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Fever During Pregnancy: Etiology and Fetomaternal Outcomes

Purpose Etiological spectrum of fever in pregnant women and its impact on fetomaternal outcomes were studied. Methods This was a hospital-based prospective study, conducted over 12 months. All pregnant women with fever were screened and detailed etiological evaluation carried out. Maternal and foetal outcomes were noted. Results One hundred and eighty-one pregnant women with fever were included. Common causes were dengue 44 (24.3%), hepatitis E 26 (14.4%) and urinary tract infection (UTI) 22 (12.2%). Mosquito-borne diseases accounted for the highest burden 61 (33.7%). Second most common were diseases transmitted by feco-oral route 46 (25.4%). Maternal deaths occurred in 29 (16%) patients. Common causes of death were hepatitis E infection in 9 of 26 (34.6%) cases, dengue in 7 of 44 (15.9%) and tuberculosis in 5 of 11 (45.5%) cases. Conclusion Dengue, hepatitis E and UTI were the most common causes of fever during pregnancy. Most cases were caused by vector- and water-borne diseases and thus potentially preventable. Overall maternal mortality was 16%.


Introduction
Most of the efforts to reduce maternal mortality in India have focussed on haemorrhage, hypertension and sepsis. There is little focus on the impact of infectious diseases on maternal, foetal and neonatal outcomes, which is demonstrated by the lack of well-conducted prospective studies in the literature.
Owing to the anatomical and physiological changes, certain infections such as urinary tract infections (UTI) are more common during pregnancy [1]. Infections like Plasmodium falciparum malaria, hepatitis E and H1N1 influenza are more severe in pregnancy due to changes in the immune system [2]. However, the contribution of these infections towards maternal mortality and near-miss morbidity is not clear. Therefore, they should be incorporated in the national maternal mortality data in greater detail. Only few studies have been conducted on the impact of fever on fetomaternal outcomes [3]. It is postulated that with the development of maternal death surveillance and response (MDSR) guidelines established by Government of India in 2017, more information will be available on the morbidity and mortality burden of these diseases [4].
Causes of fever during pregnancy and its course and outcomes should be studied in detail. This knowledge will improve maternal and foetal management and pregnancy outcomes. This is particularly important in the countries like India which have an immense burden of infectious diseases. Hence, this study was designed to fill the gaps in knowledge on the etiological spectrum of fever in the antenatal period in Northern India and its impact on maternal and feto-neonatal outcomes.

Methods
This was a hospital-based prospective study, conducted over a period of 12 months from 1 July 2016 to 30 June 2017. The study was conducted in Post Graduate Institute of Medical Education and Research, Chandigarh, a tertiary care centre in Northern India. The institute caters to the regions of Chandigarh, Punjab, Haryana, Himachal Pradesh and Jammu & Kashmir and is a major referral centre for high-risk pregnancies. The study was approved by institutional ethics committee and has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from all subjects.
All pregnant women presenting with fever over the course of study period were screened. 216 women presented with fever, of whom, non-consenting women, women with history of pelvic instrumentation and women with history of ruptured membranes were excluded, and 181 patients were recruited in the study. Fever was defined as a.m. temperature of > 37.2 °C (98.9°F) or p.m. temperature of > 37.7 °C (99.9°F) [5,6].
Detailed medical history, examination and investigations were performed, and all the data were recorded on case record sheets.

Laboratory Investigations
All cases underwent investigations as per the standard protocol followed in obstetric emergency including haemoglobin, complete and differential blood counts, serum electrolytes, urea and creatinine, liver function tests. Samples for blood cultures were obtained and tested using automated blood culture systems (BD BACTEC™). A 10 ml of mid-stream urinary sample was obtained, and urine microscopic examination as well as culture by inoculation onto CLED medium was carried out. Additionally, investigations to elucidate the etiology of fever that were carried out in all patients as per Table 1.
Further testing was done depending on the clinical profile. Ziehl-Neelsen staining from early morning sputum smears or body fluid smears for acid fast bacillus testing was performed to diagnose tuberculosis. This was supported with Mycobacteria Growth Indicator Tube (MGIT) or polymerase chain reaction where clinical suspicion was high. Sputum culture was performed whenever lower respiratory tract infections were suspected. Chest X-ray using abdominal lead shield protection was added as an adjunct, wherever indicated. Nasopharyngeal swabs were tested with real-time polymerase chain reaction (RT-PCR) for pandemic H1N1 influenza testing as per CDC protocol, wherever indicated. Patients with suspected viral hepatitis were tested as per Table 2.
Tzanck smear was performed from vesicles wherever patients presented with fever and vesicular rash. RT-PCR for chikungunya was performed wherever indicated, RT-PCR and IgM antibodies if presentation was within 1 week of onset of symptoms, and IgM antibodies (SD Bioline, Korea) if presentation was more than 1 week after symptom onset.
Neuro-imaging, cardio-imaging and abdominal imaging were performed wherever required based on the clinical Table 1 Investigations to elucidate the specific etiology of fever carried out in all women

