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Maternal and perinatal outcomes of visceral leishmaniasis (kala-azar) treated with sodium stibogluconate in eastern Sudan
International Journal of Gynecology and Obstetrics 107 (2009) 208–210
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j g o
CLINICAL ARTICLE
Maternal and perinatal outcomes of visceral leishmaniasis (kala-azar) treated with sodium stibogluconate in eastern Sudan Gamal K. Adam a, Mohamed A. Abdulla a, Ahmed A. Ahmed a, Ishag Adam b,⁎ a b
Gadarif University, Gadarif, Sudan Faculty of Medicine, University of Khartoum, Sudan
a r t i c l e
i n f o
Article history: Received 24 June 2009 Received in revised form 15 July 2009 Accepted 12 August 2009 Keywords: Kala-azar Perinatal Pregnancy Sodium stibogluconate Sudan Visceral leishmaniasis
a b s t r a c t Objective: To investigate maternal and perinatal outcomes when pregnant women with visceral leishmaniasis (VL, also known as kala-azar) are treated with the antimonial sodium stibogluconate. Method: Forty-two pregnant women with VL were treated with sodium stibogluconate at Gadarif Hospital, Gadarif, Sudan, and mother and child were followed up for 1 year. Results: The treatment began at a mean ± SD of 24.4 ± 9.2 weeks of pregnancy. None of the patients had malaria or HIV. Two (4.7%) who received the treatment in the first trimester had miscarriages; 4 (4.9%) died from hepatic encephalopathy during the second week of treatment; and 2 (4.7%) had preterm deliveries. One of the newborns had a myelomeningocele and died at 2 hours, and the other died from VL at 2 months. Conclusion: Preventive measures against VL should be employed in the region, and more research on VL and its treatment during pregnancy is needed. © 2009 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction There are 350 million individuals in 88 countries at risk for leishmaniasis, a disease with clinical manifestations ranging from selfhealing cutaneous lesions to chronic visceral disease [1,2]. Visceral leishmaniasis (VL, also known as kala-azar) is endemic in tropical and subtropical areas. It has become clear that during pregnancy the immune system enhances humoral defense mechanisms (the so-called type 2 bias), and down-regulates cellular defense responses (type 1 responses), as a way to protect the fetus while maintaining maternal immunity [3]. This delicate balance sometimes had its drawbacks, however. On the one hand, the general suppression of T-lymphocyte proliferation prevents these cells from attacking the fetus; but on the other (as an example) the proliferation of helper T cells type 1, a T-lymphocyte subset that triggers immune responses to Leishmania infection, is also suppressed. Changes in cortisol and prolactin levels are thought to play a role in these immune changes [4]. Most cases of VL are observed in children younger than 10 years. However, with the spread of the disease to peri-urban areas, where many adults have not been previously infected with Leishmania parasites, more cases of VL have been reported among pregnant women [5,6]. Visceral leishmaniasis during pregnancy may lead to severe maternal anemia, loss of the fetus, and congenital disease in the newborn [7], and treatment cannot be deferred. Currently, the ⁎ Corresponding author. PO Box 102, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Khartoum, Khartoum, Sudan. Tel.: +249 912168988; fax: +249 183771211. E-mail address: [email protected] (I. Adam).
