Clinical findings in female genital schistosomiasis in Madagascar

Tropical Medicine and International Health volume 3 no 4 pp 327 332 april 1998 Clinical findings in female genital schistosomiasis in Madagascar P. Leutscher 1,V. E. Ravaoalimalala 2, C. Raharisolo 1, C. E. Ramarokoto 1, M. Rasendramino 1,A Raobelison 1, B.Vennervald 3, P. Esterre 1 and H. Feldmeier 4 1 Institut Pasteur de Madagascar, Antananarivo, Madagascar 2 Direction de la Lutte contre les Maladies Transmissibles, Ministère de la Santé de Madagascar, Antananarivo, Madagascar 3 Danish Bilharziasis Laboratory, Charlottenlund, Denmark 4 Institute of Tropical Medicine, Berlin, Germany Summary To assess the morbidity of S. haematobium infection in women of reproductive age (15 49 years) in the western part of Madagascar, the village of Betalatala with a prevalence of urinary schistosomiasis in women of 75.6% (95% confidence limit 69.3 to 81.9%) was compared with a neighbouring village with similar socio-economic characteristics and a prevalence of 5.0% (95% confidence limit 0 to 11.75%). The women were questioned in Malagasy about obstetrical history and urogynecological symptoms. They were examined gynaecologically, parasitologically and by ultrasonography. Important STDs were excluded by appropiate diagnostics. In Betalatala significantly more women reported a history of spontaneous abortion (P 0.01), complaints of irregular menstruation (P 0.001), pelvic pain ( 0.05), vaginal discharge (P 0.0001), dysuria (P 0.05) and haematuria (P 0.01) than in the control village. Biopsies were obtained from the cervix of 36 women with macroscopical lesions, and in 12 cases S. haematobium eggs were found by histological sectioning (33.3%). In the control village no eggs were detected in the histological sections of biopsies taken from 14 women. (P 0.05). Infections with Candida albicans, Trichomonas vaginalis, Gardnerella vaginalis and Treponema pallidum were found in similar frequencies in both villages. In 9.8% of the women in Betalatala abnormalities of the upper reproductive tract were revealed by ultrasonography versus none in the women from the control village (P 0.05). Echographic abnormalities of the urinary tract were present in 24% and 3% of the women in the study village and in the control village, respectively (P 0.0001). These findings were accompanied by an elevated frequency of haematuria (55% versus 20%) and proteinuria (70.4% versus 25%) in the study population (P 0.0001). Our study indicates that S. haematobium infection in women may not only cause symptoms in the urinary tract, but also frequently in the lower and upper reproductive tract. keywords Schistosoma haematobium, female genital schistosomiasis, morbidity, Madagascar correspondence Dr. P. Leutscher, Institut Pasteur de Madagascar, BP 1274, 101 Antananarivo, Madagascar. Fax 261 2 284 07 Introduction Female genital schistosomiasis (FGS) seems to occur in all areas where S. haematobium is endemic (Feldmeier et al. 1995). Likewise, infection with S. mansoni has been reported to cause genital lesions in women (Billy-Brissac et al. 1994). Due to the distinct vascularisation of the female pelvis, internal and external genital organs seem to be easily accessible for migrating adult worms, leading to deposition of eggs at various topographic sites, chronic inflammation around eggs sequestered in epithelial or subepithelial genital tissue and a variety of clinical manifestations (Feldmeier et al. 1995). Virtually all studies of FGS published so far are based on selected groups of patients (Gelfand et al, 1971; Coulanges et al. 1975; Bullough 1976; Wright et al. 1982). Only two community-based studies and one study in an outpatient department of a province hospital allowed the drawing of conclusions about the true prevalence of FGS in the women of the population (Renaud et al. 1989, Leutscher et al. 1997, Kjetland et al. 1996). These studies show that genital lesions in the lower reproductive tract are to be expected in 30 to 75% of females with a S. haematobium infection. Moreover, little is known about the disease pattern associated with schistosomiasis of the female genital tract as most publications relate to case reports. A multitude of symptoms 1998 Blackwell Science Ltd 327

