https://orcid.org/0000-0002-2158-846X
Figures
Abstract
Background
Reports on the occurrence and outcome of Visceral Leishmaniasis (VL) in pregnant women is rare in published literature. The occurrence of VL in pregnancy is not systematically captured and cases are rarely followed-up to detect consequences of infection and treatment on the pregnant women and foetus.
Methods
A review of all published literature was undertaken to identify cases of VL infections among pregnant women by searching the following database: Ovid MEDLINE; Ovid Embase; Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials; World Health Organization Global Index Medicus: LILACS (Americas); IMSEAR (South-East Asia); IMEMR (Eastern Mediterranean); WPRIM (Western Pacific); ClinicalTrials.gov; and the WHO International Clinical Trials Registry Platform. Selection criteria included any clinical reports describing the disease in pregnancy or vertical transmission of the disease in humans. Articles meeting pre-specified inclusion criteria and non-primary research articles such as textbook, chapters, letters, retrospective case description, or reports of accidental inclusion in trials were also considered.
Results
The systematic literature search identified 272 unique articles of which 54 records were included in this review; a further 18 records were identified from additional search of the references of the included studies or from personal communication leading to a total of 72 records (71 case reports/case series; 1 retrospective cohort study; 1926–2020) describing 451 cases of VL in pregnant women. The disease was detected during pregnancy in 398 (88.2%), retrospectively confirmed after giving birth in 52 (11.5%), and the time of identification was not clear in 1 (0.2%). Of the 398 pregnant women whose infection was identified during pregnancy, 346 (86.9%) received a treatment, 3 (0.8%) were untreated, and the treatment status was not clear in the remaining 49 (12.3%). Of 346 pregnant women, Liposomal amphotericin B (L-AmB) was administered in 202 (58.4%) and pentavalent antimony (PA) in 93 (26.9%). Outcomes were reported in 176 pregnant women treated with L-AmB with 4 (2.3%) reports of maternal deaths, 5 (2.8%) miscarriages, and 2 (1.1%) foetal death/stillbirth. For PA, outcomes were reported in 88 of whom 4 (4.5%) died, 24 (27.3%) had spontaneous abortion, 2 (2.3%) had miscarriages. A total of 26 cases of confirmed, probable or suspected cases of vertical transmission were identified with a median detection time of 6 months (range: 0–18 months).
Conclusions
Outcomes of VL treatment during pregnancy is rarely reported and under-researched. The reported articles were mainly case reports and case series and the reported information was often incomplete. From the studies identified, it is difficult to derive a generalisable information on outcomes for pregnant women and babies, although reported data favours the usage of liposomal amphotericin B for the treatment of VL in pregnant women.
Author summary
Visceral Leishmaniasis (VL) is a neglected tropical disease with an estimated incidence of 50,000 to 90,000 cases in 2019. Women who are susceptible to becoming pregnant or those who are pregnant and lactating are regularly excluded from clinical studies of VL. A specific concern of public health relevance is the little knowledge of the consequences of VL and its treatment on the mother and the foetus. We did a systematic review of all published literature with an overarching aim of identifying cases of VL in pregnancy and assessing the risk-benefit balance of antileishmanial treatment to the pregnant women and the child. We identified a total of 72 records (1926–2020) describing 451 VL cases in pregnant women. In 398, infection was identified during pregnancy of whom 202 received Liposomal Amphotericin B (L-AmB) and 93 received pentavalent antimony (PA). In studies that reported maternal outcomes, reports of maternal death abortion/spontaneous abortion, and miscarriages were proportionally lower among those who received L-AmB compared to PA (no formal test of significance carried out). A total of 26 cases of confirmed, probable or suspected cases of vertical transmission were identified and the median time to detection was 6 months (range: 0–18 months). Our review brings together scattered observations of VL in pregnant women in the clinical literature and clearly highlights that the disease in pregnancy is under-reported and under-studied. The collated evidence derived mainly from case reports and case series indicate that L-AmB has a favourable safety profile than the antimony regimen and should be the preferred treatment for VL during pregnancy.
Citation: Dahal P, Singh-Phulgenda S, Maguire BJ, Harriss E, Ritmeijer K, Alves F, et al. (2021) Visceral Leishmaniasis in pregnancy and vertical transmission: A systematic literature review on the therapeutic orphans. PLoS Negl Trop Dis 15(8): e0009650. https://doi.org/10.1371/journal.pntd.0009650
Editor: Walderez O. Dutra, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, BRAZIL
Received: February 18, 2021; Accepted: July 13, 2021; Published: August 10, 2021
Copyright: © 2021 Dahal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The database(s) supporting the conclusions of this article are available within the tables and figures presented within the manuscript along with the supplemental files (S1 Data, S2 Data).
Funding: The review was funded by a biomedical resource grant from Wellcome to the Infectious Diseases Data Observatory (Recipient: PJG; ref: 208378/Z/17/Z). The funders had no role in the design and analysis of the research or the decision to publish the work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Visceral Leishmaniasis (VL) is a neglected tropical disease caused by the parasite Leishmania donovani in Asia and Africa and Leishmania infantum in the Mediterranean Basin, the Middle East, Central Asia, South America, and Central America [1]. The disease is transmitted by female sandflies with an estimated 50,000 to 90,000 cases in 2019 [2]. India, Sudan, Brazil, Ethiopia, Kenya, and South Sudan accounted for more than 80% of the total VL cases reported to the WHO in 2019 [3].
The main clinical features of VL include persistent fever, splenomegaly, weight loss, and anaemia [1]. If untreated, the disease is generally fatal within 2 years [1]. Among those with clinical suspicion of the disease, diagnosis of VL is confirmed through demonstration of the parasites in a tissue aspirate obtained from the spleen, bone marrow, or lymph node. The accuracy of the diagnosis is sample dependent with a sensitivity greater than 90% for spleen specimen (gold standard approach) and 50–80% for bone marrow sample, but a splenic aspirate carries a risk of haemorrhage in one per 1,000 procedures [1]. Lipososmal amphotericin B (L-AmB) is the drug of choice for the treatment of VL in the Indian sub-continent, while a combination of pentavalent antimony and paromomycin is used in Eastern Africa. Blood transfusion may be required before initiation of treatment [4–6] or during the treatment or post-treatment follow-up period [7, 8]. In the clinical literature, the disease is predominantly described among males [9, 10].
A specific concern of public health relevance is the little knowledge of the clinical aspects of VL and treatment outcomes in pregnant and lactating women [11]. VL in pregnancy presents a number of challenges. During pregnancy, the use of splenic aspirate poses additional risk for the foetus. Pregnant women are also more likely to present with more severe anaemia than non-pregnant women and they are at an increased risk of requiring blood transfusion [11, 12]. During pregnancy, the optimal case management must take into account the consequences of the disease and the therapeutic intervention on the pregnant woman and the foetus [13]. Of note, except amphotericin B, all other available drugs are either contraindicated or subjected to restricted use in pregnant and lactating women and in women of child-bearing age (Table 1) [14–16]. Further complexities arise from potential vertical transmission of the disease either congenitally or through transplacental infection as a result of blood exchange during labour [17–19]. Such vertical transmission can induce in utero death or can be potentially deleterious to the foetus and infant [16, 20, 21]. While vertical transmission of VL is well-studied and established in animal studies, reports in humans are sporadic with observations of clinical manifestation several months post-partum [21–24].
The regulatory restrictions and limited evidence on safety of antileishmanial chemotherapeutics on the mother-foetus pair meant that historically clinicians had to rely on personal experience or limited published case-reports to make a decision regarding treatment. This led to some clinicians delaying the treatment of pregnant women until after delivery, especially when the case was detected closer to the due date [25, 26]. Others had treated them when the adjudicated risk of VL to the mother outweighed the risk posed by the drug to the mother-foetus pair [27]. Currently liposomal amphotericin B (L-AmB) remains the preferred regimen for the treatment in pregnancy (Table 1). However, pregnant and lactating women are regularly excluded from clinical studies [10] and are considered “therapeutic orphans” [28]. In studies that enrol females of childbearing age, counselling measures are usually set in place to inform the patients regarding the potential teratogenic harms of study drugs and either adoption of suitable contraception methods or observance of abstinence is mandatory [10]. In regular clinical practice and non-clinical trial settings, pregnancy tests and counselling however, might not be done routinely. A study conducted in South Asia found that only one in every six doctors ruled out pregnancy before prescribing miltefosine, a medication which has been contraindicated in pregnancy [29].
