Dienogest Use for Recurrent Pyosalpinx as a Long-Term Complication of Cloacal Exstrophy: A Case Report

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2 Cloacal exstrophy (CE) is a rare congenital disease that requires multiple surgeries for 3 complex gastrointestinal and genitourinary anomalies. Long-term complications are not 4 uncommon; however, they are poorly reported. Pyosalpinx is sometimes encountered 5 during CE management in adolescents and young adults. 6 Case 7 A 28-year-old woman with a history of CE presented with fever, lower abdominal pain, 8 and vomiting and was diagnosed with left pyosalpinx. Computed tomography- guided 9 drainage and intravenous antibiotic administration w ere successful; however, she had 2 10 readmissions for recurrent pyosalpinx 1 week after discharge and again 4 months later. 11 She was administered Dienogest, a synthetic progestin, to prevent recurrent pyosalpinx 12 and had no recurrence for 8 months. 13 Summary and conclusion 14 Dienogest is a conservative treatment choice for preventing the recurrence of pyosalpinx 15 for CE patients. 16 17 Key Words: Cloacal exstrophy; Dienogest; Long-term complication; Pelvic 18 2 inflammatory disease; Pyosalpinx 19 20 3

21 Cloacal exstrophy (CE) is a rare congenital condition observed in 1 of 200,000-400,000 22 live births (1, 2) . CE remains a challenging disease compromising multiple 23 gastrointestinal, genitourinary, and skeletal anomalies; however, its survival rate is now 24 approximately 100% resulting from improved neonatal care and surgical management (1). 25 Conversely, CE patients experience many genitourinary and gastrointestinal problems 26 from childhood to young adulthood. In particular, most females with CE are prone to 27 gynecological complications throughout life due to congenital anomalies of the vagina 28 and uterus, and their long-term outcomes are poorly described in living adults (2, 3). 29 Pyosalpinx is a severe sequela of pelvic inflammatory disease (PID) in which the fallopian 30 tubes are filled with pus. PID is an ascending infection from the vagina or cervix to the 31 upper genital tract and is attributed to Chlamydia trachomatis , Neisseria gonorrhoeae, 32 bacterial vaginosis, and enteric pathogens (4). CE patients have been reported to 33 experience recurrent PID, such as pyosalpinx or tubo-ovarian abscess (TOA ) and are 34 often difficult to treat (3, 5). 35 Here, we present a case of a young woman with recurrent pyosalpinx following CE 36 management in childhood and adolescence. Dienogest (DNG), a synthetic progestin, was 37 effective in controlling recurrent pyosalpinx; thus , the pathogenesis of recurrent 38 4 pyosalpinx in CE patients and the efficacy of DNG are discussed. 39 40 Case 41 A 28-year-old woman with a history of CE presented with fever, lower abdominal pain, 42 and vomiting and was transferred to our hospital with a diagnosis of left pyosalpinx. She 43 was born with a weight of 2622 g at 36 weeks of gestation by cesarean section and was 44 diagnosed with CE. She underwent primary closure of CE and ileostomy on day 4 of life 45 and continent urinary diversion by right to left transureteroureterostomy with cutaneous 46 right ureterostomy, augmentation cystoplasty using an ileal patch, and intes tinal 47 vaginoplasty at the age of 5 years. Her first menstruation was at age 12, but due to 48 dysmenorrhea, she underwent a right hemi-hysterectomy for uterine didelphys and left 49 uterine to fallopian tube anastomosis at the age of 15 years. After that, her condition was 50 well controlled in the outpatient clinic without medication . She managed her bowel 51 movements with colostomy and required clean intermittent catheterization four times a 52 day. She was sexually active and had sexual intercourse with her partner one week before 53 admission. 54 Laboratory evaluation at admission revealed a C-reactive protein level of 17.52 mg/dl and 55 a creatinine level of 1.07 mg/dl , suggesting acute kidney injury . Enhanced abdominal 56 5 computed tomography (CT) showed a 79×52 mm left pyosalpinx and multiple small 57 abdominal abscesses, leading to bilateral hydronephrosis and vomiting due to intestinal 58 obstruction (Fig. 1) . CT-guided drainage was performed for the left pyosalpinx. T he 59 brown pus contained Streptococcus anginosus , Streptococcus agalactiae , and 60 Bacteroides fragilis. Samples collected from the cervix tested negative for Chlamydia 61 trachomatis and Neisseria gonorrhoeae. Renal function improved within normal limits , 62 and symptoms of fever, abdominal pain, and vomiting disappeared a few days after 63 drainage. Conservative antibiotics (intravenous tazobactam/piperacillin and penicillin G 64 for a total of 2 weeks ; thereafter, oral amoxicillin/c lavulanate) were administered 65 successfully, the drain was removed on day 21, and she was discharged on day 25. 