treatment consists of parenteral administration of pentavalent antimonials such as sodium stibogluconate, but few studies have been published concerning VL treatment during pregnancy [5,6]. The present study was conducted at Gadarif Hospital, Gadarif, in eastern Sudan, to investigate maternal and perinatal outcomes when pregnant women with VL are treated with sodium stibogluconate. It is hoped that its findings will be useful to managing physicians as well as immunologists and other researchers looking to develop a vaccine. 2. Materials and methods This prospective cohort study was carried out at Gadarif Hospital, Gadarif, in eastern Sudan, from June 2006 through January 2009. Pregnant women with symptoms and signs suggestive of VL, such as fever, weight loss, anemia, and hepatosplenomegaly, were approached to participate in the study. Besides being pregnant, the inclusion criteria were confirmation of Leishmania infection by the presence of amastigotes in Giemsa-stained smears of bone marrow, and signing an informed written consent form. The obstetric and medical histories of the study participants were taken and their socio-demographic characteristics recorded, as were clinical, hematologic, and biochemical characteristics. Sedimentation rate and creatinine levels were investigated before and at the end of treatment. The study participants were tested for HIV after receiving counseling according to the standard procedure previously described [8], and they were also tested for malaria. The latter test consisted of observing Giemsa-stained blood films using oil immersion and 100 × magnification. The participants were then hospitalized for 30 days to receive the first-line treatment for VL, a once-daily intramuscular injection of
0020-7292/$ – see front matter © 2009 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2009.08.002
G.K. Adam et al. / International Journal of Gynecology and Obstetrics 107 (2009) 208–210
20 mg of sodium stibogluconate per kilogram of bodyweight. After their discharge, they were followed up in the antenatal clinics every 2 weeks until delivery. They were considered cured when the signs and symptoms had disappeared, laboratory values had improved, and no clinical relapse was observed during the subsequent 12 months. All the deliveries that took place in the hospital were conducted according to the standard procedure of Gadarif hospital and were supervised by obstetricians. The newborns delivered in the hospital had their weight and head circumference recorded at birth; and whether they were born in the hospital or at home, all were checked monthly by pediatricians for malformations, and again when they were brought for vaccination, until they reached the age of 1 year. The pediatricians enquired in detail about fever, failure to thrive, and development milestones. If congenital VL was suspected, the diagnosis was confirmed or excluded by exploring a lymph node or bone marrow. The babies were considered disease free if no clinical signs of VL developed during the 12-month follow-up. Miscarriage was defined as the expulsion of the fetus before 28 weeks of gestation, and preterm delivery as a delivery that occurred between 28 and 37 weeks of pregnancy. Data were analyzed using the SPSS software package, version 13.0 (SPSS, Chicago, Illinois, USA). Values are reported as frequency, percentage, and mean ± SD. The study protocol received ethical clearance from the ethics committee of the Faculty of Medicine of the University of Gadarif, Gadarif, Sudan. 3. Results The baseline clinical and biochemical characteristics of the 42 participants are shown in Table 1. The treatment began at a mean of 24.4 ± 9.2 weeks of pregnancy. No participants had malaria or HIV but all received blood transfusions for severe anemia. Of the 14 participants (33.3%) with a history of miscarriage, 9 (21.4%) received treatment in their first, 21 (50%) in their second, and 12 (28.5%) in their third trimester of pregnancy. Two (4.7%) had miscarriages during their second week of treatment, which coincided with the 8th week of pregnancy for one participant and the 12th week of pregnancy for the other. Four participants (4.9%) died from hepatic encephalopathy during their second week of treatment, between the 22nd and the 30th week of pregnancy. The mean birth weight and head circumference of the 24 newborns delivered in the hospital were 2894.5 ± 722.4 g and 35.6 ± 0.69 cm, respectively. The corresponding values for those delivered at home were unknown. The newborn of a para 9, 47-year-old participant who received treatment in the first trimester of pregnancy had Down syndrome features, and the condition was confirmed by chromosomal analysis. Two participants (4.7%) were delivered preterm, one in the 32nd and the other in the Table 1 Baseline sociodemographic and biochemical characteristics of the 42 patients.a Characteristic
Value
Age, y Parity Weight, kg Gestational age, wk Spleen size, cm Liver size, cm Hemoglobin, g/dL Blood glucose, mg/dL Creatinine, mg/dL Platelets, cells/μL White blood cells, cells/μL Total protein, g/dL Albumin, g/dL Serum bilirubin, mg/dL Alanine aminotransferase, IU/L Aspartate aminotransferase, IU/L
29.7 ± 14.5 3.5 ± 2.4 60.7 ± 19.0 24.4 ± 9.2 6. 2 ± 4.3 4.2 ± 2.8 7.8 ± 3.4 125.5 ± 11.8 0.9 ± 0.3 138,271 ± 14,250 4250 ± 958.7 7.4 ± 0.84 3.3 ± 0.2 1.2 ± 0.9 65.9 ± 21.7 82.6 ± 19.5
a
Values are given as mean ± SD.
