Acute febrile illness in pregnancy: Spectrum of disease and impact on maternal and foetal outcome

Abstract

Acute febrile illness (AFI) in pregnancy is a neglected cause of maternal and foetal mortality and morbidity in low-and middle-income countries. This prospective cohort studied antenatal and postpartum women admitted with acute fever to a tertiary care university teaching hospital from July 2014 to March 2015 for aetiology, maternal and foetal complications, and the impact on maternal mortality ratio (MMR) and perinatal mortality rate. Among the 180 women admitted with AFI, urinary tract infection 54(30%) was the commonest cause, followed by airborne infections (67; 37.2%), peripartum or wound infections (25; 13.8%) and vector-borne diseases (21; 11.6%). Maternal deaths were 4 (2%) and foetal deaths 9 (5%). Post-operative gram-negative sepsis was the most common cause of maternal mortality. The MMR was ten times higher with AFI 2778 against 197 (p < 0.0001) among the other hospital deliveries during the same period. Screening for asymptomatic bacteriuria , maintaining aseptic precautions, and vaccination may impact maternal and foetal morbidity significantly.

Keywords

Acute febrile illness maternal mortality rate foetal outcome

Introduction

Acute febrile illness (AFI) in pregnancy impacts maternal and foetal morbidity; its causes are generally similar to the general population; however, pregnant and postpartum women have different clinical presentations and outcomes owing to their altered physiology and modulated immune response.¹ During the puerperium, they are susceptible to serious infections of the genital tract, and puerperal sepsis remains one of the most important causes of maternal death. Nearly 12% of patients with fever during pregnancy required admission in intensive care units, with bacteraemia complicated by foetal loss in 10% according to a recent study.²

There is, however, a paucity of data on the impact of tropical infections during pregnancy on maternal and foetal outcomes. Hepatitis E and Influenza A are known to cause significantly worse outcomes,³ although urinary tract infections (UTIs) are most frequent among the pregnant owing to their anatomical and physiological changes. Most published studies focus on a single aetiology, such as influenza, scrub typhus, pyelonephritis, and in a few South East Asian studies, dengue fever, pyelonephritis with E. coli, scrub typhus, and typhoid were the common diseases identified.⁴

Our aim was to determine the aetiology, maternal and foetal complications among women with AFI during pregnancy and the puerperium, and the effect of febrile illness on maternal mortality ratio (MMR) and perinatal mortality rate (PMR). Such data on AFI during pregnancy enable appropriate testing and therapy in an economically constrained healthcare setting, especially when culture and serology tests are unavailable.

Material and methods

Ours was a prospective cohort study conducted between July 2014 and March 2015 in a 2700 bedded tertiary care university teaching hospital in India after approval from the Institutional IRB and Ethics Committee [IRB Min. No.8903, 09.06.2014]. All pregnant and postpartum women within six weeks of delivery admitted in the obstetric and medical wards with AFI defined as fever (>38 °C) of < 14 days duration were consecutively recruited into the study.

Exclusion criteria applied were fever onset after 48 h of admission, fever onset within 48 h of delivery, and lasting <72 h post-delivery in order to exclude hospital-acquired infections, postpartum fever related to misoprostol use, and transient postpartum febrile episodes.

After informed consent, a detailed history, clinical examination, and laboratory parameters were collected, and outcomes were followed up from delivery till discharge from the electronic hospital records. Individual infections were diagnosed based on the standard of care diagnostic definitions specified in Appendix 1.

The sample size was calculated based on 9% incidence after an initial pilot study for a month, considering the most common and least common infections. A proportion of 0.09 was considered, and using the sample size calculation of ^4pq/_d², a precision of 4%, and a confidence interval of 95%, a sample size of 197 was obtained.

One-hundred ninety-two patients were recruited, and 12 were excluded leaving 180 for final analysis in the study (Fig. 1). The recalculated precision with a sample size of 178 with confidence interval of 95% was 4.2%. Data were entered into an EPIDATA form created for study purposes, and statistical analysis was performed using SPSS software for Windows version 16.0.

Figure 1.

Strobe statement.

Continuous variables were analysed by the t-test, and categorical variables with the C-test. Descriptive data were expressed as means and standard deviations (SD) for the continuous variables and frequencies and percentages for categorical variables. A non-parametric test (Mann–Whitney U-test) was used to compare the outcomes between groups. The chi-square or Fisher exact test was used to compare dichotomous variables, and t-test or Mann–Whitney test for continuous variables as appropriate. A p-value <0.05 was considered significant.

Results

The mean age of the180 patients recruited was 25 years. All but ten (94.4%) were booked for antenatal care at the study centre. Baseline characteristics are summarised in Table 1. A total of 117 (65%) were still in the antenatal period, and 61(33.8%) of those admitted for AFI were in the third trimester, 63 (35%) were post-natal, presenting within six weeks of delivery. Among those recruited, 83 (46.1%) had a high-grade fever (> 39.4 °C) at admission and were administered intravenous antipyretics.

