Polyarteritis Nodosa in Pregnancy

INTRODUCTION

Polyarteritis nodosa (PAN) is a rare necrotizing vasculitis involving medium or small arteries that is sometimes associated with hepatitis B virus infection.1 The clinical picture includes constitutional symptoms, such as fever and weight loss, as well as gastrointestinal, musculoskeletal, or neurologic features.2 The serious complications of PAN are organ ischemia as a result of vessel occlusions, aneurysmal ruptures, or thrombosis. The onset of PAN during pregnancy is exceptional; to date only 19 cases have been reported.3,4 The lack of specific immunologic tests and the presence of nonspecific biologic findings, such as fever and leukocytosis, make the differential diagnosis among a puerperal infection and systemic complications of pregnancy difficult.

We present a case of PAN with peripartum onset in a patient with a twin pregnancy that occurred after ovarian stimulation.

CASE REPORT

A 30-year-old female with euthyroid Hashimoto disease and polycystic ovary syndrome underwent ovarian stimulation with clomiphene, follitropin alfa, progesterone, and chorionic gonadotropin. The procedure was successful, resulting in a dizygotic twin pregnancy. After an uneventful pregnancy, the patient presented to the hospital in labor in the 38th week of gestation, with intact membranes and one fetus in cranial and the second in transverse presentation. Two babies of 2,200 g and 2,100 g, each with Apgar scores of 10, were delivered by cesarean section. Macroscopic examination of the mother's lower abdomen during surgery revealed enlargement of the left ovary and a slightly right-torsioned, purple-colored uterus, with significantly enlarged parauterine veins.

The patient's initial postoperative course was normal. However, 48 hours following delivery, the patient developed tachycardia, hypotension, infraumbilical abdominal wall pain, and fever (38.2°C). Abdominal ultrasonography revealed a minimal fluid collection in the abdominal muscles that was drained and interpreted as hematoma. Hemorrhagic fluid cultures were sterile, but the patient was nevertheless prescribed broad-spectrum antibiotic therapy (ceftriaxone 1 g intravenously [IV] twice daily, gentamicin 1.2 mg/kg IV every 8 hours, and metronidazole 7.5 mg/kg orally every 6 hours). Two days later, her fever recurred and the patient developed intestinal dynamic occlusion. Laboratory findings were remarkable for a white blood cell (WBC) count of 29,600 mm³, C-reactive protein >100 mg/dL (reference range, <3 mg/dL), and persistent low serum potassium levels. Reintervention revealed 150 mL of serohemorrhagic peritoneal fluid and a hypotonic uterus and myometrium. A subtotal hysterectomy was performed to prevent disseminated intravascular coagulation. Cultures from the uterine cavity and the peritoneal exudate were sterile. Antibiotic therapy was continued (ceftriaxone was replaced with teicoplanin 6 mg/kg every 24 hours), along with an anticoagulant (nadroparin 0.6 mL every 12 hours) and volemic support as required. Despite these measures, the patient's fever spiked again in the presence of tachycardia, dynamic intestinal occlusion, and a WBC count of 44,700 mm³. Postoperative peritonitis and abdominal wall phlegmon were suspected. Reintervention could not confirm the diagnosis but revealed infiltrated abdominal walls and agglutinated intestinal ansae.

Persistent deterioration of the patient's condition led to another intervention that revealed ischemia of the left ovary with subcapsular hematoma and 500 mL of serohemorrhagic odorless fluid in the pouch of Douglas. Left adnexectomy was performed, but the biopsy findings were noncontributory to the diagnosis.

Extensive screening for infection was again negative (hemocultures, Brucella testing, and ultrasound imaging), although the patient had a 5-fold increase in procalcitonin level to 2.6 ng/mL (reference range, <0.5 ng/mL). Antinuclear antibodies and the antiphospholipid panel were negative; further, anti–double-stranded DNA and hepatitis C virus antibodies, hepatitis B surface antigen, antineutrophil cytoplasmic antibodies, rheumatoid factor, and antistreptolysin O titers were normal or negative. Because sepsis could not be ruled out, the patient was continued on broad-spectrum antibiotic therapy (imipenem/cilastatin 500 mg/500 mg every 6 hours, metronidazole 7.5 mg/kg orally every 6 hours, and moxifloxacin 400 mg orally daily). Clinical and biologic tests found arterial hypertension (140/100 mmHg), spiking fevers, leukocytosis (15,000-25,000 mm³), increased fibrin degradation products, and persistent hypokalemia.

Finally, repetitive physical examination revealed several nodules on a vascular tract of the left forearm, suggesting PAN or infectious vasculitis. The histopathologic examination of a nodule biopsy was consistent with PAN, showing vasculitis with fibrinoid necrosis, intravascular thrombi, and lymphoplasmacytic intramural infiltrates with lesions in different stages of the disease (Figure 1).

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Figure 1

Intramural inflammatory infiltrate and fibrinoid necrosis with disruption of the vessel wall (hematoxylin and eosin stain, ×20). (To see this image in color, click to https://education.ochsner.org/publishing-services/toc/damian_17-0025_fig1.)