Finally, there is a lack of active pregnancy registries for most of the antileishmanial drugs except for miltefosine. In the context of Impavido (Profounda Inc.), the commercial name of miltefosine registered to the US medicines regulatory agency (US Food Drug Administration), a pregnancy registry was established to fulfil post marketing requirements [30, 31]. The recruitment of pregnant women as part of the observational study started in 2015 and the study is expected to be completed in 2026, and is estimated to recruit 0–1 patients per year over the 10 year study period, hence unlikely to generate a large volume of new safety data [30]. There are no other active pregnancy registries on exposures to VL treatments from which to derive information on consequences on gestation, mother, foetus, and the newborn. Therefore, to understand the risks and benefits of treatment to the pregnant woman and the child, one must turn to the published literature.
The most comprehensive reviews on VL in pregnant women were conducted in the mid 2000s [21, 32]. We therefore conducted a systematic review of all published literature with an overarching aim of identifying cases of VL in pregnancy. The specific objectives were to assess the risk-benefit balance of antileishmanial therapies to the pregnant woman and the child and to identify the cases of vertical transmission. The review was not limited by language or any interventions.
Material and methods
Literature search
A review of all published literature was undertaken on 26th of March 2020 to identify records describing VL in pregnant women or any reports of vertical transmission of the disease in humans by searching the following clinical databases: Ovid MEDLINE; Ovid Embase; Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials; World Health Organization Global Index Medicus: LILACS (Americas); IMSEAR (South-East Asia); IMEMR (Eastern Mediterranean); WPRIM (Western Pacific); ClinicalTrials.gov; and the WHO International Clinical Trials Registry Platform (ICTRP). The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic-Reviews and Meta-Analyses (PRISMA) guidelines (S1 Text)[45]. In addition, full text screening of the publications indexed in the Infectious Diseases Data Observatory (IDDO) clinical trials library was carried out to identify any description of VL in pregnant women [46]. The references of all included publications were further checked to identify any relevant articles. This review is not registered and the protocol describing the search strategy including search strings, search dates and eligibility criteria for screening is presented in supplemental file (S2 Text).
Study screening
Study screening was carried out in two stages to identify the studies fulfilling the inclusion and exclusion criteria (S2 Text): title and abstract screening (stage I) and then full-text screening (stage II). As reports on VL in pregnancy are sparse, articles meeting minimal inclusion criteria and non-primary research articles such as opinion pieces, clinical guidelines, textbooks, chapters, correspondences, reports of accidental inclusion in trials, or case reports of unplanned pregnancies during the study follow-up were also considered for comprehensiveness. No restrictions were applied regarding study design, follow-up duration, sample size, region, or the treatment regimen for eligibility of inclusion in this review. Articles that were not in English language (Spanish, Portuguese, Korean, and German) were reviewed using google translation (https://translate.google.co.uk/).
The articles were screened against eligibility criteria by a single reviewer (PD). A second reviewer was consulted (SSP) when the first reviewer could not reliably assess the eligibility. The first reviewer (PD) extracted data from all the eligible records and it was verified by the second reviewer (SSP) (who was not blinded) on all publications included in the review. Any discrepancy in the extracted information was flagged by the second reviewer and the differences were resolved through consensus. Screening and data extraction was carried out on a prospectively designed Excel database (S1 and S2 Data).
Data extraction
The following bibliographic information were extracted: study title, name of the first author, year of publication, name of the study site and country. The following maternal and child characteristics were extracted: age of the pregnant woman, period of gestation (or trimester), treatment administered including drug dosage, follow-up duration, the outcome of the treatment for pregnant woman (cured, relapsed, death), and foetal outcomes (abortion, stillbirth, premature birth, healthy born, vertical transmission).
Definitions
The records were classified as: case report/case series, prospective cohort or retrospective cohort studies. Records describing one or a small group of patients included as a part of prospective (or retrospective) studies in which VL in pregnancy was not of primary focus were considered as case report/case series. Similarly, studies that described a cohort of pregnant women without selection of a non-pregnant comparator group were also considered as case series. Countries were classified into sub-regions according to United Nations designation of geographical regions [47].
Data analysis
Since the majority of the studies included were either case reports or case series, analysis of data was restricted to presentation of descriptive statistics and meta-analysis was not carried out. Descriptive summaries were presented for the characteristics of the studies included in the review, characteristics of pregnant woman (trimester, gestational age), treatment regimen including dosage and duration, clinical outcomes on the pregnant woman and the child. Graphics were generated using R software [48].
Assessment of risk of bias
The risk of bias in case report/case series was assessed using a checklist proposed in Murad-2018 [49]. The following domains were assessed: patient selection, ascertainment of exposure, follow-up of pregnant women until delivery to record pregnancy related outcomes, and completeness of reporting of treatment and outcome status. Methodology and definitions adopted for assessment of risk of bias is presented in S1 Table. Briefly, bias in ascertainment of exposure was considered high if VL diagnosis was based solely on clinical features. A single case report was considered to be at a high risk of selection bias whereas a series of cases selected based on an audit of complete records over a study period was considered to be at a low risk of selection bias. If a study followed-up the pregnant women until birth and reported outcomes of the treatment for the mother–foetus pair, then follow-up was considered adequate to assess pregnancy-related outcomes. Bias in reporting of results was assessed based on the completeness of reporting on treatment status and clinical outcomes (See S1 Table for further explanations). For cohort studies (prospective or retrospective), risk of bias was assessed using The Newcastle-Ottawa scale. Two authors (PD, SSP) assessed the risk of bias in the studies included.
Results
We identified 395 records from the literature searches up until 26th of March 2020, of which 272 were unique after removing duplicate entries. Of the 272 unique records, 99 were excluded at title and abstract screening stage leaving 173 records for full-text assessment of which 54 met the eligibility criteria for inclusion in the review (Fig 1). An additional 18 records were identified by searching the references of the eligible records or through personal communication. A total of 72 records published from 1926 through 2020 were included in this review of which 71 were case-reports or case-series and one was a retrospective cohort study with non-pregnant patient as a comparative group (Table 2). Further details on the studies included in this review are presented in supplemental files (S1 and S2 Data).
Spatial and temporal distribution
A total of 21 (29.2%) records were from Europe (1926–2019), 23 (31.9%) from Southern Asia (1955–2018), 13 (18.1%) from South America (1986–2019), 8 (11.1%) from Northern Africa (1988–2018), 5 (6.9%) from Eastern Africa (1984–2020), and 1 (1.4%) record each were from Eastern Asia (1928) and Western Asia (1979). There were 18 (25.0%) records from India, 13 (18.1%) from Brazil, 8 (11.1%) from Sudan, and further breakdown by country is presented in Fig 2 (left panel). There were 64 (88.9%) records in English language, 7 (9.7%) in Portuguese, and 1 (1.4%) in French. The 72 records included in this review described 451 cases of VL in pregnant women, of whom 159 (35.3%) were from Sudan, 113 (25.1%) from South Sudan, 84 (18.6%) from India, 23 (5.1%) from Bangladesh, 20 (4.4%) from Brazil, 12 (2.7%) from Italy, 10 (2.2%) from Uganda, and the rest of the breakdown is presented in Fig 2 (right panel). Overall, there were 10 (13.9%) records published from 1926 through 1990, 14 (19.4%) from 1991 through 2000, 22 (30.6%) from 2001 through 2010, and 26 (36.1%) from 2011 through 2020 (Table 2).
