Cerebral hemorrhage associated with vitamin K deficiency in congenital tuberculosis treated with isoniazid and rifampin

We report a male infant with congenital tuberculosis who developed cerebral hemorrhage associated with vitamin K deficiency during treatment with isoniazid and rifampin. Despite an absence of risk factors for vitamin K deficiency, the severe hemorrhagic disorder occurred at 4 months of age. We speculate that vitamin K deficiency in the present case may have resulted from a synergic effect of antituberculosis agents and immaturity of vitamin K metabolism and/or its absorption. Congenital tuberculosis is a rare disease, but the reemergence of tuberculosis has made it a new threat to certain vulnerable pregnant women and their children. 1–3 There is limited information regarding antituberculosis treatment and its side effects in early infancy. We present a case of congenital tuberculosis in a male infant who developed cerebral hemorrhage associated with vitamin K deficiency during antituberculosis treatment. We discuss a possible pathogenesis of this unusual complication of the therapy. Patient report. A male infant was born by spontaneous vaginal delivery at 34 weeks gestation and weighed 2138 g with an Apgar score of 8 at 1 min. His mother was 32 years old and had neither underlying disease nor a family history of tuberculosis. All the family members had received Calmette-Guérin bacillus vaccination. During pregnancy no remarkable changes were noted; therefore she did not receive any medications, including antituberculosis agents. On the day of delivery the mother developed high grade fever of 39.5°C, arthralgia and dry cough. Thereafter she had limited contact with the infant because of the possibility of postnatal infection. Her symptoms were refractory to several antibiotics and worsened when she was referred on Day 12 postpartum. On admission a tuberculin skin test was positive with a diameter of 13 by 13 mm without induration. A chest roentgenogram disclosed miliary infiltrates. A bronchoalveolar lavage smear failed to show acid-fast bacilli, but the culture subsequently grew Mycobacterium tuberculosis. With a presumptive diagnosis of miliary tuberculosis with a presumptive onset during the pregnancy, the patient was treated with isoniazid, rifampin, streptomycin, pyrazinamide and vitamin B6. She became afebrile on Day 2 after initiation of therapy. The baby was well until 12 days of age, when he developed low grade fever and cough. He was also referred to our hospital at 15 days of age. On admission body weight was 2450 g, heart rate was 160/min, respiratory rate was 70/min and body temperature was 37.2°C. The anterior fontanel was normal. Auscultation of the chest disclosed harsh vesicular sounds. The liver was palpable 2.5 cm below the right costal margin. Laboratory investigations showed a white blood cell count of 10 × 109/l (band forms 57%, segmented neutrophils 24%, lymphocytes 17%, monocytes 2%), a hemoglobin of 16.0 g/dl, a platelet count of 213 × 109/l, a C-reactive protein of 9.6 mg/dl and an erythrocyte sedimentation rate of 40 mm/h. A chest roentgenogram showed miliary changes. A tuberculin skin test was negative. Smear of a gastric aspirate showed acid-fast bacilli, and the culture subsequently grew M. tuberculosis, which was later found to be resistant to isoniazid. Cerebrospinal fluid was considered normal and was sterile on culture. A cranial ultrasound examination was normal. The patient had had since birth no direct contact with his mother, which excluded the possibility of postnatal transmission. Based on the findings described above, a diagnosis of congenital tuberculosis was made and isoniazid, rifampin, pyrazinamide, streptomycin and vitamin B6 were given. On Day 5 of therapy he showed signs of improvement. He received the above antituberculosis therapy for the initial 2 months. He was discharged on isoniazid and rifampin at 3 months of age, at which time the cranial magnetic resonance imaging was normal. During the treatment he was bottle-fed and had no side effects. Oral vitamin K (2.0 mg) prophylaxis was given at the time of birth, and intravenous vitamin K (2.0 mg) was given at the age of 15 and 30 days. Both the mother and infant were anti-HIV antibody-negative. At the age of 4 months the baby suddenly developed frequent vomiting and lethargy. On examination the anterior fontanel was bulging, and the eyes were deviated to the right. Laboratory investigations showed a white blood cell count of 10 × 109/l with normal differential counts, a hemoglobin of 6.1 g/dl and a platelet count of 365 × 109/l. Coagulation tests were as follows (normal