Maternal and foetal outcomes of scrub typhus in pregnancy: A retrospective study

Introduction

The World Health Organization (WHO) has classified scrub typhus as a neglected tropical disease and a major public health issue in the Asia-Pacific region. ¹ It is caused by mite-borne intracellular Gram-negative bacterium Orientia tsutsugamushi.^1–3 The disease presents with a spectrum of clinical manifestations ranging from self-limiting features including fever, headache or myalgia to a fatal course complicated by pneumonia, pulmonary oedema, myocarditis, encephalitis and shock.^1–3 Case fatality rate in untreated cases or with delayed treatment ranges from 1.3 to 30%, highlighting the importance of early diagnosis.^1,4 However, this is challenging as the initial presentation of scrub typhus is often non-specific and can be mistaken for other tropical infections such as dengue fever, enteric fever, leptospirosis and malaria. Prior studies have reported that scrub typhus in pregnant women is associated with poor maternal and foetal outcomes.^3–6

Materials & methods

We retrospectively reviewed the medical records of pregnant women diagnosed with scrub typhus over a 7-year period [Jan 2014–December 2020] at a tertiary teaching and referral hospital.

The clinical case definition of scrub typhus as per WHO criteria was acute undifferentiated febrile illness reported by the participant or their care provider plus an IgM-positive ELISA, a positive qPCR test or the presence of an eschar typical of scrub typhus if no blood sample could be obtained. Serological evidence of scrub typhus was obtained by demonstration of IgM antibodies to 56 kDa antigen of O. tsutsugamushi, using a commercial IgM ELISA (Scrub Detect™, InBios International Inc., Seattle, Washington, USA). The cut-off used for the IgM ELISA was an optical density of >0.5.

Demographic details, clinical manifestations, laboratory results, drug details, mode of delivery, foetal outcomes and need for additional treatment or intensive care were noted. Gestational age was determined by ultrasound confirmation. Exclusion criteria were mixed infections and patients with co-morbidity such as hypertension, diabetes or chronic medical conditions.

Results

During the study period, 391 pregnant women with fever were admitted to the Obstetrics and Gynecology ward of our hospital. Fever work up was done in all the cases. Tests were done to rule out scrub typhus, malaria, leptospirosis and dengue. In addition, urine and blood cultures were also sent.

A total of 48 pregnant women were diagnosed with scrub typhus according to the case definition. However, 14 patients were excluded owing to co-morbidity, inadequate history and co-infection with malaria and dengue.

Statistical analyses were performed to identify factors associated with poor foetal outcomes in pregnant women with scrub typhus. Continuous variables were analyzed using t-tests (normally distributed) or Wilcoxon rank-sum tests (non-normal), reported as mean ± SD or median[IQR] as appropriate [Table 1].

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Table 1.

Baseline clinical and laboratory investigations of pregnant women with scrub typhus.

Clinical and laboratory features	Total n = 34	Good foetal outcome = 16	Poor foetal outcome = 18	p-value
Duration of illness (days), mean ± SD	6.9 ± 3.1	4.2 ± 2.2	8.1 ± 3.3	<0.05
Fever, n (%)	34 (100)	16 (100)	18 (100)	NS
Myalgia, n (%)	13 (38)	7 (43)	6 (33)	NS
Vomiting, n (%)	11 (32)	5 (31)	6 (33)	NS
Diarrhea, n (%)	7 (20)	3 (19)	4 (22)	NS
Cough, n (%)	18 (53)	9 (56)	9 (50)	NS
Breathlessness, n (%)	15 (44)	7 (43)	8 (44)	NS
Abdominal pain, n (%)	11 (32)	5 (31)	6 (33)	NS
Altered sensorium, n (%)	4 (12)	2 (12)	2 (11)	NS
Jaundice, n (%)	5 (15)	2 (12)	3(17)	NS
Eschar, n (%)	7 (20)	4 (25)	3 (17)	NS
Hepatosplenomegaly, n (%)	8 (23)	3 (19)	5 (28)	NS
Lymphadenopathy, n (%)	13 (38)	7 (43)	6 (33)	NS
Hemoglobin gm/dL, mean ± SD	9.7 ± 2.1	9.6 ± 1.9	9.1 ± 2.2	NS
Total leucocyte count*109/L,mean ± SD	12.8 ± 4.2	11.6 ± 4.3	13.8 ± 3.7	NS
Platelet count *109/L, median [IQR]	85 [58–112]	90 [62–118]	82 [55–105]	NS
Serum bilirubin, median [IQR]	1.0 [0.7–1.4]	0.9 [0.6–1.2]	1.2 [0.9–1.5]	NS
Serum albumin, mean ± SD	2.3 ± 0.48	2.6 ± 0.5	2.1 ± 0.3	<0.05
SGPT/ALT (IU/L), median [IQR]	64 (42–89)	68 (45–92)	52 (40–68)	<0.05
Serum creatinine mg/dL, median [IQR]	0.9 [0.7–1.2]	0.9 [0.7–1.3]	0.8 [0.6–1.1]	NS
Serum sodium (mEq/L), mean ± SD	129.6 ± 9	130.6 ± 8	128.2 ± 12	NS

Data presented as mean ± SD (normally distributed) or median [IQR] (non-normally distributed). p-values from t-tests (normal) or Wilcoxon tests (non-normal). NS = not significant.