Etiology Investigation
Malaria Peripheral blood thin smears examined for malarial parasites on 3 successive days and rapid immune-chromatographic tests for malarial antigen (based on the detection of histidine-rich protein 2 from Plasmodium falciparum and parasite-specific lactate dehydrogenase (pLDH) (Nicholas Piramal, India, and SD Bioline, Korea) performed to diagnose malaria infection and causative species of Plasmodium Dengue Dengue IgM antibodies were detected using ELISA (NIV, Pune) if presentation was more than 3-5 days after the onset of clinical symptoms and/or NS1 antigen assay (Pan Bio, Queensland, Australia) if the presentation was within 3-5 days within onset of clinical symptoms Enteric fever Blood was cultured to detect Salmonella typhi as well as paratyphi A and Widal tube agglutination test performed for serological diagnosis of enteric fever Leptospira IgM ELISA (SD Bioline, Korea) or microscopic agglutination test (MAT) Scrub typhus PCR for scrub typhus (if presentation was within 10 to 15 days of onset of symptoms) and IgM ELISA (InBios, Fullers laboratories, USA) if fever was more than 7 days 1 3 assessment of each patient. Ultrasound for foetal assessment was performed by obstetric consultants in the department of obstetrics and gynaecology of the Institute. Dating, foetal weight, malformations, liquor and bio-physical profile were assessed. All women were managed according to the institute protocol. Supportive management, anti-pyretics and specific anti-microbial therapy according to laboratory investigations were prescribed. Women were reviewed again after discharge from hospital. Further, all women were followed up till delivery and maternal and feto-neonatal outcomes were noted.

Results
The study included 181 pregnant women with fever. Etiology of fever and maternal outcomes were assessed for all 181 patients. Out of total 181, 175 (96.7%) patients were given a specific diagnosis, of whom 156 patients had laboratory evidence of disease and 19 were clinically diagnosed (upper respiratory tract infection (URTI) = 11, gastroenteritis = 8). A specific diagnosis could not be reached in 6 (3.3%) patients ( Table 3). Details of the 11 (6.1%) patients with recurrent episodes of fever are listed in Table 4.
Seventeen (9.4%) patients had received antibiotics before presentation, and all were empirical in nature. All antibiotics were penicillins (co-amoxyclav, cephalosporins, piperacillin-tazobactam) except 1 patient who had been started on chloroquine empirically.
Dengue was the most common cause of fever followed by hepatitis E and UTI (Table 5). Of 44 patients with dengue, 27 (61%) demonstrated positivity for NS1 antigen and out of these, 24 (89%) presented within 5 days of symptom onset. Seventeen (39%) patients had IgM positivity at admission. Twenty-two (50%) patients had dengue with warning signs (WHO definition), while 14 (31.8%) patients had severe dengue (WHO definition) at admission; of these, 7 patients died and 7 were classified as maternal near-miss cases (WHO MNM criteria). There were 2 miscarriages, 4 still births, 15 pre-term births, 13 low birth weight babies and 2 neonatal deaths.
Twenty-two patients had UTI of whom 12 (46%) had pyelonephritis. Twelve patients had urine culture positivity for Escherichia coli, 6 for Klebsiella spp, 1 for Pseudomonas aeruginosa and 1 for Proteus mirabilis. Both urine and blood cultures were positive in 2 patients (1 = Escherichia coli, 1 = Klebsiella spp). All patients were treated with appropriate antibiotics based on culture and sensitivity reports and safety of antibiotic use in pregnancy. Most commonly used antibiotics were nitrofurantoin, ceftriaxone and piperacillin-tazobactam. Four patients required drainage of pyonephrosis/perinephric collections. Five women developed oligohydramnios, 9 had pre-term births, 9 low birth weight babies and 1 still birth.