Treatment regimens
Of the 451 pregnant women identified, the disease was detected during pregnancy in 398 (88.2%), retrospectively confirmed after giving birth in 52 (11.5%), and the time of identification was not clear in one (0.2%). Of the 398 pregnant women whose infection was identified during pregnancy, 346 (86.9%) received a treatment, 3 (0.8%) were untreated, and the treatment status was not clear in the remaining 49 (12.3%) (Table 2). The outcomes among 3 untreated cases and 346 who received a treatment during pregnancy is presented next.
Liposomal amphotericin B (n = 202; 1994–2020).
Of the 202 pregnant women treated with Liposomal Amphotericin B, 124 (61.4%) were from Africa (2006–2020), 59 (29.2%) were from the Indian sub-continent (2010–2018), 13 (6.4%) were from Europe (2010–2018), and 6 (3.0%) were from South America (2005–2019).
Treatment was administered in 5 (2.5%) cases in the first trimester, 8 (4.0%) in the second trimester, 9 (4.5%) in the third trimester, while the time in pregnancy was not clear in 180 (89.1%). Survival status was not reported or was unclear in 26 (12.9%) pregnant women and from the remaining 176, a total of four (2.3%, 4/176) maternal deaths were reported. There were five (2.8%) miscarriages, 1 (0.6%) stillbirth, and 1 (0.6%) premature birth (Table 3). One foetal death was reported from a pregnant woman in her first trimester from South America [50].
Three cases of vertical transmission were identified [51–53] (Tables 2 and 4). The first one was detected at 11 months after birth. The pregnant woman was admitted to a hospital few days before labour and was administered L-AmB at a daily dose of 4 mg/kg on 6 consecutive days and repeated doses at days 14 and 21 [51]. The treatment status on the baby was not available. For the second case, vertical transmission was suspected at 8 months after birth. During weeks 31–32 of pregnancy, the pregnant woman was treated with a full course of L-AmB (3 mg/kg on days 1–5 followed by a single dose of 3 mg/kg on day 10). Delivery by an elective C-section occurred at 38 weeks of gestation. Upon detection of the Leishmania parasites in the bone marrow, the baby was treated with sodium stibogluconate at an intravenous dose of 20 mg/kg for 20 days and discharged after 30 days [52]. The third one was detected in a baby born to a mother with HIV co-infection immediately after vaginal birth [53]. Leishmania amastigotes were found during the microscopic examination of the placenta, and diagnosis was confirmed by a polymerase chain reaction. The baby was administered intravenous L-AmB at dosage of 5 mg/kg per day from days 1 to 4 followed by a weekly injection of 5 mg/kg and recovered successfully. The mother had received L-AmB 15 weeks after her last menstrual period at a total dose of 40 mg/kg, followed by secondary prophylaxis with a dose of 5 mg/kg every 15 days until delivery.
Pentavalent antimony (n = 93; 1926–2010).
There were 93 pregnant women who were treated with pentavalent antimony, of whom 70 (75.3%) were from Africa (1984–2009), 19 (20.4%) from Asia (1955–2010), 2 (2.2%) from Europe (1926–1995) and 2 (2.2%) from South America (1994–2003) with majority of the cases treated between 2000–2010 (82 of 93 cases). Treatment was administered to 20 (21.5%) pregnant women in the first trimester, 46 (49.5%) in the second, 22 (23.7%) in the third, while the time in pregnancy was not clear in 5 (5.4%).
Survival status was available for 88 (94.6%) pregnant women of whom 4 (4.5%, 4/88) died due to hepatic encephalopathy [12]. There were 24 (27.3%) abortions (or spontaneous abortions) of which 13 were among African patients and 11 among patients from Asia (Table 3). There were 2 (2.2%) miscarriages, 2 (2.2%) pre-term births, and 1 (1.1%) required splenectomy after delivery due to poor recovery and due to persistence of parasitaemia in the spleen sample (Table 3) [54]. There were 3 foetal deaths reported; one of the babies died due to myelomeningocele 3 hours after birth [12], another died a day after being born [55], and another died due to VL at 2 months [12]. Further details are presented in Table 3.
There were 3 cases of vertical transmission identified [18, 19, 56], detected at 6, 7, and 12 months after birth. The first case (reported in 1926 in the UK) was born to a woman who acquired VL during her third trimester and was treated with urea stibamine [19]. The baby had a normal birth and vertical transmission was detected at 12 months after birth. Upon detection, the baby was treated with antimony and made a recovery. The second case (reported in 1955 in India) was born to a woman in whom the disease was identified during the second trimester and was treated with urea stibamine [56]. Vertical transmission was detected at 6 months; the baby was treated with antimony and was cured after one recurrence. The third case (reported in Sudan in 1922) was born to a woman in whom the disease was identified during the second trimester and was treated with sodium stibogluconate for 30 days [18]. At birth, the baby had signs of intrauterine growth retardation. The baby was diagnosed with VL at 7 months and died two days later (Table 4).
Amphotericin B deoxycholate (n = 20; 1993–2015).
Of the 20 pregnant women treated with amphotericin B deoxycholate, 17 (85.0%) were from Asia (1993–2015) and 3 (15.0%) from South America (2003–2008). There were 3 (15.0%) pregnant women in their first trimester, 6 (30.0%) in the second, 3 (15.0%) in the third, and the trimester was not clear in 8 (40.0%). There was one (5.0%) maternal death after 7 days of treatment due to haemorrhagic complications occurring after delivery; the pregnant woman was in 28.7 ± 7.8 weeks of pregnancy [57]. The remaining 19 pregnant women were discharged alive. The delivery of babies were described as normal for 18 pregnant women, haemorrhagic complication occurred in one after delivery (as described earlier) [57], and the information was not reported on 1 (Table 2 and S2 Data). There was no reports of vertical transmission of the disease in 12 (60.0%) babies in whom the information was reported (11 were followed-up for 12-months and the status was reported at birth for 1 baby). Further details are presented supplemental file (S2 Data).
Pentavalent antimony plus paromomycin (aminosidine) (n = 11; 1993–2017).
Eleven pregnant women (all from Africa) were treated with sodium stibogluconate plus aminosidine (paromomycin) [27, 58]. Information regarding trimester, maternal survival status, or vertical transmission were not available (see S2 Data). One spontaneous abortion was reported [58].
Liposomal amphotericin B plus pentavalent antimony (n = 4; 2006).
Four pregnant women were treated with the combination regimen in a study from Sudan published in 2006 [59], of whom two were in their second trimester and two in their third. L-AmB was administered at 3–7 mg/kg/day on days 1, 6, 11 and 16 (or on days 1, 2, 3, 4, 10 and 15), followed by a 20 mg/kg dose of sodium stibogluconate intramuscularly once daily for 30 days. All four pregnant women were discharged alive. At discharge, one pregnant woman delivered a healthy baby and the remaining three were still pregnant–no follow-up data was reported.
Paromomycin (aminosidine) (n = 3; 2011).
Three pregnant women were treated with paromomycin in a study from India [60]. The drug regimen was administered at 11 mg/kg/day (base) by deep gluteal intramuscular injection once daily for 21 consecutive days [60]. All three babies were described as being healthy at birth.
Trimothoprim, sulphadiazine and tinidazole (n = 1; 1994).
One study from India treated a pregnant woman in the first trimester with the combination of Trimothoprim, sulphadiazine and tinidazole [61]. There were no reports of side effects and the pregnant woman delivered a healthy baby at term. The mother remained well at one year after completion of treatment with no further information available on the infant.
Unclear drug substance (n = 12;1987–2009).
Three publications reported treating pregnant women with VL in whom either the drug name was not specified or the allocated drug group (in multi-arm study) could not be identified. Two publications described a case each without reporting the name of the drug administered [17, 62]. In the third report, the number of pregnant women (n = 10) allocated to each drug arm (pentavalent antimony or amphotericin B deoxycholate) was not clear [63]. Two (16.7%) of the pregnant women were in their third trimester and the status was unknown for the remaining 10 (83.3%). There were two (16.7%) maternal deaths [63] and two cases of vertical transmission [17, 62]. The first one was identified at 8 months after birth and another at 6 weeks after birth (the baby died after 3 days). Both babies were administered treatment upon detection of VL (See S2 Data for further details).
