Clinical management of paroxysmal nocturnal haemoglobinuria in pregnancy: three case reports

First described in 1928, paroxysmal nocturnal haemoglobinuria (PNH) is a rare disease resulting from an acquired defect of one or more lineages of haematopoietic stem cells. The prevalence is estimated to be approximately 1–10 cases per million people, with the disease mainly affecting young adults, including women of childbearing age1. PNH is characterised by paroxysmal intravascular haemolysis with anaemia, neutropenia, thrombocytopenia, bone marrow disorders, a thrombotic tendency and increased susceptibility to infections2,3. Until 2007, the treatment of this condition was mainly supportive, including transfusions of red blood cells and platelets, folic acid and iron replacement, glucocorticoids and anticoagulation therapy. Bone marrow transplantation appears to be the only potentially curative option, but it carries a 10–20% risk of early mortality3. Eculizumab, a humanised monoclonal antibody, has recently revolutionised the treatment of PNH. The use of this antibody for the treatment of PNH was approved by the United States Food and Drug Administration in March 2007 and subsequently by the European Medicines Agency in June 20073,4. We describe the clinical evolution during pregnancy and post-partum period of three women diagnosed with PNH and referred to the obstetric outpatient clinic of our tertiary care level hospital (Table I). The diagnosis of PNH was confirmed by laboratory studies in all three cases. Venous blood samples were collected in EDTA K3 and a Redquant® kit from Biocytex was used. The samples were treated according to standard protocols and submitted to flow cytometry in a FACS Calibur® (Becton-Dickinson, Enzifarma Portugal) using the "Cell Quest" program. The data were analysed with "Paint-a Gate" PRO software. Three cell lineages were studied after appropriate labelling: red blood cells (CD55-FITC and CD59-FITC), monocytes (CD48-FITC/CD87-PE/CD14-PerCP/CD4-APC), and granulocytes (CD24-FITC/CD87-PE/CD16-PerCP). Diagnostic criteria were the existence of at least two positive markers in a cell line, with at least two cell lines affected. Table I Description of cases. Case reports Case 1 A 29-year-old primipara of African descent was referred to our outpatient clinic in the 9th week of gestation for monitoring of her pregnancy. She had been diagnosed with PNH 5 years previously, following investigations for persistent fatigue and haemolytic anaemia (haemoglobin [Hb]=8.2 g/dL, lactate dehydrogenase=2,384 U/L). After oral iron replacement, she had remained asymptomatic without needing regular transfusion therapy. She had no prior history of thrombosis but she is heterozygous for the MTHFR mutation with a normal homocysteine level. At the time of referral she was taking aspirin (100 mg/day), advised by her general practitioner, and we decided not to discontinue this until the 35th week of pregnancy. At the first appointment, she had moderate haemolytic anaemia (Hb=9.4 g/dL) but, during pregnancy, she needed to be transfused with a total of 7 units of red blood cells (in weeks 14, 21, 29 and 35), in order to maintain her Hb level around 10 g/dL. Pregnancy was uncomplicated until the 33rd week, when she began to complain of a strong frontal headache and was given prophylactic subcutaneous Low Molecular Weight Heparin (LMWH), (enoxaparin 4,000 UI anti-Xa, daily). Despite this, 2 weeks later, the patient was admitted to hospital because of persistent headache; she was treated with intravenous analgesia and was discharged home after clinical improvement and cerebral magnetic resonance imaging, which showed no abnormalities. At the beginning of the 37th week she was readmitted to our hospital because of worsening symptoms and computed tomography of the brain showed a longitudinal sinus thrombosis. Anticoagulation therapy was started with unfractionated intravenous heparin and, in order to avoid the stress of vaginal delivery, we performed an elective caesarean section. The woman's baby, a female, weighed 2,300 g, had an Apgar score of 9 at the 1st minute and 10 at the 5th minute and did not require neonatal intensive care. The puerperium was uneventful and the patient began anticoagulation with warfarin, before being discharged home on the 16th day after delivery. Cerebral magnetic resonance imaging performed 1 month later showed complete resolution of the thrombosis. Contraception with a levonorgestrel-releasing intrauterine device (IUD) was instituted 3 months after delivery.