I09 ~ ... ~ ._.. BRIEF REPORT WEGENER'S GRANULOMATOSIS: FIRST REPORT OF A CASE WITH ONSET DURING PREGNANCY SHERYL FLASCHEN TALBOT, DENISE M. MAIN, a n d AKNOLD 1. LEVINSON Wegener's granulomatosis (WG) is an uncommon systemic disease characterized by a necrotizing granulomatous vasculitis of the upper and lower respiratory tracts with or without glomerulonephritis and disseminated small vessel vasculitis. The disease has a rapidly fatal course, particularly after the onset of renal impairment. The efficacy of cyclophosphamide and steroid therapy is well-established with complete remission achieved in 93% of 85 patients treated in one large series ( I ) . We recently treated a woman who had onset of WG during pregnancy. Questions arose about the likelihood of placental or fetal involvement with disease, the alteration in the natural course of the disease because of pregnancy, and the potential effects of proposed immunosuppressive therapy on the developing fetus. One case of WG in pregnancy has been reported previously; however, that patient was in partial remission taking prednisone and azat hioprine at the time of conception and throughout pregnancy (2). We now report the first case of active WG diagnosed and treated during pregnancy. Case report. The patient is a 28-year-old woman, pregnant for the first time, who presented to the From the section of Allergy and Clinical Immunology. Department of Internal Medicine and the section of Maternal Fetal Medicine. Department of Obstetrics and Gynecology. The Hospital of the University of Pennsylvania. Philadelphia. PA. Sheryl Flaschen Talbot. MI): Dcnise M. Main. MD: Arnold I. Levinson. MD. This work was supported in part by The Asthma and Allergy Foundation o l America, Burroughs Wellcome Fund. Address reprint requcsth to Arnold I . Levinson. MD. University of Pennsylvania School of Medicine. 5 I5 Johnson Pavilion/GZ, 36th and Hamilton Walk. Philadelphia, PA 19104. Submitted for publication June 6. 1983; accepted in revised form August 4. 1983. Arthritis and Rheumatism, Vol. 27, No. I (January 1984) Hospital of the University of Pennsylvania at 26 weeks' gestation. She had been well before her pregnancy except for nasal stuffiness which she attributed to allergies. The initial 4 months of her pregnancy were complicated by nausea and vomiting. Nevertheless, she gained weight appropriately and considered herself to be well. At 22 weeks' gestation, the patient developed nasal stuffiness, a right earache with decreased auditory acuity, frontal and maxillary sinus pressure, and a dry cough. She was treated for otitis media with a 10-day course of ampicillin without improvement, and her cough became productive of small amounts of yellow blood-streaked sputum. Staphy/ococcus aureus was cultured from samples of her nasal mucosa; a nasal septum perforation was noted. and cephalexin treatment was started. At 25 weeks' gestation a nasal septum biopsy was obtained. Over the next 10 days she developed transient bilateral knee and ankle arthralgias. fevers of 37-38°C. fatigue, weakness, anorexia, and a weight loss of 4 pounds. Three days before admission to the hospital, she noted painful red lesions on the soles of her feet and the development of cool, blue, painful toes. For 24 hours prior to admission she had constant dribbling incontinence without the sensation of the need to urinate. On the day before admission, results of her nasal biopsy showed a heavy infiltrate of lymphocytes, plasma cells. and eosinophils with neutrophilic infiltration of vessel walls. There were giant cells present but no granuloma was seen. The pathologic impression was that the results of the biopsy were consistent with Wegener's granulomatosis. 'l'he patient was referred to the Hospital of the University of Pennsylvania for further evaluation. At the time of admission she was 110 taking cephalexin, codeine, and a multivitamin with iron. Her temperature was 37.5”C rectally. pulse 120, blood pressure 112170, and her respiratory rate was 20. Therc was serous otitis of the right ear, retraction of the left tympanic mcrnbrane, and a mild perivasculitis of thc retinal arteries. Shc had a saddle nose deformity with intranasal pus, and a large septa1 pcrforation which extended into the bony septum posteriorly. There were 2 tonguc ulcers, each measuring 0.5 cm in diameter. The lungs and hcart were normal. Her uterus measurcd 26 cm, and fetal heart sounds were present. Therc was erythematous mottling of her palms and soles. Six toes wcrc cool and cyanotic with several periungual infarcts. Initial laboratory data included hemoglobin of 10.6 gm/dl, white blood cell count of 12,300/mm3with 48% polymorphonuclear cells, 13% bands, 6% lymphocytes, 2% monocytes. 29% cosinophils. 