Untreated (n = 3; 2001–2017).
Three cases of VL identified during pregnancy were untreated [25, 64, 65]. Treatment was deferred until after delivery due to safety concerns in one report in a pregnant women in third trimester [25]; there were signs of intra-uterine growth retardation requiring an emergency C-section, and both mother and the child were alive. The second pregnant woman in third trimester was not treated due to lack of adequate hospital resources [64]; the baby born to the mother died after 2 months due to malnutrition with no evidence of vertical transmission. In the third case, VL was diagnosed nearer the delivery time before treatment could be administered but the mother died after giving birth and before treatment could be administered [65]; the baby also died and foetal part placenta examination revealed presence of Leishman Donovan bodies by polymerase chain reaction indicating vertical transmission.
Confirmed/probable/suspected vertical transmission
We identified a total of 26 cases of confirmed, probable or suspected cases of vertical transmission (Table 4). The median time to detect vertically transmitted VL was 6 months (range: 0–18 months). Eleven babies were born to women in whom the disease status was confirmed during their pregnancy; three of the mothers were treated with L-AmB, three with PA, the drug name was not clear in two, a mother was untreated and the treatment status was not clear in the remaining two (Table 4). Histopathological examination of the placenta confirmed the vertical transmission of the disease in two cases [18, 65] and this was not reported for the remaining cases. Treatment status was described in 18 children, of whom 11 received pentavalent antimony, 6 received L-AmB and 1 received amphotericin b deoxycholate. Two of the children died; one had received pentavalent antimony and the drug name was not clear in the other (See S2 Data for further details).
Risk of bias assessment
Of the 71 case reports/case series, 49 (69.0%) were judged to be at a high risk of bias for patient selection and the remaining 22 (31.0%) were at low risk of bias. For the ascertainment of exposure status, 6 (8.5%) were at high risk of bias, 17 (23.9%) were at moderate risk, 41 (57.7%) at low risk, and the risk of bias status was not clear in 7 (9.9%) studies. For the adequacy of follow-up, four (5.6%) studies were considered to be at moderate-high risk of bias, 37 (52.1%) at low risk of bias, 23 (32.4%) were retrospective studies, and the risk of bias was unclear in 7 (9.9%). For the completeness of reporting domain, 5 (7.0%) studies were at high risk of incomplete reporting, 20 (28.2%) at moderate risk of bias, and 46 (64.8%) were at low risk of bias (See S1 Table). One retrospective cohort study with a comparative group of non-pregnant patient group was considered of high quality.
Discussion
The occurrence and effects of VL during pregnancy is under-researched and poorly understood as evidenced by having identified only 72 publications describing a total of 451 cases of VL in pregnancy in the past 94 years.
The small case volume reported in the literature could have several explanations. In the first place, there is an apparent imbalance in caseloads with predominance of the disease among males; ascribed to biological or behavioural causes [10, 13, 73, 114–116]. Pentavalent antimony was the first line therapy before the development of Liposomal amphotericin B (L-AmB)–this might have traditionally dissuaded physicians from treating VL during pregnancy and leaning towards postponing the treatment until after delivery unless treatment is absolutely warranted [25]. However, this situation might have changed recently as L-AmB has no contraindication during pregnancy and is the treatment of choice adopted in national guidelines (Table 1). It has also been postulated that early pregnancies are missed due to spontaneous abortion caused by VL [73]. Women with childbearing potential or those who are already pregnant are systematically excluded from VL clinical studies and only a third of the patients enrolled in clinical trials are females [10]. It is clear that the likely caseload of VL in pregnancy is much bigger than what can be estimated from available reports. For example, during Jan 2016–Jul 2019 in Lankien, Jonglei state, South Sudan, out of 4,448 cases of VL diagnosed, 824 (18.5%) occurred in females aged 15–44 years and 110 (13%, 110/824) of them were pregnant (2.5% of all cases) (Personal communication with Dr. Ritmeijer).
There was also geographical disparity in the treatment regimens used. Among the cases identified during pregnancy, just over two-thirds of the patients received amphotericin B regimens (any formulations or in combination with another drug) in studies conducted in Africa compared to more than 75% of the patients from Asia. This could reflect either heterogeneity in treatment practices or the differential parasite susceptibility against drug regimens in the regions.
Among 346 cases in whom VL was diagnosed during pregnancy and received a treatment, there were a total of 11 (3.2%) maternal deaths reported; four (4.5%, 4/88) occurred in those treated with pentavalent antimony-based regimens, 4 (4/176; 2.3%) among those treated with L-AmB, 1 (1/20, 5.0%) with amphotericin b deoxycholate, and the drug name used for the treatment was not clear in 2 (16.7%,2/12) cases. Abortion following PA regimen was observed in just over a quarter of the pregnant women (24/88, 27.3%) of whom 13 were from Africa and 11 were from Indian sub-continent. Following the L-AmB regimen, there were a total of 5 (2.8%) miscarriages and 1 (0.6%) foetal death and no cases of abortion were reported (Table 3). Taken together, these results support the use of liposomal amphotericin B for the treatment of VL during pregnancy.
Our review identified 26 confirmed/suspected/possible cases of vertically transmitted VL with a median time of detection of 6 months (range: 0–18 months); 12 (46%) cases were identified after 6 months of birth. This suggests that children born to mothers with VL during pregnancy may require a longer post-treatment follow-up than the standard 6-months follow-up duration among non-pregnant patients to identify cases of vertical transmission. The underlying mechanism of the onset of clinical leishmaniasis among neonates and infants born to a successfully-treated mother during pregnancy is currently not clear; it has been ascribed to imbalances in immune-mechanism modulated by T cell responses (Th1/Th2) [24] or by parasites entering a state of dormancy in the lymph nodes [81].
Our review has identified limitations in reporting of VL in pregnancy. Complete information was often not available on treatment administered or on efficacy and safety outcomes for the mother and baby. For 12% (54/451) of the pregnant women, it could not be ascertained whether they had received any treatment or not. Just over two-third of the studies were considered to be a high risk of bias for patient selection while a nearly a third of the studies were at moderate to high risk of bias for ascertainment of exposure domain as VL diagnosis was purely based on clinical signs and symptoms or on serological methods (S1 Table). Overall, the large number of case reports/case series included in this review provides an explanation for such high risk of bias and likely indicates that the reported evidence would be regarded as low quality. This review also suggested that existing practices for management of VL in pregnancy is guided by limited evidence generated from case reports and small case series (71 of the 72 studies were case-reports/case series). High quality studies (such as Pekelharing-2020 [11]) is warranted for generation of a robust evidence regarding safety and efficacy of antileishmanial agents during pregnancy. There was also a lack of standardised reporting as information was missing on several critical parameters such as trimester status, time of detection of VL, and therapeutic outcomes for the mother and the child. Taken together, these findings highlight the need to improve and harmonise the reporting of VL in pregnant women. We have outlined a minimum checklist of items that might be useful for reporting purposes (Box 1).
Box 1. Proposed checklist on pregnancy related variables for studies or case reports describing visceral leishmaniasis in pregnancy. Adapted from Saito-2017 [123]
In addition to the articles presented in this review, data from women who become pregnant after completion of therapy but within the follow-up period enrolled in trials might provide further evidence on drug safety, especially on the reproductive consequences of the treatment (Table 5). The recently proposed safe ethical framework for the recruitment of women susceptible to and becoming pregnant is an important development towards filling the existing knowledge gap [28]. Like for many neglected tropical diseases, there is currently an absence of a comprehensive pregnancy-specific registry for exposures to antileishmanials, with the exception of the one dedicated for miltefosine [117]. Therefore, creating an open registry where all these cases are indexed and continually updated would help in better characterisation of the safety aspects of the drugs. Finally, the Infectious Diseases Data Observatory (IDDO) data platform, that is currently standardising individual participant data from several VL clinical studies, offers a unique resource to explore host, parasite, and drug dynamics affecting the safety and efficacy in pregnant populations [118].