Table 1.

Baseline characteristics.

Characteristic	N (%)
Age (years) Mean ± SD	25.3 ± 4.1
Booked	170 (94.4%)
Antenatal (N = 117 (65%))
Gestation age (GA) < 28 weeks	56 (31.%)
GA > 28 weeks	61 (33.8%)
Postnatal	63 (35%)
Hemodynamic stability at presentation
Stable (%)	141 (78.3%)
Unstable (%)	39 (21.6%)
Comorbid illnesses
No comorbidities (%)	115 (63.8%)
Anaemia (%)	37 (20.5%)
Diabetes mellitus (%)	17 (9.4%)
Hypertension (%)	9 (5%)
Bronchial asthma (%)	2 (1.1%)
Hypothyroidism (%)	5 (2.7%)
Others (%)	5 (2.7%)
More than 1 of the above comorbidities (%)	10 (5.5%)
Blood culture n = 125
Negative (%)	120 (96%)
Positive (%)	5 (4%)
Escherichia Coli	2
Klebsiella Pneumoniae	2
Enterococci sp	1
Urine culture n = 115
Negative (%)	64 (55.6%)
Positive (%) n = 51	51 (44.3%)
Escherichia Coli	41/51 (80.3%)
Klebsiella Pneumoniae	3/51 (5.8%)
Enterococcus	3/51 (5.8%)
Beta haemolyticus Streptococcus	3/51 (5.8%)
Methicillin resistant Staphylococcus Aureus	1/51 (1.9%)
Dengue serology NS1/IgM positive (n = 30)	12/30 (40%)
Scrub typhus IgM serology positive (n = 39)	9/39 (23%)
H1N1 nasopharyngeal swab positive (n = 29)	8/29 (27.5%)

Among those admitted with AFI, 39 (21.6%) were unstable and required haemodynamic resuscitation. There were 115 (63.8%) with no comorbidity. However, the most common comorbidity was anaemia (Hb <100 g/L) among 37 (20.5%), followed by diabetes mellitus in 17 (9.4%) and hypertension in 9 (5%). Blood investigations showed leucocytosis (>12 × 10⁹/L) in 70 (38.8%), thrombocytopenia (<100 × 10⁹/L) in 23 (12.8%), raised serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase > 50U/L in 33 (18.3%) and 19 (10.5%) respectively. Only 5/125 (4%) had blood culture positivity, two being with E.coli, two with Klebsiella and one Enterococci.

The aetiology of AFI is depicted in Figure 2. Dengue and scrub typhus are grouped as vector-borne; community-acquired pneumonia, influenza, other respiratory tract infections, and diarrhoeal disease as air and water-borne. UTI, post-operative sepsis, wound infections, and others were grouped together as potentially preventable diseases, the rationale for this grouping being to assess the burden likely to be impacted by preventive healthcare measures. Maternal and foetal mortality data are summarised in Table 2, and outcomes in Table 3.

Figure 2.

Aetiology of acute febrile illness in pregnancy.

Table 2.

Aetiology of acute febrile illness in pregnancy with maternal and foetal outcomes.

Disease	Number (%) n = 180	Maternal Mortality N (%)	Foetal Mortality^a N (%)	Maternal ICU admissions N (%)
Urinary tract infections	54 (30)	0	2 (3.7)	3 (5.5)
Undifferentiated short febrile illness	34 (18.8)	0	0	0
Wound infection (episiotomy and LSCS)	18 (10)	0	0	1 (5.5)
Dengue	12 (6.6)	0	2 (16.6)	3 (25)
Acute gastroenteritis	10 (5.5)	0	0	0
Scrub typhus	9 (5)	0	1 (11.1)	2 (22.2)
Community acquired/Atypical pneumonia	9 (5)	0	0	2 (22.2)
H1N1 pneumonia	8 (4.4)	0	2 (25)	2 (25)
Post-operative sepsis (post laparotomy)	7 (3.8)	2 (28.5)	1 (14.2)	2 (28.2)
Skin and soft tissue infections	7 (3.8)	0	0	2
Others^b	6 (3.3)	2 (33.3)	1 (16.6)	5 (83.3)
Upper respiratory tract infections	3 (1.67)	0	0	0
Tuberculosis	3 (1.67)	0	0	0

Foetal mortality at discharge and 2 more deaths on follow up.

Acute fatty liver of pregnancy with septic shock (1), haemolytic uremic syndrome (1), acute intermittent porphyria with septic shock (1), deep vein thrombosis (1), HIV drug fever (1), peripartum cardiomyopathy with sepsis (1).