and signs have been described, including pelvic pain, dyspareunia, vaginal discharge, menstruation disturbances, infertility (Bullough 1976; Bayo et al. 1980; Mbenti et al. 1981; De Grecy 1982; Vass 1982; Attili et al. l983; Harouny & Petersen 1988; Mawad et al. 1992; Balash et al. 1995; Krolikowski et al. 1995). Abortion and ectopic pregnancy are also considered to be consequences of FGS (Youssef & Abdine 1958; Ekoukou et al. 1995). To obtain further epidemiological validation of these observations, our study aimed to assess the morbidity related to the uro-genital organs in women in a rural setting exposed to S. haematobium infection. Patients and methods The study was conducted in the western part of Madagascar. A village with a high prevalence of urinary schistosomiasis was compared to a village in the same region with a rather low prevalence. Betalatala village, with a prevalence of urinary schistosomiasis of 75.9% (95% confidence limit 72.5 to 79.4%) in 574 inhabitants 5 years old (Serieye et al. 1996) was compared to Bebako village, located 15 kilometers from Betalatala. The control village has a population of 230 individuals and a prevalence of urinary schistosomiasis of 7% (95% confidence limit 3.5 to 10.5% in 177 inhabitants ( 5 years old). Geographical situation and agricultural environment are identical for both villages. The region has a tropical sub-humid climate with an average temperature of 26 C and an annual average rainfall of 1500 mm. The basic agricultural crops are rice, corn, and tobacco. Due to immigration from different parts of Madagascar, the population in this region consists of groups of different ethnicity. Although in former times Betsileo and Merina groups predominated in Betalatala and Sakalava in Bebako, inter-tribal marriages, which are common in the region, have resulted in a similar mixture of ethnicity in the two villages. The inhabitants of Betalatala and Bebako have access to health care at the nearest district health center in Miandrivazo, 12 and 20 kilometers away, respectively. Medical history and gynaecological examination A standardized questionnaire was used to ask women of childbearing age (15 49 years) about obstetrical history and present gynaecological complaints. The questions were expressed in Malagasy by a female interviewer. Each woman was interviewed individually and if necessary further explanations were given. Thereafter the women were invited to undergo a gynaecological examination. Virgins, women within 2 months of giving birth or those menstruating at the time were excluded from the study. In Betalatala the gynaecological examination was postponed 3 weeks after a mass chemotherapy campaign with praziquantel (40 mg/kg) due to logistical problems. In Bebako the treatment with praziquantel was given after the gynaecological examination. The pelvic examination was performed by an experienced gynaecologist. A bimanual examination was performed to evaluate the uterus and the adnexae. Inspection of the external genitals was followed by inspection of the vagina and the cervix using disposable speculae. If pathological changes were observed in the vagina or the cervix, and if the patient consented, a biopsy was taken using a 5 mm cervical punch forceps. From each biopsy histological sections were prepared. Smears according to Papanicolaou were obtained systematically from the exocervix and the vagina with disposable cell collecting spatulae and from the endocervix with a cytobrush. Microbiological and biochemical examinations Egg excretion in urine was measured by filtration of two 10ml urine samples obtained between 0900h and 1300h on two days using a Nucleopore R membrane (Costar Co, Cambridge, USA). Haematuria and proteinuria were semiquantitatively assessed by use of urine reagent strips (Nephur 7 Test R, Boehringer Mannheim, Germany). Infection with Trichomonas vaginalis, Gardnerella vaginalis and Candida albicans was diagnosed in a drop