Discussion
This study spanned a full year and thus covered all seasons. Since many febrile illnesses are seasonal, coverage of a full year removes this bias and reflects the true incidence of various causes of fever in our population. Diseases with strong seasonal variations were the most common causes of fever in pregnant women. As a group, mosquito-borne diseases and those transmitted by the feco-oral route were the most common. Thus, most cases of fever in pregnancy are preventable. This suggests that strengthening of the public health Table 5 Demographic features, clinical profile and maternal outcomes of pregnant women with fever by three most common aetiologies   Still births (n = 167) 20 (11.9) Low birth weight babies (n = 160, 167 minus 7 abortions excluded) 75 (46.9) Requirement of Neonatal ICU (NICU) care (n = 160, 167 minus 7 abortions excluded) 31 (22.1) Neonatal death (n = 160, 167 minus 7 abortions excluded) 9 (6.4) infrastructure can effectively reduce the incidence of fever and improve maternal and foetal outcomes. Use of mosquito nets and supply of potable water are likely to prevent febrile illness in a majority of cases. The overall maternal mortality was 16%. Our institute being a referral centre gets sicker patients which is likely the cause for a high maternal mortality. Dengue was overall the most common cause of fever among pregnant women being responsible for almost a quarter of patients. Other common aetiologies were hepatitis E infection and UTI. Previous studies from tropics have found malaria to be the commonest cause of fever in pregnancy [7][8][9]. In our study, dengue was by far the commonest vector-borne disease with malaria forming only 6.1% cases. Dengue was associated with significant morbidity and mortality. 15.9% patients died, and another 15.9% were classified as maternal near-miss cases. This suggests that dengue is more severe in pregnant patients [10][11][12]. Potential referral of sicker patients to a tertiary care centre could confound the results. With an increasing annual incidence of dengue nation-wide, and observations of adverse maternal and foetal outcomes of pregnancy, seasonal preventive measures should be instituted and referral and management protocols standardized for optimal and timely management of pregnant women with dengue.
Hepatitis E was the second most frequent cause of fever during pregnancy, which is understandable as India is hyperendemic to hepatitis E virus [13]. This is again a preventable condition. In our study, a high rate of maternal and foetal complications was recorded with a maternal mortality of 23.1%. Poor maternal-foetal outcomes with hepatitis E infection in pregnant women have been well reported with high case fatality rates, and foetal complications include still births, miscarriages and risks of vertical transmission [14,15]. Hepatitis A and hepatitis B were less common and encountered in 3.3% and 0.6% patients, respectively. No patient with hepatitis C was seen.
UTI was found to be the third most frequent cause. There were no maternal deaths, but adverse foetal outcomes including pre-term births and low birth weight babies were seen. Adverse pregnancy outcomes in pregnant women with UTI have similarly been previously reported [16]. This suggests the need for promotion of screening urine cultures during pregnancy to detect asymptomatic bacteriuria and use of bacterial sensitivity guided antibiotic use in pregnant women with UTI.
Both pulmonary tuberculosis and extra-pulmonary tuberculosis were encountered, and all patients were treated with modified DOTS regimen anti-tubercular therapy. Studies have found that with early initiation of therapy, pregnancy does not adversely affect tuberculosis [17]. However, our patients commonly had adverse outcomes, likely because they were referred at a late stage. There is resurgence in the cases of scrub typhus in the country, and we encountered 6 patients with scrub typhus during pregnancy.  The strengths of our study include its large sample size and the thorough investigative process that was carried out with only 3 cases remained undiagnosed. Important limitations of this study include the hospital-based nature of this study, and hence, this study does not evaluate the profile of pregnant women with fever in the community. Also, ours is a regional referral and training centre; therefore, it is likely that a large number of complicated patients are referred to our institute and may not be representative of true complication rates in the community.
To conclude, dengue, hepatitis E and UTI were the most common causes of fever during pregnancy. Most cases were caused by vector-and water-borne diseases and are potentially preventable. The maternal mortality rate was high at 16%. Common causes of death were hepatitis E infection, dengue and tuberculosis.