Case Report of Exposure to Voriconazole in the Second and Third Trimesters of Pregnancy

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Abstract
A 28-year-old woman without medical history developed at 16 weeks of gestation fever (39°C), agranulocytosis (neutrophil count = 76/mm3), anemia (hemoglobin [Hb] = 8.2 g/dl), and hepatic cytolysis (aspartate aminotransferase [ASAT], 395 IU/liter; alanine aminotransferase [ALAT], 454 IU/liter [normal values < 50]; gamma glutamyl transpeptidase [GGT], 30 IU/liter; total bilirubin, 31 μmol/liter; free bilirubin, 5 μmol/liter; alkaline phosphatase, 270 IU/liter). Bone marrow aspiration revealed aplastic anemia. An extensive viral and immunological work-up, including anti-cytomegalovirus (CMV), anti-Epstein-Barr virus (EBV), anti-hepatitis A, B, and C, anti-HIV-1/2, anti-human T-lymphotropic virus 1 and 2 (HTLV-1/2), anti-parvovirus B19, anti-nuclear, anti-DNA, anti-extractable nuclear antigens, anti-mitochondrial, anti-LKM1, anti-ribosomal, and anti-smooth muscle antibodies, and CMV, EBV, human herpesvirus 8 (HHV-8), and HHV-6 viremia, was negative. Autoimmune aplastic anemia was suspected, and intravenous polyvalent immunoglobulins (1 g/kg of body weight/day) and oral cyclosporine (150 mg/day) were prescribed. At day 12 of neutropenia, invasive aspergillosis was diagnosed (maxillary sinusitis, periorbital cellulitis, pulmonary nodule on computed tomography with positive Aspergillus antigenemia [index = 0.67], and acute-angle branching septate hyphae on meatotomy and ethmoido-maxillar drainage samples) (1). Sinus cultures at 4 days yielded on chloramphenicol-gentamicin Sabouraud agar colonies of Aspergillus identified by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) as Aspergillus flavus (2). The strain was considered sensitive to all tested azoles (3). MICs through Etest were as follows: itraconazole, 0.500 μg/ml; voriconazole, 0.190 μg/ml; amphotericin B, 0.750 μg/ml; posaconazole, 0.190 μg/ml. Intravenous liposomal amphotericin B was initiated (3 mg/kg/day). Neutropenia recovery was observed at day 21, with simultaneous major local extension requiring median maxillectomy. Treatment was switched to oral voriconazole (200 mg twice daily [BID]). The plasma trough concentration at day 7 was in the therapeutic range (1.38 mg/liter, single dosage) (4). Clinical and radiological improvement was obtained. Voriconazole was prescribed for 5 months and stopped after clinical/radiological resolution, 1 month after delivery.

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