Univariate logistic regression identified predictors of poor foetal outcome (p < 0.20 threshold). Significant variables were entered into a multivariate logistic regression model to determine independent associations, reported as adjusted odds ratios with 95% confidence intervals [Table 2]. All analyses were performed using R statistical software (version 4.2.2), with statistical significance set at p < 0.05.

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Table 2.

Univariate and multivariate analysis of factors associated with poor foetal outcome.

Variable	Univariate analysis	Multivariate analysis
	OR (95% CI)	p-value	aOR (95%)	p-value
Duration of illness	1.52 (1.12–2.07)	0.007	1.48 (1.05–2.09)	0.025
Serum albumin	6.25 (1.89–20.6)	0.003	5.80 (1.51–22.3)	0.010
Hepatosplenomegaly	1.67 (0.35–7.97)	0.52	1.42 (0.25–8.12)	0.70
Jaundice	1.50 (0.22–10.3)	0.68	1.21 (0.15–9.82)	0.86

OR = odds ratio; aOR = adjusted odds ratio; CI = confidence interval. Multivariate model adjusted for duration of illness and serum albumin. Variables with p < 0.20 in univariate analysis were included in the multivariate model.

All 34 pregnant women included in the study were younger than 35 years (range 19–35 years, mean 26.85 ± 3.6 years). Some 6, 9 and 19 patients presented in the first, second and third trimester, respectively.

Fever, headache, myalgia, breathlessness and vomiting were the common clinical presentations.

On examination, eschar was present in seven patients and hepatosplenomegaly in eight patients. Fifteen patients required intensive care including assisted ventilation and inotropic support. The baseline clinical and laboratory features are summarized in Table 1.

All patients received Azithromycin 500 mg od for 7 days. There was no maternal mortality reported in our study but 15 (44.1%) required intensive care admission. Longer duration of illness (adjusted OR 1.48 per day, 95% CI 1.05–2.09; p = 0.025) and lower serum albumin levels (adjusted OR 5.80 per 1 g/dL decrease, 95% CI 1.51–22.3; p = 0.010) were independent predictors of poor foetal outcome.

General complications included acute kidney injury in three patients, acute respiratory distress syndrome in two patients and pneumonia in four.

In obstetric complications, oligohydramnios and antepartum haemorrhage was seen in three and two patients respectively. Caeserean section was done in thirteen patients. Gestational age at the time of admission was variable ranging from 10 to 38 weeks. Poor foetal outcomes were observed in 18 (53%) pregnancies with intrauterine deaths and spontaneous abortion occurring in 12 cases, while six had preterm births between 32 and 35 weeks of gestation.

Discussion

Scrub typhus is a common cause of undifferentiated febrile illness in India. ⁷ The clinical and laboratory features in pregnant women in our study seem to be similar to those of non-pregnant women with the majority having fever, headache, myalgia and eschar. Similar findings have been reported in previous studies on pregnant women with scrub typhus infection.^3–5,7 The higher proportion of presentation (55.8%) in the third trimester probably reflects referral bias as complicated patients tend to be referred to the tertiary care centre. However, irrespective of the gestation age, 33–66% of pregnant women required intensive care therapy. The risk of foetal loss was highest in the first trimester and decreased with advancing age. Similar findings were observed in a case series of 42 cases, ⁸ where foetal loss with scrub typhus was significantly higher as compared to their routine obstetric data (33% vs 2.8%; p < 0.001).

Previous studies corroborate with our findings of unfavorable outcomes in the form of preterm birth, spontaneous abortion, foetal loss and oligohydramnios.^2,3,6,9 Our study noted a lower maternal case fatality rate as compared to previous studies probably due to improved supportive treatment and early diagnosis at our tertiary centre. Drugs used for the treatment of scrub typhus include doxycyline, azithromycin and chloramphenicol.^3–5 Azithromycin is the drug of choice for pregnancy with scrub infection due to its excellent safety profile. The optimal duration of therapy mentioned in various studies varies from single dose of 500 mg azithromycin to a period of 1 week.^2,3,5,7 Devervescence within 36 h with no relapse or adverse effects were seen in our patients.

No neonates had any congenital malformations, transplacental nor perinatal transmission of scrub typhus infection, as in other studies. ³ Hence, early diagnosis and management is crucial for good foetal outcome.

Our study's limitations include a small sample size, and further large-scale prospective studies are necessary to validate our findings.

Conclusion

In summary, scrub typhus should be considered as an important cause of febrile illness during pregnancy, particularly in endemic areas. Increasing awareness of the disease amongst primary care physicians is crucial for early diagnosis and timely referral, which can result in favorable maternal and perinatal outcome.