209
34th week, the former of a baby with a myelomeningocele who died at 2 hours from respiratory distress. This participant received treatment during the first trimester. At the age of 2 months one baby failed to thrive and had fever, an enlarged lymph node, and hepatosplenomegaly, all signs of VL, and the parasite was found in a lymph node. This baby died during the first week of treatment. 4. Discussion We recently reported a high maternal mortality from various infectious diseases in different regions of Sudan [9–12], and 4 maternal deaths occurred in the course of the present study. The previous studies on VL or its treatments during pregnancy reported no maternal death [5,6], however, perhaps because they were small retrospective case series. Two participants (4.8%) had miscarriages in the first trimester while receiving sodium stibogluconate. This frequency is similar to the 3.8% previously recorded in Sudan among pregnant women who received quinine [13] or the (3.2%) who received artemisinins in early pregnancy [14], and is also similar to the frequency for healthy pregnant women [15]. A limitation of the present study is that, in Sudan, as in many sub-Saharan countries, the frequency rates of miscarriage, preterm labor, and congenital abnormalities in the general population are unknown. The observation that almost one-third of the women enrolled in the present study had a history of miscarriage indicates that this outcome is common in the study area. However, in their retrospective study conducted in Sudan with 39 pregnant women with VL treated with sodium stibogluconate alone, amphotericin B, or their combination, Mueller et al. [5] reported 13 miscarriages among the 23 treated with sodium stibogluconate alone and none in the other 2 groups. One participant treated in the first trimester was delivered of a child with a myelomeningocele and another was delivered of a child with Down syndrome. Among the factors reported to increase the risk of these 2 conditions are a maternal genetic effect and a sex-influenced effect for the myelomeningocele [16], and older maternal age and high parity for Down syndrome [17]. In the present study, the participant delivered of a child with Down syndrome was 47 years old and had previously given birth to 9 live children. A study of cutaneous leishmaniasis during pregnancy reported poor fetal outcomes with no maternal treatment; of 19 patients, 2 (10.5%) were delivered preterm and another 2 had a stillbirth [18]. Another study of VL during pregnancy reported unfavorable fetal outcomes without maternal treatment [7] but favorable fetal outcomes following maternal treatment with amphotericin B (AmB) [19]. In yet another study, one pregnant woman with VL was treated with AmB during pregnancy and the other was not, but her child was treated with meglumine antimoniate after delivery. Both infants were followed up until the age of 8 or 9 months and both were free of Leishmania infection at that age [20]. Amphotericin B is currently the second drug of choice for the treatment of VL in non-pregnant individuals. Recent reports on VL and its treatment during pregnancy favor using AmB over sodium stibogluconate because of its greater efficiency and safety [5,6], and AmB has the additional advantage of offering a prompt improvement of clinical signs and laboratory values after a short treatment course. However, AmB is not registered and hence not available in Sudan, and the high cost of its lipid formulations may place it beyond the means of Sudan and many other developing countries. We report poor maternal and perinatal outcomes following VL treatment with sodium stibogluconate in eastern Sudan. Preventive measures are needed in this area, as well as further studies on VL and its treatment during pregnancy using larger study populations. 5. Conflict of interest The authors have no conflicts of interest.