of vaginal discharge on clean slides using saline and aqueous 10% potassium hydroxide solution, respectively. When these pathogens or mucopurulent cervicitis were present, women and their partners were treated with the appropiate drugs. Blood samples were collected and sera were subsequently stored at 20 C before being tested for Treponema pallidum antibodies with an indirect haemagglutination test (TPHAkit) and a non-treponemal flocculation test (VDRL). When both tests were positive, the patient was considered to be infected with Treponema pallidum and was treated appropriately. Ultrasonographical examination Abdominal ultrasound examinations performed to assess pathological changes of the urinary tract by an experienced radiologist following the Cairo Working Group Classification (WHO 1991; The Cairo Working Group 1992). Abnormalities of the internal genital organs were also recorded. Pregnant women in the third trimester were excluded from the ultrasonographic evaluation of the urinary tract (Richter et al. l996). 328 1998 Blackwell Science Ltd

Table 1 Parasitological, ultrasonographical and biochemical findings of the urinary tract Betalatala Bebako Significance S. haematobium in urine 133/176 (75.6%) 2/40 (5.0%) P 0.001 Egg excretion 10ml (median) 76 6 P 0.001 Bladder abnormalities* 39/163 (23.9%) 1/38 (2.6%) P 0.01 Kidney abnormalities* 14/163 (8.6%) 0/38 (0%) NS Haematuria** 93/169 (55%) 8/40 (20%) P 0.0001 Proteinuria** 119/169 (70.4%) 10/40 (25%) P 0.0001 *Detected by ultrasonography; ** Measured by use of reagent strips; see Patients and methods. Statistical evaluation Comparison of relative frequencies was done by either 2 test or Fischer s exact test. Results Parasitological, biochemical and ultrasonographical findings in the urinary tract Urine filtration was performed in 176 women of reproductive age from Betalatala (median 27 years) and in 40 women from Bebako (median 26 years). S. haematobium egg excretion in urine was found in 133 women (75.5%) and in 2 women (5.0%) in Betalatala and Bebako, respectively (P 0.001). Intensity of infection was 10 times higher in the study than in the control population (median 76 ova/10ml versus 6 ova/10ml, (P 0.001). Accordingly, haematuria and proteinuria as detected by reagent strips were more frequent in Betalatala than in Bebako (55.0% versus 20% and 70.4% versus 25%, P 0.001, Table 1). The ultrasonographical examination showed bladder wall abnormalities characteristic of S. haematobium, such as thickened regular or irregular wall or localized hypertrophy, in 39 women of 163 (23.9%) in Betalatala compared to 1 woman of 38 (2.6%) in Bebako (P 0.01). 8.6% of the women in Betalatala, but none in Bebako, had congestive alterations of the kidneys. Various abnormalities in the reproductive tract were revealed by abdominal ultrasonography in 16 of 176 examined (9.1%) from Betalatala: ovarian cysts (11), fibroid mass in the uterus (3), hydrosalpinx (1) and cervical calcification (1), as opposed to none in the control village (P 0.05). Medical history and gynaecological findings The results of the interrogation are summarized in Table 2. Spontaneous abortions were reported by 54 of 154 women (35.1%) in Betalatala and 4 of 38 women (10.5%) in Bebako (P 0.01). Of the 54 women in Betalatala with a history of spontaneous abortion, 47 had experienced one abortion, six two and one woman 4 (2.98 abortions per 100 women/year), whereas in Bebako four women reported a spontaneous Table 2 Results of interviews of women age 15 49 years Betalatala Bebako Significance Menarche (years) 14.8 14.6 NS First sexual intercourse (years) 17.1 16.8 NS Primary infertility* 9/137 (6.6%) 5/28 (17.9%) NS Secondary infertility* 19/137 (13.9%) 3/28 (10.7%) NS Dyspareunia** 12/154 (7.8%) 1/28 (3.6%) NS Postcoital bleeding** 2/154 (1.3%) 0/29 (0%) NS Spontaneous abortion** 54/154 (35.1%) 4/38 (10.5%) P 0.01 Irregular menstruation 38/176 (21.6%) 1/40 (2.5%) P 0.01 Dysmennorrhoea 51/176 (29.1%) 6/40 (15%) NS Pelvic pain 17/176 (9.7%) 0/40 (0%) P 0.05 Vaginal discharge 62/176 (35.2%) 1/40 (2.5%) P 0.001 Vulval itching 13/176 (7.4%) 0/40 (0%) NS Haematuria 31/176 (17.6%) 0/39 (0%) P 0.01 Dysuria 19/176 (10.8%) 0/39 (0%) P 0.05 *n 137 women aged 20 49 years; **n 159, virgins were not interviewed 1998 Blackwell Science Ltd 329