2% myelocytes, platelets 368,000/mm3,and an erythrocyte sedimentation rate of 130 mm/hour. Her electrolyte levels were normal, blood urea nitrogen was 11 mg/dl, and creatininc was 0.7 mg/dl. Results of urinalysis showed a pH of 6 with trace blood and no protcin on dipstick test; many vaginal epithelial cells, few red blood cells, and 0-1 granular casts pcr microscopic high powered field. Chest radiograph showcd bilateral largc nodular infiltrates with sevcral smaller non-cavitary nodules. Sinus radiograph showed complete opacification of the ethmoid and maxillary sinuses without bony destruction. Subsequent laboratory data included antinuclear antibodies of I :40 and anti-native DNA of 5% (normal 0-15%). C3, C4. and CHSO tests gave normal results; cryoglobulins were weakly positivc for IgG and IgM. Hepatitis B surface antigcn, Coombs’ tcsts, and blood cultures yielded negative results. Creatinine clearance was 120 ml/minute. with 1.19 gm of protein per 24 hours. For the first 3 days of hospitalization, the paticnt receivcd 160 mg of mcthylprednisolone and 3 mg/kg of cyclophosphamidc per day. Subscquently, she was treated with 60 mg prednisone and 2 mg/kg cyclophosphamide per day. Rupture of the amniotic membranes was diagnosed on the fifth day of hospitalization. Duration of rupture may have been as long as 7 days considering her history of dribbling incontinence. Bccause of the patient’s immunosuppressed status, induction of labor by administering oxytocin. rathcr than expectant management, was elected. A baby boy, presenting in the vertex position. was delivered. He weighed 1.000 gm, and Apgar BRIEF REPORTS scores, measured at I and 5 minutes, were 9 (range 010). The baby experienccd mild respiratory distress syndrome but was on room air by the second day of life. He had bccn exposcd to cyclophosphamide and methylprednisolone therapy for 5 days before dclivcry, at which time he was 26-27 weeks’ gestation by dates. At delivery he appeared to be 28 weeks’ gcstational age on Dubowitz evaluation and, though prcmature, was entirely normal. His initial white blood cell count was 10,500/mm3,and there was no subsequent leukopenia. Pathologic evaluation of the placenta revealcd a marginal infarct and hemorrhage, but no evidence of vasculitis. The woman has progrcssively improved while receiving cyclophosphamide and prednisone therapy. The distal phalanges of 3 toes are undergoing autoamputation. Oral contraceptive therapy was begun shortly after discharge from thc hospital, in an effort to protcct ovarian function during cyclophosphamide therapy (3). Discussion. This case raises several important questions about the coursc and management of WG in the pregnant woman. Is the natural course of WG altered by pregnancy? What arc thc potential cffects of the disease and its therapy on the fetus? Should cytotoxic therapy be delayed until a viable fetus can be delivered? At what point should a therapeutic abortion be advised? Although no generalizations can be made on the basis of a single case, pregnancy did not appear to have either an ameliorative or detrimental influence on disease activity. The paticnt’s course and response to therapy wcre similar to that observed in non-pregnant patients, and her symptoms did not flare after delivery (as often occurs in patients who have systemic lupus erythematosus). Since there was no evidence of vasculitic involvement of the placenta, wc have no evidcnce that the mothcr’s having WG dircctly or indirectly jeopardized fetal well-being in this instance. Survival timc of the patient who has WG improves markedly with the combination of steroid and cytotoxic therapy ( I ) . Extensive studies involving the therapeutic use of steroids during pregnancy have shown a remarkable lack of ill effects on the human fetus. The increased incidence of cleft lip and palate seen in fetal laboratory animals has not been observed in humans. Thcre is somc suggestion of reduced fetal growth following high-dose, long-term therapy with corticosteroids, although this effect is difficult to separate from the effects of underlying disease in the BRIEF REPORTS mother (4). Neonatal subclinical adrenal insufficiency, as evidenced by reduced cortisol level or adrenocorticotropic hormone responsiveness, is an unusual complication (5). Corticosteroids have been shown to enhance fetal lung maturation (4). In this case, where the chance of neonatal survival was estimated to be 30%, the child's benign course may have resulted in part from steroid administration. The experience with cyclophosphamide therapy during pregnancy has been limited, although it has been used during all three trimesters of pregnancy. As with other alkylating agents, the major risk for fetal morbidity occurs when the drug is given during the first trimester during active organogenesis. Toledo et a1 reported a woman with stage IIIB Hodgkin's disease who was treated with radiation therapy and 100-150 mg of cyclophosphamide per day. At 5 months' gestation a therapeutic abortion yielded a fetus with no toes and a single left coronary artery (6). A woman who was treated for nephrotic syndrome with 150 mg of cyclophosphamide per day through the eighth week of pregnancy delivcred a 32week infant with a small umbilical hernia and a I-cm thigh hemangioma, both of which were probably coincidental (7). Greenberg reported a woman with Hodgkin's disease who received 100 mg of cyclophosphamide daily throughout pregnancy, in