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G.K. Adam et al. / International Journal of Gynecology and Obstetrics 107 (2009) 208–210
Acknowledgments This study was funded by the Sudanese Sugar Company and Assalaya Sugar Factory, Sudan. References [1] Murray HW, Berman JD, Davies CR, Saravia NG. Advances in leishmaniasis. Lancet 2005;366(9496):1561–77. [2] Markell E, John D, Krotoski W, editors. Markell and Voge's Medical Parasitology. 8th ed. Philadelphia, Pennsylvania, USA: WB Saunders; 1999. [3] Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 1993;14(7):353–6. [4] Bayoumi NK, Elhassan EM, Elbashir MI, Adam I. Cortisol, prolactin, cytokines and the susceptibility of pregnant Sudanese women to Plasmodium falciparum malaria. Ann Trop Med Parasitol 2009;103(2):111–7. [5] 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(4):811–5. [6] Topno RK, Pandey K, Das VN, Kumar N, Bimal S, Verma RB, et al. Visceral leishmaniasis in pregnancy: the role of amphotericin B. Ann Trop Med Parasitol 2008;102(3): 267–70. [7] Eltoum IA, Zijlstra EE, Ali MS, Ghalib HW, Satti MM, Eltoum B, et al. Congenital kala-azar and leishmaniasis in the placenta. Am J Trop Med Hyg 1992;46(1): 57–62. [8] Mahmoud MM, Nasr AM, Gassmelseed DE, Abdalelhafiz MA, Elsheikh MA, Adam I. Knowledge and attitude toward HIV voluntary counseling and testing services among pregnant women attending an antenatal clinic in Sudan. J Med Virol 2007;79(5):469–73. [9] Ahmed RE, Karsany MS, Adam I. Brief report: acute viral hepatitis and poor maternal and perinatal outcomes in pregnant Sudanese women. J Med Virol 2008;80(10): 1747–8.
[10] Haggaz AA, Radi EA, Adam I. High maternal mortality in Darfur, Sudan. Int J Gynecol Obstet 2007;98(3):252–3. [11] Elhassan ME, Mirgahani OA, Adam I. Maternal mortality and stillbirth in central Sudan. Tropical Doctor; in press. [12] Adam I, Elbashir MI. Maternal death due to severe pulmonary edema caused by falciparum malaria: case report. East Mediterr Health J 2004;10(4–5):685–8. [13] Adam I, Idris HM, Elbashir MI. Quinine for chloroquine-resistant falciparum malaria in pregnant Sudanese women in the first trimester. East Mediterr Healt J 2004;10(4–5):560–5. [14] Adam I, Elhassan ME, Omer EM, Abdullah MA, Mahgoub HM, Adam GK. Safety of artemisinins during early human pregnancy. Ann Trop Med Parasitol 2009;103(3): 205–10. [15] ElGhazali G, Adam I, Hamad AA, Elbashir MI. Plasmodium falciparum infection during pregnancy in an unstable transmission area in eastern Sudan. Eastern Mediterr Health J 2003;9(4):570–80. [16] Deak KL, Siegel DG, George TM, Gregory S, Ashley-Koch A. Speer MC; NTD Collaborative Group. Further evidence for a maternal genetic effect and a sexinfluenced effect contributing to risk for human neural tube defects. Birth Defects Res A Clin Mol Teratol 2008;82(10):662–9. [17] Allen EG, Freeman SB, Druschel C, Hobbs CA, O'Leary LA, Romitti PA, et al. Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects. Hum Genet 2009;125(1):41–52. [18] Morgan DJ, Guimaraes LH, Machado PR, D'Oliveira Jr A, Almeida RP, Lago EL, et al. Cutaneous leishmaniasis during pregnancy: exuberant lesions and potential fetal complications. Clin Infect Dis 2007;45(4):478–82. [19] Thakur CP, Sinha GP, Sharma V, Barat D. The treatment of kala-azar during pregnancy. Nation Med J India 1993;6(6):263–5. [20] Gradoni L, Gaeta GB, Pellizzer G, Maisto A, Scalone A. Mediterranean visceral leishmaniasis in pregnancy. Scand J Infect Dis 1994;26(5):627–9.