Table 3.

Maternal and foetal outcomes among the different groups.

	UTI, wound infections, postoperative sepsis and others N (%)n = 92 (51.1%)	Air and water borne N(%)n = 67 (37.2%)	Vector borne N(%)n = 21 (11.6%)
Gestation age < 28 weeks	20 (21.70%)	24 (35.7%)	12 (57.2%)
Gestation age >28 weeks	21 (22.8%)	32 (47.7%)	8 (38.1%)
Post-natal	51 (55.4%)	11 (16.4%)	1 (4.7%)
Maternal mortality	4 (4.3%)	0 (0%)	0 (0%)
Antibiotics	65 (70.6%)	33 (50%)	18 (85.7%)
ICU admission	12 (13.0%)	5 (7.6%)	5 (23.8%)
Inotropes use	6 (6.5%)	1 (1.5%)	2 (9.5%)
SOFA score among critically ill Mean(SD)	9.5 (5.8)	3.4 (0.8)	8.4 (2.7)
Hypoxia (SpO₂< 94%)	12 (13.0%)	4 (5.9%)	6 (28.5%)
Mechanical ventilation	4 (4.3%)	0 (0%)	2 (9.5%)
Foetal mortality during hospitalisation for AFI	3 (3.2%)	1 (1.5%)	3 (14.2%)
Foetal demise on follow up	1 (0.9%)	1 (1.5%)	0
Term delivery	32 (78.0%)	48 (85.7%)	13 (65%)
Term delivery	n = 41	n = 56	n = 20
Birthweight more than 2.5 kg	32 (91.4%)	41 (78.8%)	8 (53.3%)
Birthweight more than 2.5 kg	n = 35	n = 52	n = 15

UTI were the most common cause, accounting for 54 (30%) of AFI in pregnancy. Among those with UTI, 31.4% (17/54) were in the third trimester and 39% (21/54) in the post-natal period.

There was no maternal mortality, although 3/54 (5.5%) were critically ill. There was one foetal death at discharge and one elective termination for anencephaly after UTI in the first trimester, who had been treated with intravenous ceftriaxone. About 25/54 (46.2%) of patients had term delivery, and 4/54 (7.4%) preterm delivery. (Details on two deliveries were not found.)

Post-LSCS and episiotomy wound infections contributed to 18/92 (19.5%), and post-operative sepsis to another 7/92 (7.6%). Another 7/92 (7.6%) had skin and soft tissue infections. Other causes for AFI in 6/92 (6.5%) included deep vein thrombosis, HIV-related fever, septic abortion, and septic shock with underlying acute fatty liver of pregnancy (AFLP), Porphyria and Peripartum cardiomyopathy. A high maternal mortality, with four deaths, was attributed to Gram-negative sepsis, documented in this group. There were two foetal deaths during hospitalisation for AFI and one more foetal demise on follow-up.

Air- and water-borne diseases causing AFI were diagnosed in 67 (37.2%). Among these, H1N1 pneumonia was the cause in 8 (11.9%) and other lower respiratory tract infections in 9 (13.4%); 10 (14.9%) had acute gastroenteritis. Thirty-four (50.7%) had undifferentiated short febrile illness, 3 (4.4%) had microbiologically proven tuberculosis (two sputum positive and one extrapulmonary), while 3 (4.4%) who had upper respiratory tract infections were postnatal women. Though 5 (7.4%) required intensive care, there was no maternal mortality, with the mean SOFA score being 3.14 (SD 0.8). There were two foetal deaths in this group, both in patients with H1N1 pneumonia, with one during admission for AFI and the second on follow-up.

Vector-borne diseases contributed to 21 (12%) of AFI, with 12 dengue and 9 scrub typhus infections. Eight (38.1%) were more than 28 weeks gestational age (GA), 12/21 (57.2%) less than 28 weeks GA, and 1/21 (4.7%) postnatal. Though 5 (23.8%) women were admitted to the ICU, and two required ionotropic support and mechanical ventilation, there were no maternal deaths. However, there were three foetal deaths, all antenatal.

MMR among those with AFI was 2778 against 197 (p < 0.0001) during the same period among hospital deliveries. The proportion of maternal deaths due to AFI was 21.4%. Maternal death was secondary to septic shock in four, with one being a post-septic abortion. The other three had underlying conditions of porphyria, peripartum cardiomyopathy and AFLP. Perinatal deaths due to AFI were 5 (2.2%) of the total perinatal deaths recorded during the same time at the hospital (223/9654 live births). The PMR due to AFI was calculated to be 29.2 for every 1000 live births. Of the five perinatal deaths (>28 weeks’ gestation), three were in the vector group, one due to airborne infections, and one to puerperal sepsis.