addition to 2 intravenous pulses (2.5 mg/kg and 15 mg/kg) at 7 and 8 weeks. She delivered a full-term baby with multiple congenital anomalies including four toes on each foot. hard palate grooves, a flattened nasal ridge, and bilateral inguinal hernia sacks (8). Six other case reports describe women who were given cyclophosphamide with or without other chemotherapeutic agents during the second and/or third trimesters of pregnancy. From these 6 women, 4 normal babies (9-12), 1 normal premature baby (13), and 1 normal leukopenic baby (14) were delivered. In our case, the fetus was exposed to cyclophosphamide for only 5 days during the third trimester and suffered no apparent ill effects. An additional concern regarding the use of alkylating agents during pregnancy is the possibility of inducing subsequent leukemia in the infant. In adults, alkylating agent-induced leukemia develops following prolonged therapy and is often preceded by refractory pancytopenia. It has been suggested that this represents a profound bone marrow stem cell injury. In his review of acute nonlymphocytic leukemia following cytotoxic therapy, Casciato included 6 patients with 111 WG, 4 of whom were treated with cyclophospharnide (24,51,54, and 85 months) and 2 of whom were treated with chlorambucil (30 and 54 months) (15). One might infer that a fetus would be at low risk for the subsequent development of leukemia because of the limited duration of exposure to the drug. However, the fetus is in a state of rapid systemic cell division and growth such that the risk factors (dose and duration) for adults may not be directly applicable to the fetus. On the basis of the above outlined literature, experience with cyclophosphamide therapy during pregnancy, and the poor prognosis of WG when treatment is delayed or is instituted with steroids alone, the following course seems rational and prudent. If the diagnosis is established in the late second or third trimester, we would suggest treatment with steroids and cyclophosphamide as dictated by disease severity in the mother, and we would not induce delivery of the premature fetus. If cyclophosphamide therapy is required in the first trimester, we would advise performing a therapeutic abortion. In the early second trimester the fetus is probably still at markedly increased risk for disordered organogenesis, and decisions should be made based on all aspects of the individual situation. Our patient's case of coincident pregnancy and WG will probably remain distinctly unusual. Further experience with cyclophosphamide therapy during pregnancy will most likely come from treatment of pregnant women who have Hodgkin's and non-Hodgkin's lymphomas. 1. REFERENCES Fauci AS. Haynes BF. Katz P, Wolff SM: Wcgcner's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 ycars. Ann Intern Med 98:76-85. 1983 2. Cooper K. Stafford J , Warwick MT: Wegener's granuloma complicating pregnancy. Br J Obstet Gynaecol 77: 1028-1030, 1970 3. Chapman RM. Sutcliffe SB: Protection of ovarian function by oral contraceptives in women receiving chemotherapy for Hodgkin's discase. Blood 58:849-851, 1981 4. l'dcusch H W: Glucocorticoid prophylaxis for rcspiratory distress syndrome: a review of potential toxicity. J Pediatr 87:617-623. 1975 5. Ohrlander S, Gennser G, Nilsson 0, Eneroth P: ACTH tcst to neonates after administration of corticosteroids during gestation. Obstet Gynecol 49:691-694, 1977 6. lolcdo TM. Harper RC, Moser RH: Fetal effects during cyclophospharnide and radiation therapy. Ann Intern Mcd 74:87-91, 1971 7. Coates A: Cyclophosphamide in pregnancy. Aust N Z J Obstet Gynaecol 10:33-34. 1970 BRIEF REPORTS 112 8. Greenberg LH, Tanaka KR: Congenital anomalics probably induced by cyclophosphamide. JAMA 188:423426, 1964 9. Ortega J: Multiple agent chemotherapy including bleomycin of non-Hodgkin's lymphoma during pregnancy. Cancer 40:2829-2835, 1977 10. Seers HF, Reid J: Granulocytic sarcoma, local presentation of a systemic disease. Cancer 37:1808-1813. 1976 I I . Hardin JA: Cyclophosphamide treatment of lymphoma during the third trimester of pregnancy. Obstet Gynecol 39:850-851, 1972 12. Gililland J , Weinstein L: The effects of cancer chemo- therapeutic agents on the developing fetus. Obstet Gynecol Surv 38:6-13, 1983 13. Webb GA: The use of hyperalimentation and chernotherapy in pregnancy: a case report. Am J Obstet Gynecol 137:263-266, 1980 14. Wheeler GE: Cyclophosphamide associated leukemia in Wegener's granulomatosis. Ann Intern Med 94: 161-162, 1981 IS. Casciato J: Leukemia following cytotoxic therapy. Medicine 58:32-47, 1979 NATO Advanced Study Institute on the Application of Material Sciences to the Practice of Orthopedic Surgery July 15-28, 1984, Costa del Sol, Spain. Syllabus to include theory and applications of materials properties, physiologic functions, and host response, approached from the clinical practice and engineering perspectives. Participation limited; application deadline is March 1, 1984. For additional information, contact Dr. Ram Kossowsky, Westinghouse R & D Center, Pittsburgh, PA 15235. 412-256-1209 (Telex 703669).