abortion and only once (0.93 abortions per 100 women/year) (P 0.001). One provoked abortion was reported by one woman in Betalatala. The rates of primary infertility (women who had never conceived) and secondary infertility (women who had conceived previously) were similar. No difference in the average age for menarchy was found in the two groups. Gynaecological and urinary symptoms such as irregular menstruation, pelvic pain, vaginal discharge, haematuria and dysuria were significantly more frequent in Betalatala than in the control village (Table 2). Finally, symptoms like dysmenorrhoea, dyspareunia, postcoital bleeding and vulval itching were more commonly reported in Betalatala, although the difference to Bebako was statistically not significant. Of the 176 and 40 women questioned in Betalatala and Bebako, 138 (83.6%) and 18 (60%), respectively, came for a gynaecological examination. Of the 103 women who had the gynaecological examination in Betalatala, 15 were diagnosed with genital schistosomiasis: 12 were positive for S. haematobium eggs in the histological sections, and three women had eggs in the smears from vagina or exo/endocervix. In Bebako 15 women were examined gynaecologically. However, none of the biopsies and no smear contained S. haematobium eggs. Moreover no vulval lesions were found in this group. Signs of cervicitis were found in 36% and 40% of the women in Betalatala and Bebako, respectively (Table 3). None of the women in the two villages had cervical dysplasia according to the Bethesda System (The Second National Cancer Institute Workshop 1991). The frequencies of Candida albicans, Trichomonas vaginalis and Gardnerella vaginalis infection were identical in the two villages. Antibodies (VRDL/TPHA) to Treponema pallidum were found in 17 of 93 women (18.3%) in Betalatala and in 6 women of 24 in the control village. Discussion In S. haematobium infection, urinary pathology has so far been considered as the primary object in morbidity studies. Our findings confirm previous reports that in females S. haematobium infection frequently leads to manifestations in the reproductive tract. It seems that FGS causes gynaecological signs and symptoms of considerable diversity. Likewise, pathological changes due to infection with S. haematobium have been observed in any part of the reproductive tract (Gelfand et al. 1971; Wright et al. 1982). However, symptoms and signs are rather unspecific and may be confounded with those of other pelvic inflammatory diseases. Irregular menstruation, pelvic pain and vaginal discharge were significantly more frequently reported in Betalatala than in the control village. The findings are consistent with previous observations (Bayo et al. 1980; Mbenti et al. 1981; Wright et al. 1982; De Cresy et al. 1982; Ekoukou et al. 1995; Vass 1982). As the two populations were similar as to living conditions, ethnic background and genital infections with Candida albicans, Trichomonas vaginalis, Gardnerella vaginalis and Treponema pallidum, a different prevalence and/or intensity of S. haematobium infection could explain the difference in frequency of gynaecological symptoms and signs in the women in Betalatala. The significantly higher proportion of women reporting spontaneous abortions in Betalatala suggest that affection of the internal genital organs by schistosomiasis may be associated with miscarriage. Similar observations have been made by De Cresy (1992) and Youssef & Abdine (1958). The pathophysiological mechanism, though, remains unexplained and deserves further investigation. Primary and secondary infertility was reported in both villages in similar frequency. It is important to stress, though, Betalatala Bebako Significance Table 3 Gynaecological findings Macroscopic genital abnormalities Vulva* 4/103 (3.7%) 0/15 (0%) NS Vagina** 3/103 (2.9%) 0/15 (0%) NS Cervix 36/103 (35%)*** 6/15 (40%) NS Ultrasonographical abnormalities in the genital tract 16/176 (9.1%) 0/40 (0%) P 0.05 S. haematobium eggs in the cervical biopsy 12/36 (33%) 0/14 (0%) P 0.05 *vesicle (1), nodular swelling (1), ulceration (1), depigmentation (1); **induration (2), inflammation (1); ***Cervicitis mucopurulent discharge (30) Cervicitis -mucopurulent discharge (4), ectropion (1), polyp (1); Cervicitis mucopurulent discharge; ovarian cyst (11), fibroid mass in the uterus (3), hydrosalpinx (1) and cervical calcification (1). 330 1998 Blackwell Science Ltd

