A 38-year-old woman, gravida 3 para 1 abortion 1, was admitted to the Department of Obstetrics and Gynecology of the China-Japan Friendship Hospital (Beijing, China) on October 5, 2019, with complaints of 7 weeks amenorrhea, cornual pregnancy treated with MTX for 5 days and fever (38.5 C) for 2 days. About a week earlier, the patient was presented in a local hospital, and was diagnosed with cornual pregnancy, vaginal bleeding, the elevated beta-human chorionic gonadotropin (beta-hCG) level (987-1,959 mIU/L) and ultrasound findings that a mixed echogenic mass of 13.4 x 7.9 mm in the right cornu uteri. Then, she intramuscularly (IM) received the routine LD-MTX (75 mg) for EP on October 1, 2019. After 1 day of LD-MTX administration ("day 1" was abbreviated as "D1"), nausea, vomiting, and diarrhea appeared, while no special treatment was given. Next, other symptoms, such as fever (38.5 C), sore throat, and left back pain, appeared (D2). On admission (D4), a few maculopapular rashes on the left neck were observed, the beta-hCG level was 8,279 mIU/L, and ultrasound showed the mixed echogenic mass in the right cornua uteri was 20 x 16 mm. CT of chest ruled out pulmonary infection and the patient denied the history of allergic diseases. So, she was diagnosed cornual pregnancy (an uncommon form of EP) that failed LD-MTX treatment. Whether the fever and skin rashes were due to LD-MTX or other causes, it had to be further investigated for a definitive answer.
During the next 3 days ("D5-D7"), the skin rashes of the patient progressed to small blisters, and covered ~80% of her body surface, excluding the palms and soles. Areas of desquamation were identified, while Nikolsky's sign, which is typically present in the cases of toxic epidermal necrolysis (TEN), was negative. Oral mucositis was gradually aggravated. Oral mucositis caused difficulty in the oral intake and swallowing. The perianal mucositis and fecal occult blood appeared on D8. In addition, a persistent fever was found until 20 days after administration of LD-MTX. Physical examination further revealed purulent secretions in the bilateral tonsillar fossa, ear swelling, percussion pain in both the kidneys, especially in the left kidney, and a mild tenderness in the right adnexal area.
The testing of peripheral blood sample of the patient on admission performed in our hospital revealed the following outcomes: hemoglobin (110 g/L), absolute neutrophils count (ANC, 9.18 x 109/L), platelet count (144 x 109/L), C-reactive protein (CRP, 111 mg/L), alanine aminotransferase (ALT, 13 IU/L), total bilirubin (TBIL, 20.95 muM/L). Laboratory examinations carried out on the next days showed severe neutropenia (nadir dropped to zero, D11-D13), thrombocytopenia (nadir was 4 x 109/L, D16), decreased hemoglobin (nadir was 65 g/L, D20), elevated CRP (the highest value was 200 mg/L, D11 and D16), and increased ALT and TBIL (the highest values were 130 IU/L and 34.37 uM/L, respectively, D11). The renal function of the patient was normal as well (Figure 1; Table 1).
Although LD-MTX was given, therapeutic drug monitoring showed that the serum MTX concentrations were 0.04 muM/L (D7) and 0.013 muM/L (D11), which were significantly higher than the normal level. In addition, the personalized genetic testing of MTX showed that MTHFR TT (677C>T) and MTHFR AA (1298A>C) were detected, indicating a 75% decrease in the MTHFR activity. The administration of folic acid was seriously prohibited, which resulted in the decrease of MTX clearance, as well as a relatively high risk of hematotoxicity, hepatotoxicity, and mucosal toxicity after receiving LD-MTX.
Being neutropenic and febrile, the patient was treated simultaneously with the prophylactic broad-spectrum antibiotics since D4. Due to the grade IV neutropenia, prophylactic broad-spectrum antibiotics were switched to ertapenem [1 g, q8h, intravenous (IV)], vancomycin (1 g, qd, IV), and fluconazole sodium (200 mg, qd, IV). She was simultaneously treated with granulocyte colony-stimulating factor (G-CSF, 300 mug, bid, IH) and thrombopoietin (TPO, 15,000 units/day, IH). MTX retention was treated by initiating calcium leucovorin (CF) rescue, which was started since D8 (20 mg, q6h, IV), and the dose was elevated on D11 (100 mg, q6h, IV) due to the abnormal MTX concentration. Continuous renal replacement therapy (CRRT) was performed four times from D7 to D13 after LD-MTX administration, with 2,000 ml plasma each time. Supportive measures were required, such as protective isolation, IV fluid, urine alkalinization, oral washes and perineum rinsing, and transfusion of 4 units of the platelet.
On D17, the peripheral blood counts began to return to normal gradually. On D19, the G-CSF treatment was discontinued, and hemoglobin level and platelet count reached 70 g/L and 60 x 109/L, respectively. On D20, the beta-HCG level descended to the normal level. On D27, the mucositis and skin rashes had improved significantly, the patient reported no feeling of discomfort, and was discharged from the hospital (Figure 2). The beta-HCG level was monitored until it turned negative more than twice; peripheral blood counts, and the function of the liver and kidney were monitored regularly; the transvaginal ultrasound was carried out again and showed no obvious abnormalities. To date, we have followed up her for 20 months, and her general condition is satisfactory.