Conclusions
In conclusion, this review brings together scattered observations on VL in pregnant women and the cases of vertically transmitted VL reported in the clinical literature. Available reports clearly underestimate the scale of the problem. Existing therapeutic guidelines regarding the usage of drugs in pregnancy is guided by limited evidence generated from case reports and small case series. Our review suggests that liposomal amphotericin B should be the preferred treatment for VL during pregnancy.
Acknowledgments
We would like to thank for the Prof. Bernhard Lämmle and his team for helpful responses on queries related to their manuscript. We would like to thank Christina Woodward for locating some of the articles included in the review.
References
- 1. Burza S, Croft SL, Boelaert M. Leishmaniasis. Lancet. 2018;392:951–70. pmid:30126638
- 2.
WHO. Leishmaniasis: Key facts [Internet]. WHO. 2020 [cited 2020 Jul 5]. Available from: https://www.who.int/news-room/fact-sheets/detail/leishmaniasis
- 3.
World Health Organization. The Global Health Observatory: Number of cases of visceral leishmaniasis reported [Internet]. 2021 [cited 2021 Jun 8]. Available from: https://www.who.int/data/gho/data/indicators/indicator-details/GHO/number-of-cases-of-visceral-leishmaniasis-reported
- 4. Thakur CP, Kumar M, Pandey AK. Comparisons of regimens of treatment of antimony-resistant Kala-Azar Patients: A randomized study. Am. J. Trop. Med. Hyg. 1991;45. pmid:1659239
- 5. Thakur CP, Singh RK, Hassan SM, Kumar R, Narain S, Kumar A. Amphotericin B deoxycholate treatment of visceral leishmaniasis with newer modes of administration and precautions: A study of 938 cases. Trans. R. Soc. Trop. Med. Hyg. 1999;93:319–23. pmid:10492770
- 6. Thakur CP, Kumar A, Mitra DK, Roy A, Sinha AK, Ranjan A. Improving outcome of treatment of Kala-Azar by supplementation of amphotericin B with physiologic saline and potassium chloride. Am. J. Trop. Med. Hyg. 2010;83:1040–3. pmid:21036834
- 7. Moore E, O’Flaherty D, Heuvelmans H, Seaman J, Veeken H, De Wit S, et al. Comparison of generic and proprietary sodium stibogluconate for the treatment of visceral leishmaniasis in Kenya. Bull. World Health Organ. 2001;79:388–93. pmid:11417033
- 8. Dietze R, Milan E, Berman J, Grogl M, et al. Treatment of Brazilian kala-azar with a short course of amphocil (amphotericin B cholesterol dispersion). Clin. Infect. Dis. 1993;17:981–6. pmid:8110956
- 9. Cloots K, Burza S, Malaviya P, Hasker E, Kansal S, Mollett G, et al. Male predominance in reported Visceral Leishmaniasis cases: Nature or nurture? A comparison of population-based with health facility-reported data. PLoS Negl. Trop. Dis. 2020;40:e0007995. pmid:31995564
- 10. Dahal P, Singh-Phulgenda S, Olliaro PL, Guerin PJ. Gender disparity in patients enrolled in clinical trials of visceral leishmaniasis: a systematic review and meta-analysis. PLoS Negl. Trop. Dis. 2021;15:e0009204. pmid:33725005
- 11. Pekelharing JE, Gatluak F, Harrison T, Maldonado F, Siddiqui R, Ritmeijer K. Outcomes of visceral leishmaniasis in pregnancy: A retrospective cohort study from South Sudan. PLoS Negl. Trop. Dis. 2020;14:e0007992. pmid:31978116
- 12. Adam GK, Abdulla MA, Ahmed AA, Adam I. Maternal and perinatal outcomes of visceral leishmaniasis (kala-azar) treated with sodium stibogluconate in eastern Sudan. Int. J. Gynecol. Obstet. 2009;107:208–10. pmid:19766208
- 13.
World Health Organization. Control of the leishmaniases: Report of a meeting of the WHO Expert Committee on the Control of Leishmaniases, Geneva, 22–26 March 2010. World Heal. Organ. Tech. Rep. Ser. 949. 2010. [cited 2021 Aug 17]. Available from: http://apps.who.int/iris/bitstream/handle/10665/44412/WHO_TRS_949_eng.pdf?sequence=1isAllowed=y
- 14. Alvar J, Croft S, Olliaro P. Chemotherapy in the treatment and control of Leishmaniasis. Adv. Parasitol. 2006;61:223–74. pmid:16735166
- 15. Sundar S, Olliaro PL. Miltefosine in the treatment of leishmaniasis: Clinical evidence for informed clinical risk management. Ther. Clin. Risk Manag. 2007;3:733–40. pmid:18472998
- 16.
Boelaert M, Sundar S. Leishmaniasis. In: Farrar J, Hotez PJ, Junghanss T, Kang G, Lalloo D, White NJ, editors. Manson’s Trop. Dis. 23rd ed. Elsevier Health Sciences; 2013. p. 631–51.
- 17. Elamin A, Omer MIA. Visceral leishmaniasis in a 6-week-old infant: possible congenital transmission. Trop. Doct. 1992;22:133–5. pmid:1641898
- 18. Eltoum IA, Zijlstra EE, Ali MS, Ghalib HW, Satti MMH, Eltoum B, et al. Congenital kala-azar and leishmaniasis in the placenta. Am. J. Trop. Med. Hyg. 1992;46:57–62. pmid:1536385
- 19. Low GC, Cooke WE. A congenital case of Kala-Azar. Lancet. 1926;208:1209–11.
- 20. Pagliano P, Ascione T, Di Flumeri G, Boccia G, De Caro F. Visceral leishmaniasis in immunocompromised: Diagnostic and therapeutic approach and evaluation of the recently released IDSA guidelines. Infez. Med. 2016;24:265–71. pmid:28011960
- 21. Pagliano P, Carannante N, Rossi M, Gramiccia M, Gradoni L, Faella FS, et al. Visceral leishmaniasis in pregnancy: A case series and a systematic review of the literature. J. Antimicrob. Chemother. 2005;55:229–33. pmid:15649998
- 22. Nuwayri-salti N, Khansa HF. Direct non-insect-vector transmission of leishmania parasites in mice. Int. J. Parasitol. 1985;15:497–500. pmid:3840776
- 23. Utili R, Rambaldi A, Tripodi MF, Andreana A. Visceral leishmaniasis during pregnancy treated with meglumine antimoniate. Infection. 1995;23:182–3. pmid:7499009
- 24. Berger BA, Bartlett AH, Saravia NG, Galindo Sevilla N. Pathophysiology of Leishmania infection during pregnancy. Trends Parasitol. 2017;33:935–46. pmid:28988681
- 25. Kumar A, Mittal M, Prasad S. Treatment of leishmaniasis in pregnancy. Int. J. Gynecol. Obstet. 2001;72:189–90. pmid:11166754
- 26. Miah M, Ayaz F, Maniruzzaman M, Ahasan M, Bari S, Mawla S, et al. Kala azar in pregnancy. Mymensingh Med. J. 2010;Oct; 19:529–32. pmid:20956894
- 27. Seaman J, Pryce D, Sondorp HE, Moody A, Bryceson ADM, Davidson RN. Epidemic Visceral Leishmaniasis in Sudan: A randomized trial of Aminosidine plus Sodium Stibogluconate versus Sodium Stibogluconate alone. J. Infect. Dis. 1993;168:715–20. pmid:8394861
- 28. Couderc-Pétry M, Eléfant E, Wasunna M, Mwinga A, Kshirsagar NA, Strub-Wourgaft N. Inclusion of women susceptible to and becoming pregnant in preregistration clinical trials in low-and middle-income countries: A proposal for neglected tropical diseases. PLoS Negl. Trop. Dis. 2020;14:1–15. pmid:32525876
- 29. Banjara MR, Hirve S, Siddiqui NA, Kumar N, Kansal S, Huda MM, et al. Visceral leishmaniasis clinical management in endemic districts of India, Nepal, and Bangladesh. J. Trop. Med. 2012;2012. pmid:22649459
- 30.