values): prothrombin activity of <1.0% (80 to100); partial thromboplastin test <1.0% (65 to 95); and protein induced in vitamin K absence <143 350 mAU/ml (40). The liver enzymes were normal. Computed tomography disclosed a hematoma (4 by 4 cm in diameter) in the left frontal region. He had no other bleeding symptoms. Intravenous vitamin K (5 mg) normalized the coagulation tests within 3 h, and then the hematoma was surgically removed. Extensive studies associated with the possible causes of vitamin K deficiency ruled out cholestatic or biliary hepatic disorders, hepatitis and metabolic disorders. Both serum amino acid analysis and alpha-1-antitrypsin level were also normal. He had had no episodes of prolonged diarrhea or feeding difficulties. The causative mycobacterium was later found to be resistant to isoniazid, and the treatment regimen was changed at 4 months of age to streptomycin twice weekly and daily rifampin. The baby responded well to the therapy and was growing satisfactorily without any sequelae for a 1-year period after discharge (Fig. 1).Fig. 1: Clinical course of the patient. INH, isoniazid (10 mg/kg daily);RFP, rifampin (10 mg/kg, daily);PZA, pyrazinamide (20 mg/kg daily);SM, streptomycin (20 mg/kg daily);SM *, 20 mg/kg, twice weekly). PIVKA, protein induced in absence of vitamin K.Discussion. Congenital tuberculosis is rare, but the reemergence of tuberculosis has resulted in a shift in its patient population to young adults and children. 1–3 The recent epidemiology implies that tuberculosis in pregnancy is becoming more prevalent, with a possible increase of the disease in the newborn period. 2, 3 Symptoms of congenital tuberculosis are often nonspecific and can occur as early as 2 to 3 weeks of life. Our present case met the diagnostic criteria of congenital tuberculosis proposed by Cantwell et al., 3 i.e. proved tuberculous lesions and exclusion of the possibility of postnatal transmission. 1 Several reports have stressed the importance of early diagnosis and initiation of the therapy for the disease, but information, especially regarding its therapy and adverse effects, particularly in relation to vitamin K deficiency, is limited. 4–6 To our knowledge this is the first report of an infant who developed a cerebral hemorrhage associated with vitamin K deficiency during antituberculosis treatment. Antituberculosis agents, especially rifampin, are known to interfere with vitamin K metabolism, leading to hypoprothrombinemia in certain clinical circumstances. Van Steenbergen et al. 7 have reported a patient with primary biliary cirrhosis who developed marked hypoprothrombinemia during treatment with rifampin. Ishii et al. 8 reported hypoprothrombinemia in patients with small intestinal dysfunction treated with antituberculosis agents. The pathogenesis of the coagulation disorder is considered to be a result of both a disturbed absorption of vitamin K from the intestine and interference of rifampin with vitamin K metabolism. Severe bleeding diathesis has been reported in newborns from mothers treated with rifampin and isoniazid during pregnancy. 9, 10 There have been no reports of a patient developing hypoprothrombinemia in response to single isoniazid therapy. In an experiment evaluating the effects of antituberculosis agents on prothrombin activity in the rat, only rifampin induced hypoprothrombinemia in a dose-dependent manner by inhibiting vitamin K epoxide reductase activity. Such a drug interaction has also been described with cephalosporin antibiotics containing N- methylthiotetrazole side chains. 8, 11 The phenomenon is induced when rats are fed only a vitamin K-deficient diet. These findings suggest the possibility that this drug interaction may occur only in conjunction with a preexisting low vitamin K status. 8 Concentrations of vitamin K-dependent coagulation factors are lower in infants than in adults, presumably because of decreased vitamin K deposition in the body, poor gastrointestinal absorption of fat-soluble vitamins and immaturity of the enzyme activity responsible for producing the coagulation factors. 12–14 A hemorrhagic event of late onset has been reported even in infants who have received oral vitamin K at birth, for whom the incidence has varied from 1.5 to 6.4 cases per 100 000 newborn births. 15 In the present case the patient was bottle-fed and growing satisfactorily during the antituberculosis therapy without any known risk factors such as hepatic disease, gastrointestinal disease or lack of vitamin K prophylaxis. 12,13,15,16 We believe that the coagulopathy resulted from drug-induced vitamin K deficiency, with rifampin as the primary causative agent.