Discussion

AFI during pregnancy and the puerperium increases the risk of maternal mortality. The MMR in this cohort was 10-fold more than that of hospital deliveries during the same period.

We recruited all patients admitted with AFI according to study criteria, to ensure that most seasonal diseases were included; the most common cause of AFI, however, remained UTI in over 80%. This is similar to other studies from India and South East Asian countries where pyelonephritis was the commonest cause, often in the second trimester, with E.coli positivity likewise in 80%.³

Early screening and treatment of asymptomatic bacteriuria (ASB) reduces the risk of pyelonephritis as the pregnancy progresses.¹³ Screening with the nitrite and leucocyte esterase test (dipstick) costs ¹/₁₀₀ the cost of urine culture and has good sensitivity and specificity;¹⁴ thus early treatment of ASB with appropriate antibiotics is likely to offset the serious impact of UTI during pregnancy.

The maternal mortality was much higher in the group that had postoperative infections and gram-negative sepsis related to this cause, emphasising that the latter is still a significant problem. Of note, all women were referred with pre-existing multi-organ dysfunction post-delivery (one septic abortion, two post LSCS, one instrumental delivery), and 75% had a pyoperitoneum. Adherence to strict asepsis, particularly when there is an emergency indication to surgery, is paramount. The low blood culture positivity was probably due to the prior antibiotic exposure.

Vector-borne and air- and water-borne diseases did not result in maternal mortality, although one quarter required critical care. There was increased foetal mortality especially with Scrub Typhus and Influenza, as has been previously described.^{15, 16} Advocacy for influenza vaccination and sanitation measures will enable control of these diseases and their impact on foetal mortality and maternal morbidity to be felt.

One limitation of our study is that it was performed in a tertiary care referral hospital which may overestimate maternal and foetal mortality due to referral bias. It should be noted that our study was carried out before the COVID-19 pandemic.

We believe that our study demonstrates the usefulness of simple healthcare measures such as maintaining asepsis during procedures, screening for UTI and promoting vaccination in impacting maternal and foetal mortality.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was funded by the Institutional Fluid Research Grant from Christian Medical College, Vellore.

ORCID iDs

Sudha Jasmine Rajan

Sheba Meriam Thomas

Appendix

Definitions

Acute febrile illness in pregnancy was defined as fever for less than 14 days with a recorded temperature of more than 38 °C for more than 48 h requiring admission. Acute febrile illness in peripartum and post-partum period was defined as fever more than 38 °C on two separate occasions at least 24 h after delivery.⁵

Pyelonephritis

Presence of urinary tract infection by urine routine and microscopy with >8–12 white blood cell count, and < 2–4 epithelial cells and urine culture of >100,000 colony forming units along with flank pain, renal angle tenderness and fever more than 38 °C.⁶

Pneumonia/lower respiratory tract infection

Fever more than 38 °C, cough and shortness of breath associated with respiratory findings consistent with pneumonia, high WBC counts and with/without Chest X-ray findings.⁷

Influenza like illness

Fever (>38 °C), plus cough or sore throat.⁸

Influenza

Fever more than 38 °C along with cough, sore throat, and positive throat swab for H1N1/H3N1.⁸

Scrub typhus

Presence of scrub IgM ELISA being positive along with an eschar in prototype febrile illness or positive serology with a prototype clinical presentation, the eschar.⁵

Malaria

Presence of vivax/mixed or of falciparum parasites on thin blood smear along with the typical clinical presentation.⁵

Enteric fever

WIDAL showing a 4-fold rise in titre or a Blood culture positive for Salmonella typhi or S. paratyphi.⁵

Dengue fever

Dengue IgM positive and other serology negative OR seroconversion on convalescent sera.⁵

Dengue haemorrhagic fever (DHF)

Presence of thrombocytopenia along with fulfilment of criteria for dengue with a positive dengue serology.⁵

Dengue shock syndrome (DSS)

Fulfilment of criteria for dengue haemorrhagic fever along with hypotension.⁵

Leptospiroses

Positive Leptospira IgM with other serologies negative.⁵

Endometritis

Lower abdominal tenderness on one or both sides of the abdomen, adnexal and parametrial tenderness elicited with bimanual examination, foul smelling lochia and temperature elevation of more than 38 °C.⁹

Wound infections

Erythema, oedema, tenderness out of proportion to expected postpartum pain, and discharge from the wound or episiotomy site associated with temperature elevation (38 °C).¹⁰

Post-operative infection

Febrile morbidity with a temperature of 38.3 °C or greater within the first 24 h of surgery or two temperature measurements of 38 °C or greater at least 4 h apart after the first 24 h immediately postoperative period.¹¹

Post-operative sepsis

The above criteria with evidence of organ dysfunction or a rise in qSOFA score by more than 2.¹²

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