Treatment of Leishmaniasis with Impavido® (Miltefosine): Pregnancy registry [Internet]. [cited 2021 Jul 29]. Available from: https://clinicaltrials.gov/ct2/show/NCT02427308
- 31.
IMPAVIDO (miltefosine) pregnancy registry [Internet]. [cited 2021 Feb 9]. Available from: https://www.impavido.com/about-registry
- 32. Figueiró-Filho EA, Duarte G, El-Beitune P, Quintana SM, Maia TL. Visceral leishmaniasis (kala-azar) and pregnancy. Infect. Dis. Obstet. Gynecol. 2004;12:31–40. pmid:15460194
- 33. Silva JSF e., Galvao TF, Pereira MG, Silva MT. Treatment of American tegumentary leishmaniasis in special populations: A summary of evidence. Rev. Soc. Bras. Med. Trop. 2013;46:669–77. pmid:24474006
- 34. Kip AE, Schellens JHM, Beijnen JH, Dorlo TPC. Clinical pharmacokinetics of systemically administered antileishmanial drugs. Clin. Pharmacokinet. 2018;57:151–76. pmid:28756612
- 35.
WHO. Guidelines for diagnosis, treatment and prevention of visceral leishmaniasis in South Sudan [Internet]. WHO. [cited 2021 Jul 28]. Available from: https://www.who.int/leishmaniasis/burden/Guidelines_for_diagnosis_treatment_and_prevention_of_VL_in_South_Sudan.pdf
- 36.
The electronic medicines compendium. AmBisome [Internet]. 2019 [cited 2021 Jul 28]. Available from: https://www.medicines.org.uk/emc/product/1022#PREGNANCY
- 37.
Ministry of Health-Republic of Kenya. Prevention, diagnosis and treatment of Visceral Leishmaniasis (Kala-Azar) in Kenya [Internet]. 2017 [cited 2019 Aug 30]. Available from: https://www.who.int/leishmaniasis/burden/Kala_Azar_Kenya_2017.pdf?ua=1
- 38.
WHO. Guideline for diagnosis, treatment & prevention of leishmaniasis in Ethiopia [Internet]. WHO. 2013 [cited 2021 Jul 28]. Available from: https://www.who.int/leishmaniasis/burden/Guideline_for_diagnosis_treatment_and_prevention_of_leishmaniasis_in_Ethiopia.pdf
- 39.
Ministry of Health—Somali Fedral Government. Guidelines for diagnosis, treatment and prevention of visceral leishmaniasis in Somalia [Internet]. WHO. 2012 [cited 2021 Jul 28]. Available from: https://www.who.int/leishmaniasis/burden/Guidelines_for_diagnosis_treatment_and_prevention_of_VL_in_Somalia.pdf
- 40.
Federal Ministry of Health—Republic of Sudan. Manual for the diagnosis and treatment of leishmaniasis [Internet]. WHO. 2014 [cited 2021 Jul 28]. Available from: https://www.who.int/leishmaniasis/burden/Manual_for_the_diagnosis_and_treatment_Leishmaniasis_Guideline_Sudan_2014.pdf?ua=1
- 41.
Ministry of Health-Uganda. Guidelines for the diagnosis, treatment and prevention of visceral leishmaniasis in Uganda [Internet]. WHO. 2019 [cited 2021 Jul 28]. Available from: https://www.who.int/leishmaniasis/burden/MOH_Uganda_Guidelines_diagnosis_treatment_prevention_VL.pdf
- 42. Anversa L, Tiburcio MGS, Richini-Pereira VB, Ramirez LE. Human leishmaniasis in Brazil: A general review. Rev. Assoc. Med. Bras. 2018;64:281–9. pmid:29641786
- 43.
Brasília: Ministério da Saúde. Manual de vigilância e controle da leishmaniose visceral. [Internet]. 2014 [cited 2021 Jul 28]. Available from: http://www.saude.ba.gov.br/wp-content/uploads/2019/05/2014-Manual-de-vigilância-e-controle-da-leishmaniose-visceral.pdf
- 44.
FDA. IMPAVIDO (miltefosine) prescribing information [Internet]. www.accessdata.fda.gov. [cited 2019 Oct 10]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204684s000lbl.pdf
- 45. Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA Group (2009) Preferred Reporting Items for Systematic Reviews and Meta- Analyses: The PRISMA Statement. PLoS Med. 2009;6:e1000097. pmid:19621072
- 46.
Infectious Diseases Data Observatory. VL Surveyor [Internet]. www.iddo.org. 2020 [cited 2020 Sep 17]. Available from: https://www.iddo.org/vlSurveyor/#0
- 47.
United Nations. Standard country or area codes for statistical use [Internet]. [cited 2018 Sep 13]. Available from: https://unstats.un.org/unsd/methodology/m49/overview/
- 48.
R Core Team. R: A language and environment for statistical computing. R Found. Stat. Comput. Vienna, Austria. 2018.
- 49. Murad MH, Sultan S, Haffar S, Bazerbachi F. Methodological quality and synthesis of case series and case reports. Evid. Based. Med. 2018;23:60–3. pmid:29420178
- 50. Silva Jde A, Araujo Ide M, Pavanetti LC, Okamoto LS, Dias M. [Visceral leishmaniasis and pregnancy in renal transplanted patient: case report]. J. Bras. Nefrol. 2015;37:268–70. pmid:26154649
- 51. Papageorgiou T, Pana Z, Tragiannidis A, Tsotoulidou V, Pratsiou E, Tzouvelekis G, et al. The first case of congenital leishmaiasis in a female infant in Greece. J. Paediatr. Child Health. 2010;46:611–2. pmid:20958824
- 52. Zinchuk A, Nadraga A. Congenital visceral leishmaniasis in Ukraine: case report. Ann. Trop. Paediatr. 2010;30:161–4. pmid:20522305
- 53. Argy N, Lariven S, Rideau A, Lemoine A, Bourgeois Moine A, Allal L, et al. Congenital Leishmaniasis in a newborn infant whose mother was coinfected with Leishmaniasis and HIV. J. Pediatr. Infect. Dis. Soc. 2020 Apr 30;9(2):277–280. pmid:31589299
- 54. El-Saaran AM, Harries JR. Visceral Leishmaniasis in Dubai. Trans R Soc Trop Med Hyg. 1979;73:475. pmid:555083
- 55. Silveira BP, Sobrinho JA, Leite LF, Andrade Sales M das N, Araújo Gouveia M do S, Mathias RL, et al. Parto prematuro após uso de antimonial pentavalente: Relato de um caso. Rev. Soc. Bras. Med. Trop. 2003;36:523–5. pmid:12937733
- 56. Banerji D. Possible congenital infection of Kala-Azar. J. Indian Med. Assoc. 1955;24. pmid:14367842
- 57. Figueiro-Filho EA, El Beitune P, Queiroz GT, Somensi RS, Morais NO, Dorval ME, et al. Visceral leishmaniasis and pregnancy: analysis of cases reported in a central-western region of Brazil. Arch. Gynecol. Obstet. 2008;278:13–6. pmid:18087708
- 58. Kimutai R, Musa AM, Njoroge S, Omollo R, Alves F, Hailu A, et al. Safety and effectiveness of Sodium Stibogluconate and Paromomycin combination for the treatment of Visceral Leishmaniasis in Eastern Africa: Results from a pharmacovigilance programme. Clin. Drug Investig. 2017;37:259–72. pmid:28066878
- 59. Mueller M, Balasegaram M, Koummuki Y, Ritmeijer K, Santana MR, Davidson R. A comparison of liposomal amphotericin B with sodium stibogluconate for the treatment of visceral leishmaniasis in pregnancy in Sudan. J. Antimicrob. Chemother. 2006;58:811–5. pmid:16916865
- 60. Sinha PK, Jha TK, Thakur CP, Nath D, Mukherjee S, Aditya AK, et al. Phase 4 pharmacovigilance trial of Paromomycin injection for the treatment of Visceral Leishmaniasis in India. J. Trop. Med. 2011;2011:1–7. pmid:22174722
- 61. Bano P, Shahab SM. A combination of sulphadiazine, trimethoprim and metronidazole or tinidazole in kala-azar. J. Assoc. Physicians India. 1994;42:535–6. pmid:7868522
- 62. Mittal V, Sehgal S, Yadav T, Singh VK. Congenital transmission of kala-azar. J Commun Dis. 1987;Jun:184–5. pmid:3454359
- 63. Mueller Y, Mbulamberi DB, Odermatt P, Hoffmann A, Loutan L, Chappuis F. Risk factors for in-hospital mortality of visceral leishmaniasis patients in eastern Uganda. Trop. Med. Int. Heal. 2009;14:910–7. pmid:19552645
- 64. Vieira ML, Jacobina RR, Soares NM. Visceral leishmaniasis in a pregnant teenager. Journal of Medical and Biological Sciences 2007;6(3), 357–361.