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j g o
CLINICAL ARTICLE
Maternal and perinatal outcomes of visceral leishmaniasis (kala-azar) treated with sodium stibogluconate in eastern Sudan Gamal K. Adam a, Mohamed A. Abdulla a, Ahmed A. Ahmed a, Ishag Adam b,⁎ a b
Gadarif University, Gadarif, Sudan Faculty of Medicine, University of Khartoum, Sudan
a r t i c l e
i n f o
Article history: Received 24 June 2009 Received in revised form 15 July 2009 Accepted 12 August 2009 Keywords: Kala-azar Perinatal Pregnancy Sodium stibogluconate Sudan Visceral leishmaniasis
a b s t r a c t Objective: To investigate maternal and perinatal outcomes when pregnant women with visceral leishmaniasis (VL, also known as kala-azar) are treated with the antimonial sodium stibogluconate. Method: Forty-two pregnant women with VL were treated with sodium stibogluconate at Gadarif Hospital, Gadarif, Sudan, and mother and child were followed up for 1 year. Results: The treatment began at a mean ± SD of 24.4 ± 9.2 weeks of pregnancy. None of the patients had malaria or HIV. Two (4.7%) who received the treatment in the first trimester had miscarriages; 4 (4.9%) died from hepatic encephalopathy during the second week of treatment; and 2 (4.7%) had preterm deliveries. One of the newborns had a myelomeningocele and died at 2 hours, and the other died from VL at 2 months. Conclusion: Preventive measures against VL should be employed in the region, and more research on VL and its treatment during pregnancy is needed. © 2009 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction There are 350 million individuals in 88 countries at risk for leishmaniasis, a disease with clinical manifestations ranging from selfhealing cutaneous lesions to chronic visceral disease [1,2]. Visceral leishmaniasis (VL, also known as kala-azar) is endemic in tropical and subtropical areas. It has become clear that during pregnancy the immune system enhances humoral defense mechanisms (the so-called type 2 bias), and down-regulates cellular defense responses (type 1 responses), as a way to protect the fetus while maintaining maternal immunity [3]. This delicate balance sometimes had its drawbacks, however. On the one hand, the general suppression of T-lymphocyte proliferation prevents these cells from attacking the fetus; but on the other (as an example) the proliferation of helper T cells type 1, a T-lymphocyte subset that triggers immune responses to Leishmania infection, is also suppressed. Changes in cortisol and prolactin levels are thought to play a role in these immune changes [4]. Most cases of VL are observed in children younger than 10 years. However, with the spread of the disease to peri-urban areas, where many adults have not been previously infected with Leishmania parasites, more cases of VL have been reported among pregnant women [5,6]. Visceral leishmaniasis during pregnancy may lead to severe maternal anemia, loss of the fetus, and congenital disease in the newborn [7], and treatment cannot be deferred. Currently, the ⁎ Corresponding author. PO Box 102, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Khartoum, Khartoum, Sudan. Tel.: +249 912168988; fax: +249 183771211. E-mail address: [email protected] (I. Adam).
