/kg) following improvement of her leukopenia and symptoms. Further discussion with rheumatology led to the addition of hydroxychloroquine 300 mg and azathioprine 50 mg daily. The treatment led to a rapid improvement. Rheumatology and maternal fetal medicine followed her closely and the patient continued to improve. Ultrasonography throughout pregnancy showed good fetal movement, fetal growth, and cardiac rhythm. At 35 weeks and four days of gestation, estimated fetal weight was in the 27th percentile and abdominal circumference in the 46th percentile. The baby was delivered at term at another hospital without complications, and the baby was reported to be doing well without any evidence of neonatal lupus.

3. Discussion

SLE is often referred to as the great imitator, which was highlighted in this challenging case. The patient's initial presentation shared signs and symptoms of sepsis and other diagnoses and pregnancy complications, which caused a delay in the identification of SLE. Delayed diagnosis increases the risk of maternal and fetal complications [2], but this case had successful maternal and fetal outcomes. Currently, distinguishing SLE in pregnant women from other diseases is difficult because of its shared presentation and the limited literature reporting new-onset SLE cases in pregnancy. The majority of the current literature focuses on flare management and maternal and fetal outcomes.

In non-pregnant patients, the diagnosis of SLE is challenging and often delayed for multiple reasons [3]. First, the onset of the disease often is not evident until many years due to its gradual progression. Due to its limited and non-specific features in its initial presentation, SLE often resembles other pathologic processes such as infectious or hematological abnormalities, which can lead patients to specialists not trained in diagnosing or managing SLE. In addition, SLE can mimic many of the symptoms and pathological processes of pregnancy [3], and SLE symptoms can overlap with physiological changes of pregnancy such as fatigue, myalgia, skin changes, and hair loss [4].

However, there are some distinguishing clinical characteristics reported in the literature. New-onset SLE appears to occur in the first and second trimesters [5]. When compared to non-pregnant women with SLE, women with new-onset SLE in pregnancy are less likely to have clinical features such as fever, arthralgia, hair loss, Raynaud's phenomenon, and oral ulcerations [4]. Three retrospective analyses from China showed that when compared to women with preexisting SLE, those with new-onset SLE had higher disease activity, hematological abnormalities (primarily thrombocytopenia and anemia), renal disease activity, and pregnancy loss [4,6]. However, hematological and renal abnormalities are also seen in severe hypertensive disorders of pregnancy such as preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, which makes the diagnosis of new-onset SLE in pregnancy very challenging [4]. Nonetheless, SLE, preeclampsia, and HELLP syndrome can be distinguished by laboratory findings of abnormal complement levels and inactive urine sediment [4]. Clinical findings such as new-onset lymphadenopathy, arthritis, fever, or rash may help in distinguishing the two processes [6]. In cases in which it still is unclear, renal biopsy may be obtained. Obtaining a diagnosis is critical because management varies between the two disease states: while SLE may be treated medically, preeclampsia often requires delivery [7].

SLE in pregnancy predisposes many adverse maternal and fetal outcomes. In 2008, maternal mortality in women with SLE and pregnancy was reported to be 20-fold higher than in non-pregnant women [7]. Fortunately, maternal mortality has significantly improved. A study by Mehta et al. found that mortality rates decreased five-fold in pregnant women with SLE in the United States [8]. Although improvement is noted, adverse pregnancy complications occur at a higher rate in pregnant women with SLE, specifically preterm delivery, low-birth-weight infants, and fetal loss [5]. The risk of pregnancy loss increases more for women with new-onset SLE (62.4%) compared to those with preexisting disease (27.1%), with the majority of cases occurring during the first and second trimesters (95.3%) [5]. Thus, a multidisciplinary approach to monitor obstetric and neonatal complications is necessary to manage maternal and fetal outcomes.

The mainstay for treatment in pregnancy consists of hydroxychloroquine and azathioprine [9]. Hydroxychloroquine, an anti-malarial drug, is to be initiated or continued during pregnancy because it decreases the number of flares, risk of congenital heart block, and neonatal lupus without adverse fetal effects [9]. Azathioprine is considered safe in pregnancy based on renal transplant studies. The dose should be limited to a maximum of two mg/kg/day, to avoid the risk of fetal cytopenias and immune suppression [9]. Other immunosuppressive agents like cyclophosphamide, methotrexate, and mycophenolate are contraindicated during pregnancy and should be discontinued three months before conception [9]. Corticosteroid exposure should be limited to the least effective dose during pregnancy due to the risk of maternal diabetes, preeclampsia, and hypertension [9].

In summary, new-onset SLE in pregnancy can be challenging due to its ability to present in a myriad of presentations. Although rare, a high index of suspicion for SLE should be present, especially in cases such as the one reported, where initial treatment for suspected differentials fails. Prompt recognition and management can prevent possible adverse outcomes. Thus, disseminating specific cases of SLE and the methods of diagnosis during pregnancy are warranted.