- 65. Basher A, Nath PN. Transplacental transmission of visceral Leishmaniasis; Looking for the evidence-A case series [2P29]. Trop. Med. Int. Heal. 2017; 22 (Suppl. I):115–345.
- 66. Hindle E. Further observations on Chinese Kala-Azar. Proc. R. Soc. B Biol. Sci. 1928;103:599–619.
- 67. Rees PH, Kager PA, Wellde BT, Hockmeyer WT. The response of Kenyan kala-azar to treatment with sodium stibogluconate. Am. J. Trop. Med. Hyg. 1984;33:357–61. pmid:6329010
- 68. Blanc C, Robert A. [5th case of congenital kala-azar]. Press. Med. 1984;Jul 7:1751. pmid:6235503
- 69. Badaró R, Rocha H, Carvalho EM, Queiroz AC, Jones TC. Leishmania Donovani: An opportunistic microbe associated with progressive disease in three immunocompromised patients. Lancet. 1986;327:647–9. pmid:2869348
- 70. Nyakundi PM, Muigai R, Were JBO, Oster CN, Gachihi GS, Kirigi G. Congenital visceral leishmaniasis: Case report. Trans. R. Soc. Trop. Med. Hyg. 1988;82:564. pmid:2855677
- 71. Yadav T, Gupta H, Satteya U, Kumar R, Mittal V. Congenital kala-azar. Ann Trop Med Parasitol. 1989;Oct:535–7. pmid:2619366
- 72. Aggarwal P, Wali JP. Profile of Kala-azar in North India. Asia-Pacific J. Public Heal. 1991;5:90–3. pmid:1665981
- 73. Thakur C, Sinha G, Sharma V, Barat D. The treatment of kala-azar during pregnancy. Natl. Med. J. India. 1993;6:263–5. pmid:7950931
- 74. Giri OP. Amphotericin B therapy in kala-azar. J. Indian Med. Assoc. 1993; 91(4):91–3. pmid:8409490
- 75. Gradoni L, Gaeta GB, Pellizzer G, Maisto A, Scalone A. Mediterranean visceral leishmaniasis in pregnancy. Scand. J. Infect. Dis. 1994;26:627–9. pmid:7855563
- 76. Jeronimo SMB, Oliveira RM, Mackay S, Costa RM, Sweet J, Eliana T, et al. An urban outbreak of visceral leishmaniasis in Natal, Brazil. Trans. R. Soc. Trop. Med. Hyg. 1994;88:386–8. pmid:7570812
- 77. Sharma R, Bahl L, Goel A, Upadhaya A, Kaushik S, Sharma R, et al. Congenital kala-azar: a case report. J Commun Dis. 1996;Mar:59–61. pmid:8778183
- 78. Thakur C, Kumar P, Kumar N, Singh G, Singh A, Narain S. A randomised comparison of classical mode of administration of amphotericin B with its newer modes of administration in kala-azar. J. Assoc. Physicians India. 1998;46:779–83. pmid:11229246
- 79. Meinecke CK, Schottelius J, Oskam L, Fleischer B. Congenital transmission of visceral leishmaniasis (Kala Azar) from an asymptomatic mother to her child. Pediatrics. 1999;104:e65–e65. pmid:10545591
- 80. Vianna VL, Takiya CM, de Brito-Gitirana L. Histopathologic analysis of hamster hepatocytes submitted to experimental infection with Leishmania donovani. Parasitol. Res. 2002;88:829–36. pmid:12172815
- 81. Dereure J, Duong Thanh H, Lavabre-Bertrand T, Cartron G, Bastides F, Richard-Lenoble D, et al. Visceral leishmaniasis. Persistence of parasites in lymph nodes after clinical cure. J. Infect. 2003;47:77–81. pmid:12850167
- 82. Caldas AJM, Costa JML, Gama MEA, Ramos EAG, Barral A. Visceral leishmaniasis in pregnancy: A case report. Acta Trop. 2003;88:39–43. pmid:12943975
- 83. Pagliano P, Rossi M, Rescigno C, Altieri S, Coppola MG, Gramiccia M, et al. Mediterranean visceral leishmaniasis in HIV-negative adults: A retrospective analysis of 64 consecutive cases (1995–2001). J. Antimicrob. Chemother. 2003;52:264–8. pmid:12865389
- 84. Kumar P V., Daneshbod Y, Sadeghipoor A. Leishmania in the glomerulus. Arch. Pathol. Lab. Med. 2004;128:935–6. pmid:15270599
- 85. Figueiró Filho EA, Uehara SNO, Senefonte FR de A, Lopes AHA, Duarte G, El Beitune P. Leishmaniose visceral e gestação: relato de caso. Rev. Bras. Ginecol. e Obs. 2005;27:92–7.
- 86. Boehme C, Hain U, Novosel A, Eichenlaub S, Fleischmann E, Loscher T. Congenital visceral leishmaniasis. Emerg. Infect. Dis. 2006;12:359–3. pmid:17080586
- 87. Mueller M, Ritmeijer K, Balasegaram M, Koummuki Y, Santana MR, Davidson R. Unresponsiveness to AmBisome in some Sudanese patients with kala-azar. Trans. R. Soc. Trop. Med. Hyg. 2007;101:19–24. pmid:16730363
- 88. Topno RK, Pandey K, Das VNR, Kumar N, Bimal S, Verma RB, et al. Visceral leishmaniasis in pregnancy—the role of amphotericin B. Ann. Trop. Med. Parasitol. 2008;102:267–70. pmid:18348781
- 89. Lorenzi A, Williams C, Griffiths I. Visceral leishmaniasis mimicking disease activity in mixed connective tissue disease. Rheumatology. 2008;47:737–8. pmid:18337264
- 90. Sinha PK, Roddy P, Palma PP, Kociejowski A, Lima MA, Das VNR, et al. Effectiveness and safety of liposomal amphotericin b for visceral leishmaniasis under routine program conditions in Bihar, India. Am. J. Trop. Med. Hyg. 2010;83:357–64. pmid:20682882
- 91. Haque MA, Ekram ARMS, Sharmin LS, Belaluddin M, Salam MA. Congenital visceral leishmaniasis. Pakistan J. Med. Sci. 2010;26:485–7.
- 92. Ritmeijer K, Ter Horst R, Chane S, Aderie EM, Piening T, Collin SM, et al. Limited effectiveness of high-dose liposomal amphotericin B (AmBisome) for treatment of visceral leishmaniasis in an Ethiopian population with high HIV prevalence. Clin. Infect. Dis. 2011; 53(12):e152–58. pmid:22016502
- 93. Pilaca A, Delia Z, Pepa A, Puca E, Kraja D. Vertical transmission of the Visceral Leishmaniasis: A case report. US-China Med. Sci. 2011;8:642–5.
- 94. Damodaran S, Erumbala G, Abraham D, Nirmal S. Incidence of leishmaniasis in a district general hospital. Arch. Dis. Child. 2012;97:A253.