treatment consists of parenteral administration of pentavalent antimonials such as sodium stibogluconate, but few studies have been published concerning VL treatment during pregnancy [5,6]. The present study was conducted at Gadarif Hospital, Gadarif, in eastern Sudan, to investigate maternal and perinatal outcomes when pregnant women with VL are treated with sodium stibogluconate. It is hoped that its findings will be useful to managing physicians as well as immunologists and other researchers looking to develop a vaccine. 2. Materials and methods This prospective cohort study was carried out at Gadarif Hospital, Gadarif, in eastern Sudan, from June 2006 through January 2009. Pregnant women with symptoms and signs suggestive of VL, such as fever, weight loss, anemia, and hepatosplenomegaly, were approached to participate in the study. Besides being pregnant, the inclusion criteria were confirmation of Leishmania infection by the presence of amastigotes in Giemsa-stained smears of bone marrow, and signing an informed written consent form. The obstetric and medical histories of the study participants were taken and their socio-demographic characteristics recorded, as were clinical, hematologic, and biochemical characteristics. Sedimentation rate and creatinine levels were investigated before and at the end of treatment. The study participants were tested for HIV after receiving counseling according to the standard procedure previously described [8], and they were also tested for malaria. The latter test consisted of observing Giemsa-stained blood films using oil immersion and 100 × magnification. The participants were then hospitalized for 30 days to receive the first-line treatment for VL, a once-daily intramuscular injection of
0020-7292/$ – see front matter © 2009 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2009.08.002
G.K. Adam et al. / International Journal of Gynecology and Obstetrics 107 (2009) 208–210
20 mg of sodium stibogluconate per kilogram of bodyweight. After their discharge, they were followed up in the antenatal clinics every 2 weeks until delivery. They were considered cured when the signs and symptoms had disappeared, laboratory values had improved, and no clinical relapse was observed during the subsequent 12 months. All the deliveries that took place in the hospital were conducted according to the standard procedure of Gadarif hospital and were supervised by obstetricians. The newborns delivered in the hospital had their weight and head circumference recorded at birth; and whether they were born in the hospital or at home, all were checked monthly by pediatricians for malformations, and again when they were brought for vaccination, until they reached the age of 1 year. The pediatricians enquired in detail about fever, failure to thrive, and development milestones. If congenital VL was suspected, the diagnosis was confirmed or excluded by exploring a lymph node or bone marrow. The babies were considered disease free if no clinical signs of VL developed during the 12-month follow-up. Miscarriage was defined as the expulsion of the fetus before 28 weeks of gestation, and preterm delivery as a delivery that occurred between 28 and 37 weeks of pregnancy. Data were analyzed using the SPSS software package, version 13.0 (SPSS, Chicago, Illinois, USA). Values are reported as frequency, percentage, and mean ± SD. The study protocol received ethical clearance from the ethics committee of the Faculty of Medicine of the University of Gadarif, Gadarif, Sudan. 3. Results The baseline clinical and biochemical characteristics of the 42 participants are shown in Table 1. The treatment began at a mean of 24.4 ± 9.2 weeks of pregnancy. No participants had malaria or HIV but all received blood transfusions for severe anemia. Of the 14 participants (33.3%) with a history of miscarriage, 9 (21.4%) received treatment in their first, 21 (50%) in their second, and 12 (28.5%) in their third trimester of pregnancy. Two (4.7%) had miscarriages during their second week of treatment, which coincided with the 8th week of pregnancy for one participant and the 12th week of pregnancy for the other. Four participants (4.9%) died from hepatic encephalopathy during their second week of treatment, between the 22nd and the 30th week of pregnancy. The mean birth weight and head circumference of the 24 newborns delivered in the hospital were 2894.5 ± 722.4 g and 35.6 ± 0.69 cm, respectively. The corresponding values for those delivered at home were unknown. The newborn of a para 9, 47-year-old participant who received treatment in the first trimester of pregnancy had Down syndrome features, and the condition was confirmed by chromosomal analysis. Two participants (4.7%) were delivered preterm, one in the 32nd and the other in the Table 1 Baseline sociodemographic and biochemical characteristics of the 42 patients.a Characteristic
Value
Age, y Parity Weight, kg Gestational age, wk Spleen size, cm Liver size, cm Hemoglobin, g/dL Blood glucose, mg/dL Creatinine, mg/dL Platelets, cells/μL White blood cells, cells/μL Total protein, g/dL Albumin, g/dL Serum bilirubin, mg/dL Alanine aminotransferase, IU/L Aspartate aminotransferase, IU/L
29.7 ± 14.5 3.5 ± 2.4 60.7 ± 19.0 24.4 ± 9.2 6. 2 ± 4.3 4.2 ± 2.8 7.8 ± 3.4 125.5 ± 11.8 0.9 ± 0.3 138,271 ± 14,250 4250 ± 958.7 7.4 ± 0.84 3.3 ± 0.2 1.2 ± 0.9 65.9 ± 21.7 82.6 ± 19.5
a
Values are given as mean ± SD.