66 She had 2 readmissions which were 1 week after discharge, and then again 4 months later 67 for recurrent pyosalpinx. During these hospitalizations, only intravenous antibiotics were 68 administered. Abdominal ultrasonography ( US) at the second hospitalization showed 69 hydrosalpinx and anastomotic stenosis between the left uterus and left fallopian tube, 70 which suggested a cause of recurrent pyosalpinx (Fig. 2A). A transvaginal approach using 71 hysteroscopy for releasing the anastomotic stenosis between the left uterus and fallopian 72 tube was considered; however, it was difficult due to a complicated surgical history . 73 Therefore, the decrease in menstrual fluid in the left fallopian tube may have prevented 74 6 recurrent pyosalpinx, and in the third hospitalization, she started DNG at 2 mg daily orally. 75 After DNG administration, fluid collection in the left fallopian tube completely 76 disappeared on abdominal US ( Fig. 2B), and s he had no recurrence for 8 months after 77 DNG administration. 78 79 Summary and conclusion 80 In this case, a young woman following CE management in childhood and adolescence 81 suffered from recurrent pyosalpinx, and D NG, a synthetic progestin, was effective in 82 preventing recurrent pyosalpinx. Only one young adolescent girl with a history of CE has 83 been reported to experience pyosalpinx and TOA and undergo a radical hysterectomy (5). 84 Thus, this is the first report to treat pyosalpinx as a long- term complication during CE 85 management successfully. 86 CE is a challenging disease that requires multiple surgeries for complex gastrointestinal, 87 genitourinary, and skeletal anomalies. Because of the improvements in neonatal care and 88 surgical techniques, the survival rate has been approaching 100% in the last few decades 89 (2, 3). However, as long-term survivors of CE have become more common, CE patients 90 have been found to suffer from many gynecological disorders. A recent systematic review 91 reported that 57.1% of female CE patients had vaginal -related issues and that 14.3% to 92 7 71.0% had uterine anomalies, such as uterine didelphys and uterine bipartitus (2). Owing 93 to these anomalies , many females with CE experienced dysmenorrhea during puberty, 94 with related gynecologic surgery performed in approximately two- thirds of cases (2). In 95 our case, right hemi -hysterectomy and left uterus -fallopian tube anastomosis were 96 performed for the management of dysmenorrhea, and recurrent pyosalpinx occurred as a 97 long-term complication of the anastomosis. 98 On the other hand, regarding upper genital tract tissues, including PID such as pyosalpinx 99 and TOA in CE patients, no detailed observational studies and only limited case report s 100 have been found (5). PID is one of the most common gynecological problems in young 101 women (4), and it must be considered a major problem that reduces quality of life , 102 especially in CE patients. 103 Pyosalpinx is a severe form of PID in which the fallopian tube is filled with pus. 104 Treatment of pyosalpinx ranges from conservative intravenous antibiotics and image -105 guided drainage to laparoscopic aspiration, salpingostomy, and salpingectomy. 106 Urogenital anomalies, including CE, have been reported to be one of the risk factors for 107 pyosalpinx, and surgical treatment is performed in most cases (5, 6). In our case, the 108 primary treatment for pyosalpinx was successful by CT-guided drainage and intravenous 109 antibiotics administra tion; however, pyosalpinx re curred twice. On the abdominal US 110 8 findings at recurrence, the cause of recurrent pyosalpinx was suspected to be left 111 hydrosalpinx resulting from stenosis of the uterus-fallopian tube anastomosis, which is a 112 long-term complication of CE management. 113 DNG is a unique fourth-generation synthetic progestogen mainly used for the long-term 114 management of endometriosis worldwide. It is considered effective in decreasing the size 115 of endometriomas and reducing endometriosis-associated pain (7). In addition, it has less 116 severe side effects, such as abnormal uterine bleeding and headache, with long-term use 117 compared with other progestin products (8). In cloacal anomal ies, ovarian function is 118 normal; thus, ovary-releasing estrogen stimulate s the endomet rium in the uterus after 119 puberty, and some experience menstrual flow obstruction (3). Hormonal suppression of 120 endometrial stimulation and menses prevents the continued accumulation of obstructed 121 menstrual products in CE patients (3). In this patient, hormonal suppression by DNG may 122 have played an important role in reducing menstrual blood flow, which contributed to 123 reduced fluid accumulation in the left fallopian tube and controlled recurrent pyosalpinx 124 without severe side effects. 125 In conclusion, patients with CE often experience gynecological problems as long-term 126 complications. Pyosalpinx in patients with CE is a major issue that can lead to multiple 127 hospitalizations and reduce the patient’s quality of life. DNG is a conservative treatment 128 9 option for recurrent pyosalpinx as a long-term complication of CE. 129 130 10

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