- 95. Lima TB, Villar CR, Rodrigues MAM, Baima JP, Yamashiro FDS, Franzoni LC, Caramori CA, Silva GF, Romeiro FG, Sassaki LY. Liver biopsy for visceral leishmaniasis diagnosis in pregnancy: report of 2 cases. World J. Clin. Infect. Dis. 2013;3(2): 20–24.
- 96. Mescouto-Borges MRM, Maués É, Costa DL, da Silva Pranchevicius MC, Romero GAS. Congenitally transmitted visceral leishmaniasis: Report of two Brazilian human cases. Brazilian J. Infect. Dis. 2013;17:263–6. pmid:23453409
- 97. Milosevic S, Bogavac M, Malenkovic G, Fabri M, Ruzic M, Dugandzija T. Visceral leishmaniasis as a cause of postpartum pyrexia—Case report. Cent. Eur. J. Med. 2013;8:149–52.
- 98. Salih NAW, van Griensven J, Chappuis F, Antierens A, Mumina A, Hammam O, et al. Liposomal amphotericin B for complicated visceral leishmaniasis (kala-azar) in eastern Sudan: How effective is treatment for this neglected disease? Trop. Med. Int. Heal. 2014;19:146–52. pmid:24433217
- 99. Burza S, Sinha PK, Mahajan R, Lima MA, Mitra G, Verma N, et al. Five-year field results and long-term effectiveness of 20 mg/kg Liposomal Amphotericin B (Ambisome) for Visceral Leishmaniasis in Bihar, India. PLoS Negl. Trop. Dis. 2014;8:46. pmid:24392168
- 100. Bode SFN, Bogdan C, Beutel K, Behnisch W, Greiner J, Henning S, et al. Hemophagocytic lymphohistiocytosis in imported pediatric visceral leishmaniasis in a nonendemic area. J. Pediatr. 2014;165:147–153.e1. pmid:24797953
- 101. Chiverto Llamazares Y, Cabezas Lopez E, Castro Sanchez M, Iglesias Goy E. Visceral leishmaniasis as a diagnosis of puerperal fever of unknown origin. [Spanish]. Progresos Obstet. y Ginecol. 2014;57:247–50.
- 102. Rahman KM, Olsen A, Harley D, Butler CD, Mondal D, Luby SP, et al. Kala-azar in pregnancy in Mymensingh, Bangladesh: A social autopsy. PLoS Negl. Trop. Dis. 2014;8:e2710. pmid:24786280
- 103. Colomba C, Adamoli L, Trizzino M, Siracusa L, Bonura S, Tolomeo M, et al. A case of visceral leishmaniasis and pulmonary tuberculosis in a post-partum woman. Int. J. Infect. Dis. International Society for Infectious Diseases; 2015;33:e5–6. pmid:25522871
- 104. Pawar S, Ragesh R, Nischal N, Sharma S, Panda PK, Sharma SK. Unique triad of pregnancy, kala azar and hemophagocytic lymphohistiocytic syndrome from a non-endemic region. J. Assoc. Physicians India. 2015;63:65–8. pmid:26710404
- 105. Kumar R, Kumari S, Prakash J, Kumar R. Atypical presentations of visceral leishmaniasis: A case series and review of literature. Trop. J. Med. Res. 2015;18:109–12.
- 106. Panagopoulos P, Mitsopoulos V, Papadopoulos A, Theodorou S, Christodoulaki C, Aloupogiannis K, et al. Visceral leishmaniasis during pregnancy: A rare case report from Greece. PLoS Negl. Trop. Dis. 2017;11:e0005134. pmid:28207741
- 107. Adam GK, Omar SM, Ahmed MAA, Abdallah TM, Ali AAA. Cross-sectional study of the case–fatality rate among patients with visceral leishmaniasis infections during pregnancy in Sudan. Int. J. Gynecol. Obstet. 2018;140:119–20. pmid:28960291
- 108. Goyal V, Mahajan R, Pandey K, Singh SN, Singh RS, Strub-Wourgaft N, et al. Field safety and effectiveness of new visceral leishmaniasis treatment regimens within public health facilities in Bihar, India. PLoS Negl. Trop. Dis. 2018;12:e0006830. pmid:30346949
- 109.
Russo A, Alt F, Neu MA, Eder S, Wingerter A, Malki KE, et al. Hemophagocytic lymphohistiocytosis in early infancy-pitfall of differentiation between hereditary and infectious reasons. Blood. Conf. 60th Annu. Meet. Am. Soc. Hematol. ASH. 2018;132. https://doi.org/10.1182/blood-2018-99-117519
- 110. Cunha FT, Lopes IC, Oliveira FCS, Queiroz IT. Visceral leishmaniasis in pregnant women from Rio Grande do Norte, Brazil: A case report and literature review. Rev. Soc. Bras. Med. Trop. 2019;52:10–2.
- 111. Parise ÉV, Maia FSC, Gomes NSG, Silva ACP da. Óbito por leishmaniose visceral em puérpera no município de Palmas, Tocantins, Brasil. J. Heal. Biol. Sci. 2019;7:312–9.
- 112.
Napier LE. Kala-Azar. Princ. Pract. Trop. Med. New York, USA: The Macmillan Company; 1946. p. 141.
- 113. Napier LE, Das Gupta CR. Indian Kala-Azar in a newly-born child. Ind. Med. Gaz. 1928;April:199–200. pmid:29011456
- 114. Ahluwalia IB, Bern C, Wagatsuma Y, Costa C, Chowdhury R, Ali M, et al. Visceral Leishmaniasis: Consequences to Women in a Bangladeshi Community. J. Women’s Heal. 2004;13:360–4. pmid:15186651
- 115.
Office of the director of Census. Census of India 2011 [Internet]. 2011 [cited 2019 Sep 19]. Available from: http://censusindia.gov.in/2011-prov-results/data_files/bihar/Provisional Population Totals 2011-Bihar.pdf
- 116.
UNESCO. Ethiopia [Internet]. 2017 [cited 2019 Sep 19]. Available from: http://uis.unesco.org/country/ET
- 117.
WHO TDR. Central registry for epidemiological surveillance of drug safety in pregnancy [Internet]. WHO. 2019 [cited 2019 Sep 19]. Available from: https://www.who.int/tdr/research/tb_hiv/drug-safety-pregnancy/en/
- 118.
Infectious Diseases Data Observatory. Visceral Leishmaniasis: Contributing data [Internet]. [cited 2021 Feb 12]. Available from: https://www.iddo.org/vl/data-sharing/contributing-data
- 119. Bhattacharya SK, Sinha PK, Sundar S, Thakur CP, Jha TK, Pandey K, et al. Phase 4 Trial of Miltefosine for the Treatment of Indian Visceral Leishmaniasis. J. Infect. Dis. 2007;196:591–8. pmid:17624846
- 120. Mondal D, Alvar J, Hasnain MG, Hossain MS, Ghosh D, Huda MM, et al. Efficacy and safety of single-dose liposomal amphotericin B for visceral leishmaniasis in a rural public hospital in Bangladesh: A feasibility study. Lancet Glob. Heal. 2014;2:e51–7. pmid:25104636
- 121. Jamil KM, Haque R, Rahman R, Faiz MA, Bhuiyan ATMRH, Kumar A, et al. Effectiveness study of Paromomycin IM injection (PMIM) for the treatment of Visceral Leishmaniasis (VL) in Bangladesh. PLoS Negl. Trop. Dis. 2015;99(10): e0004118. pmid:26496648
- 122. Pandey K, Ravidas V, Siddiqui NA, Sinha SK, Verma RB, Singh TP, et al. Pharmacovigilance of miltefosine in treatment of visceral leishmaniasis in endemic areas of Bihar, India. Am. J. Trop. Med. Hyg. 2016;95:1100–5. pmid:27645786
- 123. Saito M, Gilder ME, Nosten F, Guérin PJ, McGready R. Methodology of assessment and reporting of safety in anti-malarial treatment efficacy studies of uncomplicated falciparum malaria in pregnancy: A systematic literature review. Malar. J. 2017;16, 491. pmid:29254487