209
34th week, the former of a baby with a myelomeningocele who died at 2 hours from respiratory distress. This participant received treatment during the first trimester. At the age of 2 months one baby failed to thrive and had fever, an enlarged lymph node, and hepatosplenomegaly, all signs of VL, and the parasite was found in a lymph node. This baby died during the first week of treatment. 4. Discussion We recently reported a high maternal mortality from various infectious diseases in different regions of Sudan [9–12], and 4 maternal deaths occurred in the course of the present study. The previous studies on VL or its treatments during pregnancy reported no maternal death [5,6], however, perhaps because they were small retrospective case series. Two participants (4.8%) had miscarriages in the first trimester while receiving sodium stibogluconate. This frequency is similar to the 3.8% previously recorded in Sudan among pregnant women who received quinine [13] or the (3.2%) who received artemisinins in early pregnancy [14], and is also similar to the frequency for healthy pregnant women [15]. A limitation of the present study is that, in Sudan, as in many sub-Saharan countries, the frequency rates of miscarriage, preterm labor, and congenital abnormalities in the general population are unknown. The observation that almost one-third of the women enrolled in the present study had a history of miscarriage indicates that this outcome is common in the study area. However, in their retrospective study conducted in Sudan with 39 pregnant women with VL treated with sodium stibogluconate alone, amphotericin B, or their combination, Mueller et al. [5] reported 13 miscarriages among the 23 treated with sodium stibogluconate alone and none in the other 2 groups. One participant treated in the first trimester was delivered of a child with a myelomeningocele and another was delivered of a child with Down syndrome. Among the factors reported to increase the risk of these 2 conditions are a maternal genetic effect and a sex-influenced effect for the myelomeningocele [16], and older maternal age and high parity for Down syndrome [17]. In the present study, the participant delivered of a child with Down syndrome was 47 years old and had previously given birth to 9 live children. A study of cutaneous leishmaniasis during pregnancy reported poor fetal outcomes with no maternal treatment; of 19 patients, 2 (10.5%) were delivered preterm and another 2 had a stillbirth [18]. Another study of VL during pregnancy reported unfavorable fetal outcomes without maternal treatment [7] but favorable fetal outcomes following maternal treatment with amphotericin B (AmB) [19]. In yet another study, one pregnant woman with VL was treated with AmB during pregnancy and the other was not, but her child was treated with meglumine antimoniate after delivery. Both infants were followed up until the age of 8 or 9 months and both were free of Leishmania infection at that age [20]. Amphotericin B is currently the second drug of choice for the treatment of VL in non-pregnant individuals. Recent reports on VL and its treatment during pregnancy favor using AmB over sodium stibogluconate because of its greater efficiency and safety [5,6], and AmB has the additional advantage of offering a prompt improvement of clinical signs and laboratory values after a short treatment course. However, AmB is not registered and hence not available in Sudan, and the high cost of its lipid formulations may place it beyond the means of Sudan and many other developing countries. We report poor maternal and perinatal outcomes following VL treatment with sodium stibogluconate in eastern Sudan. Preventive measures are needed in this area, as well as further studies on VL and its treatment during pregnancy using larger study populations. 5. Conflict of interest The authors have no conflicts of interest.
