Study selection - A comprehensive search was done in MEDLINE/PubMed, Scopus, CENTRAL (Cochrane), Web of Science, PsycInfo, Academic Search Premier, CINAHL, and Embase using the defined search term and a total of 1279 articles were included. After hand search 17 more articles were included. After removal of duplicates 783 articles were screened for eligibility by screening of title and abstract using Rayyan platform [10]. Full text search was done for 88 articles. The remaining 695 were removed as they were having wrong population (non-pregnant), animal studies, seroprevalence and in vitro studies. Among these 88 articles 54 were included in the study and data extraction was done as given in Figure 1 Prisma diagram. Among the 54 studies included in the systematic review, 22 had data on only scrub typhus, 14 had data on only Rickettsial infection, 16 had data on leptospirosis and 2 studies had data on all three infections. The summary of the studies included are given in Table 2.
Study characteristics – A total of 54 studies were included of which 38 were case report having 12 case report for each of scrub typhus and other Rickettsia infections, and 14 case report for leptospirosis. Among the 8 case series included, 5 had data on leptospirosis, one on Rocky mountain spotted fever, one on murine typhus and one study by Chansamouth et al [13] had data on all three of murine typhus, scrub typhus and leptospirosis. Out of the 8 cross section studies two had data on leptospirosis, 5 had data on scrub typhus and one article by McGready [6] had data on all three of murine typhus, scrub typhus and leptospirosis. One study was included as cross- sectional study though the authors had mentioned it as case control study [14] as the study did not fulfil the criteria for case control study.
Risk of bias of included studies - Based on the critical appraisal of included studies using the Joanna Briggs Institute tools, there appears to be a moderate to high risk of bias across most of the evidence. The majority of studies were case reports and case series, indicating chance of low-quality evidence with high risks of confounding, selection bias, and lack of comparability (Supplementary Table 1,2,3).
Synthesis of results – The 54 included studies are plotted in the choropleth map (Figure 2). The interactive illustration has been created using Tableau software (Version 2023) [15] and available from the link: https://bit.ly/fetal_outcome. This shows that most reports of scrub typhus are from Southeast Asia including 14 studies from India [3–5,16–26], 5 from Thailand [27–31] and 2 from Korea [32,33] and one each from Bhutan [34], Laos [13] and China [35] whereas the reports of other Rickettsia infections like murine typhus and Rocky Mountain spotted fever are more prevalent in USA [36–40]. On the other hand, there is no specific geographical distribution of the cases of leptospirosis.
Among the 54 studies included in the systematic review, a total of 176 cases of scrub typhus were included with foetal loss in 53 (30.11%) and neonatal death in 3 (1.7%). These included 13 (7.4%), 17 (9.6%) and 23 (13.1%) foetal loss in first, second and third trimester, respectively. Among the 38 cases of Rickettsial infection, 4 (10.5%) had foetal loss of which 3 (7.9%) were in first trimester and 1 (2.6%) was in third trimester. Out of the total 63 cases of leptospirosis 13 (20.6%) had foetal loss. These included one foetal loss in each of first and second trimester and 11 (17.5%) in third trimester. There were 6 maternal deaths due to scrub typhus and one maternal death due to Rocky Mountain spotted fever as shown in Figure 3.
Among the 121 (68.7%) patients having live birth after infection with scrub typhus, 25 (20.7%) had preterm delivery and 19 (15.7%) had low birth weight. There were 5 cases of oligohydramnios or anhydramnios after scrub typhus infection as shown in Figure 4. Central nervous system of new born was affected in two cases – neonatal meningitis in one case in China [35] and microcephaly with encephalomalacia in another case [29]. Both the cases had evidence of vertical transmission of scrub typhus and was admitted in NICU for 4-8 weeks. Among the 33 (86.8%) live birth after Rickettsial infection, 5 (15.1%) cases were preterm and 4 (12.1%) had low birth weight (Figure 4). Among the 50 (79.4%) live birth after leptospirosis infection there were 9 (18%) cases each of preterm delivery and low birth weight baby (Figure 4). The other foetal complications included oligohydramnios [41] and pathological cardiotocography changes [42] in one case each of leptospirosis.
The maternal complications in all three infections included hepatic, renal, respiratory complications, and thrombocytopenia. The multi organ dysfunction syndrome (MODS) was seen in 11 cases in 3 studies [3,19,20] of scrub typhus. A case of right blindness due to retinitis caused R. sibirica infection was reported [43]. A case of bilateral sensorineural deafness caused by R.conori was also noted [44]. Another case of bilateral sensorineural hearing loss was seen after scrub typhus infection which did not improve even after 2 years [34]. One patient with leptospirosis had acute respiratory distress syndrome, severe coagulopathy and anterior pituitary lobe necrosis [45] while a study by Shrestha et al reported cardiovascular problems in 7 of 10 patients infected with leptospirosis [46].
The diagnosis of scrub typhus was made by serological methods including ELISA, IFA, Weil Felix test, and rapid test (2 article) in 19 studies and PCR in 5 studies. The diagnosis of Rickettsial infection was made by serological methods including IFA, Weil Felix test, ELISA) in 11 studies, molecular methods including PCR, sequencing in 5 studies of which 2 studies had PCR and IFA as the modalities of diagnosis. The diagnosis of leptospirosis was made mainly by serological methods including microscopic agglutination test (MAT) in 7 studies, ELISA in 9 studies, agglutination along with microscopy and animal inoculation in a study [47] and the method was not clearly mentioned in one study [48].
Among the different antimicrobial agents used for treatment for scrub typhus Azithromycin / erythromycin / macrolides was used in 14 studies along with combination of beta lactam/ Doxycycline in 3 more studies. Doxycycline/ tetracycline was used in 2 studies for treatment of scrub typhus, 2 studies used chloramphenicol with or without combination of other antibiotics, one study used beta lactam and fluoroquinolone and data was not available for 2 studies. For treatment of other Rickettsia infection, Azithromycin / erythromycin / macrolides was used in 7 studies, Doxycycline in 2 studies, combination of doxycycline and azithromycin in one study, beta lactams in 3 studies the drug used for treatment was not mentioned in 2 studies. For treatment of leptospirosis, beta lactams were used in 8 studies, doxycycline in 2 studies and the antimicrobial used for treatment was not mentioned in 8 studies.