Treatment with pulse methylprednisolone (500 mg/day IV for 5 days), cyclophosphamide (15 mg/day every 2-3 weeks for 6 months), and immunoglobulin therapy (total dose 0.5 g/kg) resulted in rapid resolution of the patient's fever and normalization of the inflammatory parameters. Notably, 3 months later, an abdominal bruit was perceived upon clinical examination. Computed tomography angiography revealed celiac artery stenosis (Figure 2), but because of the patient's lack of symptoms, stenting was postponed until completion of the cyclophosphamide therapy. At 1-year follow-up, the abdominal bruit has disappeared and the patient is in remission on azathioprine (2 mg/kg/day) and antiplatelet therapy (aspirin 75 mg/day).

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Figure 2

Computed tomography angiography of the abdominal aorta and branches shows circumferential stenosis of the celiac artery after its aortic branching (arrow).

DISCUSSION

PAN typically occurs in middle-aged men and is characterized by the lack of distinctive immunologic or biologic biomarkers such as antineutrophil cytoplasmic antibodies.5 Presenting features include extensive livedo reticularis, severe hypertension that is responsive to glucocorticoids, acute abdomen as a result of vessel occlusion, rupture or organ perforation, acute genital inflammation (orchitis, epididymitis, or ovarian torsion), arthritis, myopathy, proteinuria, hypokalemia, renal failure, mononeuritis multiplex, skin purpura or necrosis, and subcutaneous nodules along the vessels.2 For a diagnosis of PAN, the American College of Rheumatology requires meeting 3 of 10 criteria ⁶; our patient had 4: new-onset hypertension, myalgia, arteriographic abnormalities, and a positive biopsy. Along with these symptoms and highly suggestive for the diagnosis were the presence of subcutaneous tender nodules, the ovarian involvement, and hypokalemia reflecting inflammation of the peritubular arterioles. The bloodstained peritoneal fluid likely resulted from the rupture of microaneurysms of visceral vessels.

Vasculitis in pregnancy is rare and likely underdiagnosed. To our knowledge, only 19 cases of PAN during pregnancy have been reported, resulting in 14 healthy babies and 5 abortions (2 therapeutic and 3 spontaneous).3,4 In the case of PAN onset in advanced pregnancy, the prognosis is serious and associated with a high risk of maternal death. Gatto et al reported that in previously reported cases, 7 of 8 patients who had PAN onset during pregnancy died during gestation or within 42 days of delivery.4 PAN can involve any organ or system and may manifest as severe hypertension, often with fatal outcome,7 or with arterial ruptures that may precipitate cesarean section.8 Factors associated with a severe outcome are elevated proteinuria and creatinine, cardiomyopathy, and gastrointestinal and neurologic involvement. The clinical picture may be complicated by the presence of the hepatitis B antigen in approximately 10% of cases.4,9

If PAN remains in remission during the pregnancy, the pregnancy may not induce a flare of the vasculitis.4,10 Nevertheless, even in controlled disease, PAN relapses may occur.9 In incipient pregnancy, therapeutic abortion is considered. In advanced pregnancy, high-dose glucocorticoids, and, when mandatory, cyclophosphamide during the third trimester may be lifesaving.8

PAN may also manifest postpartum, sometimes as a breast lesion, making it difficult to differentiate the vasculitis from an infectious mastitis or malignancy.11 Our patient did not breastfeed and had no such recurrence.

In vitro fertilization (IVF) seems unlikely to have played a role in the occurrence of PAN in our patient. The few cases of necrotizing vasculitis reported after IVF or ovarian stimulation occurred early after the procedure, possibly through an allergic mechanism, as suggested by the presence of numerous eosinophils in the biopsy.12

Incidental isolated vasculitis of the genital tract has also been reported in the absence of autoimmune diseases. In all, approximately 50 cases of isolated PAN of the female genital organs have been uncovered during hysterectomy for other indications, primarily involving the cervix.13 In tumor-like presenting vasculitis, ovarian involvement is frequent,14,15 reaching 10% in a study of 46 cases.16 In our patient, oophorectomy and hysterectomy may have had a favorable impact on the outcome through the removal of the visceral vasculitis. However, in our case, the genital tract vasculitis was not isolated, as tender celiac artery involvement was documented, and nodules were found on the patient's arm.

Our case is unusual in that the patient's pregnancy was uneventful and she carried twins successfully until term. For patients with PAN, the risk of preterm birth is high.17 As an illustration of this point, the other published case report of a successful outcome of PAN with onset during pregnancy was complicated by premature rupture of membranes and premature delivery.8

CONCLUSION

A rare pathology such as PAN should be taken into account among other systemic complications of pregnancy in the presence of an inflammatory storm. Because PAN has no biologic pathognomonic red flags, severe hypertension, livedo reticularis, tender subcutaneous nodules, arterial bruits, and ovarian involvement should prompt the clinician to search for this almost-forgotten life-threatening pathology to allow timely institution of therapy. Multidisciplinary consultations with the gynecologist, neonatologist, rheumatologist, nephrologist, radiologist, and pathologist are crucial. Emergency cesarean section when necessary, infectious screening, pathologic examination of the available tissue, and prompt institution of glucocorticoids can be lifesaving.