210
G.K. Adam et al. / International Journal of Gynecology and Obstetrics 107 (2009) 208–210
Acknowledgments This study was funded by the Sudanese Sugar Company and Assalaya Sugar Factory, Sudan. References [1] Murray HW, Berman JD, Davies CR, Saravia NG. Advances in leishmaniasis. Lancet 2005;366(9496):1561–77. [2] Markell E, John D, Krotoski W, editors. Markell and Voge's Medical Parasitology. 8th ed. Philadelphia, Pennsylvania, USA: WB Saunders; 1999. [3] Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 1993;14(7):353–6. [4] Bayoumi NK, Elhassan EM, Elbashir MI, Adam I. Cortisol, prolactin, cytokines and the susceptibility of pregnant Sudanese women to Plasmodium falciparum malaria. Ann Trop Med Parasitol 2009;103(2):111–7. [5] 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(4):811–5. [6] Topno RK, Pandey K, Das VN, Kumar N, Bimal S, Verma RB, et al. Visceral leishmaniasis in pregnancy: the role of amphotericin B. Ann Trop Med Parasitol 2008;102(3): 267–70. [7] Eltoum IA, Zijlstra EE, Ali MS, Ghalib HW, Satti MM, Eltoum B, et al. Congenital kala-azar and leishmaniasis in the placenta. Am J Trop Med Hyg 1992;46(1): 57–62. [8] Mahmoud MM, Nasr AM, Gassmelseed DE, Abdalelhafiz MA, Elsheikh MA, Adam I. Knowledge and attitude toward HIV voluntary counseling and testing services among pregnant women attending an antenatal clinic in Sudan. J Med Virol 2007;79(5):469–73. [9] Ahmed RE, Karsany MS, Adam I. Brief report: acute viral hepatitis and poor maternal and perinatal outcomes in pregnant Sudanese women. J Med Virol 2008;80(10): 1747–8.
[10] Haggaz AA, Radi EA, Adam I. High maternal mortality in Darfur, Sudan. Int J Gynecol Obstet 2007;98(3):252–3. [11] Elhassan ME, Mirgahani OA, Adam I. Maternal mortality and stillbirth in central Sudan. Tropical Doctor; in press. [12] Adam I, Elbashir MI. Maternal death due to severe pulmonary edema caused by falciparum malaria: case report. East Mediterr Health J 2004;10(4–5):685–8. [13] Adam I, Idris HM, Elbashir MI. Quinine for chloroquine-resistant falciparum malaria in pregnant Sudanese women in the first trimester. East Mediterr Healt J 2004;10(4–5):560–5. [14] Adam I, Elhassan ME, Omer EM, Abdullah MA, Mahgoub HM, Adam GK. Safety of artemisinins during early human pregnancy. Ann Trop Med Parasitol 2009;103(3): 205–10. [15] ElGhazali G, Adam I, Hamad AA, Elbashir MI. Plasmodium falciparum infection during pregnancy in an unstable transmission area in eastern Sudan. Eastern Mediterr Health J 2003;9(4):570–80. [16] Deak KL, Siegel DG, George TM, Gregory S, Ashley-Koch A. Speer MC; NTD Collaborative Group. Further evidence for a maternal genetic effect and a sexinfluenced effect contributing to risk for human neural tube defects. Birth Defects Res A Clin Mol Teratol 2008;82(10):662–9. [17] Allen EG, Freeman SB, Druschel C, Hobbs CA, O'Leary LA, Romitti PA, et al. Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects. Hum Genet 2009;125(1):41–52. [18] Morgan DJ, Guimaraes LH, Machado PR, D'Oliveira Jr A, Almeida RP, Lago EL, et al. Cutaneous leishmaniasis during pregnancy: exuberant lesions and potential fetal complications. Clin Infect Dis 2007;45(4):478–82. [19] Thakur CP, Sinha GP, Sharma V, Barat D. The treatment of kala-azar during pregnancy. Nation Med J India 1993;6(6):263–5. [20] Gradoni L, Gaeta GB, Pellizzer G, Maisto A, Scalone A. Mediterranean visceral leishmaniasis in pregnancy. Scand J Infect Dis 1994;26(5):627–9.