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Wegener's granulomatosisFirst report of a case with onset during pregnancy.

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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
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
taking cephalexin, codeine, and a multivitamin with
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
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
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
Pathologic evaluation of the placenta revealcd a
marginal infarct and hemorrhage, but no evidence of
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
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
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.
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
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,
IS. Casciato J: Leukemia following cytotoxic therapy.
Medicine 58:32-47, 1979
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pregnancy, granulomatosisfirst, report, wegener, case, onset
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