that FGS and infertility have been linked in various case reports and histopathological findings in the fallopian tubes (Bullough et al. 1976; Mbenti et al. 1981; De Crecy et al. 1982; Vass 1982; Wright et al. 1982; Harouny et al. 1988; Balash et al. 1995; Ekoukou et al. 1995). Asherman syndrome caused by adhesions in the uterine cavity due to infection with S. haematobium resulting in secondary amenorrhea and reproductive impairment has been described by Krolikowski et al. (1995). However, infertility may have many reasons, among which STD s are considered to play a predominant role in many African countries (Weström & Mårdh 1990). Urinary tract complaints such as dysuria and haematuria were significantly more often reported in Betalatala and correlated to positive egg count in the urine (P 0.05 and P 0.01, respectively), whereas none of the reported gynaecological symptoms correlated with S. haematobium excretion in the urine (Table 4). This observation corresponds with previous findings that female genital schistosomiasis may exist independently and without signs of schistosomiasis infection of the urinary tract (Leutscher et al. 1997; G. Poggensee, personal communication). Abnormal ultrasonographical findings in the bladder were significantly more frequent in the women from Betalatala, whereas renal congestive findings were less frequently found and not in a significant proportion in the control village. Prevalence of sonographic abnormalities of the genital organs was significantly higher in Betalatala, which may reflect schistosomal pathology and is consistent with previous observations (Richter et al. 1995; Nko o Amvene et al. 1989; Helling-Giese et al. 1996), but further studies are needed to determine the definite aetiology. Although the control group was too small for a thorough epidemiological validation of the results, our findings nevertheless indicate that S. haematobium infection in women may not only cause symptoms in the urinary, but also in the reproductive tract. More studies are needed from other S. haematobium-endemic areas to obtain a more detailed assessment of the morbidity in women with FGS. Acknowledgement The authors are grateful to Dr. Pascal Boisier and Dr Léon Rabaritaona for the statistical work. References Attili VR, Hira SK & Dube MK (1983) Schistosomal genital granulomas: a report of 10 cases. British Journal Venereal Diseases 59, 269 272. Balasch J, Martínez-Román, Creus M, Campo E, Fortuny A & Vanrell JA (1995) Schistosomiasis: an unusual cause of tubal infertility. Human Reproduction 10, 1725 1727. Bayo S, Mamantou P & Samassekou M (1980) La bilharziose du col de l uterus au Mali. Afrique Médicale 179, 252 256. Table 4 Comparison of results of urine filtration and urogenital complaints in the women in Betalatala S. haematobium eggs in urine ve ve Significance Primary infertility 7 (5.1%) 2 (1.5%) NS n 137 90 (65.7%) 38 (27.7%) Secondary infertility 13 (9.5%) 6 (4.4%) NS n 137 84 (61.3%) 34 (24.8%) Vaginal discharge 47 (26.7%) 15 (8.5%) NS n 176 88 (50.0%) 26 (14.8%) Pelvic pain 14 (8.0%) 3 (1.7%) NS n 176 120 (68.2%) 39 (22.1%) Irregular menstruation 25 (14.2%) 13 (7.4%) NS n 176 110 (62.5%) 35 (19.9%) Dysmennoroea 38 (27.7%) 13 (7.4%) NS n 176 96 (54.5%) 29 (16.5%) Dyspareunia 11 (7.1%) 1 (1.0%) NS n 154 103 (66.9%) 39 (25.0%) Spontaneous abortion 33 (21.4%) 13 (8.4%) NS n 154 84 (54.6%) 24 (15.6%) Haematuria 30 (17.1%) 2 (1.1%) P 0.01 n 176 103 (58.5%) 41 (23.3%) Dysuria 18 (10.2%) 1 (1.0%) P 0.05 n 176 115 (65.3%) 42 (23.5%) 1998 Blackwell Science Ltd 331

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