Author Information
Kale KG*, Deshmukh P**, Chauhan AR***
(* Assistant Professor, ** 3rd year resident, ***Professor, department of Obstetrics and Gynecology, Seth G. S. Medical College and KEM hospital, Mumbai, India.)
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by episodes of intravascular hemolysis, bone marrow failure and venous thrombosis. This is a rare acquired condition of the hematopoietic stem cells. PNH in pregnancy is associated with adverse maternal and perinatal outcome. However with careful monitoring and timely treatment in a tertiary care setting, a reasonably good maternal and fetal outcome may be expected. We present a successfully managed case of PNH in pregnancy.
Introduction
Paroxysmal nocturnal hemoglobinuria is an uncommon disorder of the hematopoietic stem cells resulting from an acquired gene mutation leading to episodes of intravascular hemolysis, bone marrow failure and thrombosis.[1] The estimated prevalence of this disease is around 15.9 cases per million populations and literature has only few case reports and small case series describing its occurrence in pregnancy. The maternal mortality rate in pregnancy associated with PNH is very high (8-21 %), almost all deaths occurring secondary to thrombotic complications. The perinatal mortality rate is as high as 4-9 %.[2- 4] Hence, PNH is considered as a relative contraindication to pregnancy.[5]
Case Report
A 24 year old primigravida, known case of PNH, presented to the outpatient department at 11 weeks of gestation for routine antenatal registration. The diagnosis of PNH was made at the age of 13 years when she had severe puberty menorrhagia, dyspnea on exertion, easy fatigability and weakness. At that time, investigations revealed pancytopenia (hemoglobin- 6.5 gm/dl, total leukocyte count- 2200/cmm, platelet count- 33,000/cmm, packed cell volume- 18.4%). Peripheral smear showed hypochromasia, microcytosis, anisopoikilocytosis, tear drop cells, pencil cells and schistocytes. Investigations also revealed ongoing hemolysis with elevated serum total and indirect bilirubin (4.2 mg/dl and 3 mg/dl respectively), raised LDH (2000 U/L) and reduced serum haptoglobin (< 6 mg/dl). The coagulation profile and serum iron studies were normal and Coomb’s test was negative; hence a diagnosis of hemolytic anemia (Coomb’s negative) was made. Bone marrow biopsy was performed which showed erythrocyte excess with decreased myeloid cell lineage. She was further evaluated with screening tests for PNH, namely acid Hams test and sucrose lysis test, both of which were negative. However, due to high index of suspicion, she was subjected to peripheral blood flow cytometry which revealed absent CD55 and CD59 molecules in 33 % and 23 % neutrophils respectively, confirming the diagnosis of PNH. She received multiple blood transfusions to correct anemia and thrombocytopenia and was started on oral folic acid and danazol. She tolerated the treatment well. Dose of danazol was tapered and stopped 3 years ago. Six monthly hemoglobin and complete blood count was monitored.
She got married at 23 years of age and conceived spontaneously within one year. She was counseled jointly by the hematologist and obstetricians about the increased maternal and fetal risks associated with the disease, need of multidisciplinary management and meticulous follow up. However, she and her spouse chose to continue the pregnancy and agreed to comply with the treatment. As soon as the pregnancy was confirmed, she was started on injection LMWH (low molecular weight heparin) in a daily dose of 0.6 mg subcutaneously along with oral iron (100 mg/d) and folic acid supplementation (5 mg/d). At each antenatal visit she was evaluated for clinical signs of disease progression, possible complications, and fetal well being. Complete blood count was obtained monthly for early diagnosis of bone marrow failure. It remained normal. The antenatal course was uneventful and she did not develop severe anemia or thrombocytopenia. Hence, she did not require any transfusion. At 37 weeks of gestation she developed chickenpox for which oral acyclovir therapy along with symptomatic treatment was initiated. She recovered well from the febrile episode without any complications and went into spontaneous labor at 39 weeks of gestation. LMWH was omitted and labor was monitored carefully using partograph. Oxytocin augmentation was used. An outlet forceps delivery (in view of maternal exhaustion) of a healthy male child weighing 2.6 kg with an Apgar score of 9/10 was accomplished without any maternal or fetal complications. There was no postpartum hemorrhage or a thrombotic event. Injection LMWH was restarted subcutaneously 12 hours after delivery and was continued for 6 weeks postpartum. She was discharged on 7th postpartum day and was followed up weekly to look for possible complications. She was advised to use barrier contraception. The puerperal period was uneventful and she is currently following up with the hematologist.
Discussion
PNH is a rare disorder resulting from expansion of a clone of hematopoietic stem cells that have acquired a mutation in the PIG-A gene. The PIG-A gene is responsible for the synthesis of glycosyl phosphatidylinositol (GPI) which anchors certain proteins, mainly CD55 and CD59, to the surface membrane of marrow cells. CD55 and CD59 serve as membrane bound regulators of complement that inhibit complement mediated lysis of erythrocytes. Absence of these regulating proteins on cell surface leads to intravascular hemolysis and hemoglobinuria.[1] Other essential features of this condition are episodes of bone marrow failure and venous thrombosis at unusual sites viz. hepatic, mesenteric, portal veins, cerebral veins etc.[6] The exact reason for venous thrombosis remains unclear; however, it is the most dreaded complication responsible for 40-75% of PNH related deaths.[7]
The median age at diagnosis of PNH is 34 years, thus affecting women in their reproductive age group, although fertility appears to be unaffected.[5] Presenting symptoms are often non specific, ranging from those secondary to anemia (weakness, dizziness, dyspnea on exertion), hemoglobinuria (cola colored urine), to venous thrombosis involving various sites like brain (headache, nausea, vomiting), retina (loss of vision), deep veins of legs (pain and swelling of legs), kidney (oliguria), pulmonary embolism (sudden onset breathlessness). Our patient presented at 13 years of age with symptoms of anemia and menorrhagia (probably secondary to thrombocytopenia). She also conceived spontaneously within 1 year of marriage. The clinical course of the disease is usually chronic with intermittent flare-ups. This requires monitoring, as was done in our case. The initial laboratory investigations in PNH are usually suggestive of hemolytic anemia of Coomb's negative type. The diagnosis is established only after flow cytometric analysis of peripheral blood showing increased population of erythrocytes and/ or leukocytes deficient in GPI anchoring proteins, CD55 and CD59. In our case, 33% and 23% of the neutrophils were deficient in CD55 and CD59 respectively, thus confirming the diagnosis. The traditional screening tests for PNH; the acid Hams and the sucrose lysis test, have low sensitivity, which probably lead to the false negative result as was obtained in our patient.[1, 6]
PNH during pregnancy poses an increased risk for both the mother and the fetus. The rate of spontaneous miscarriage is as high as 45%.[5] They have high risk of developing severe anemia during pregnancy, more severe than the non pregnant state, requiring frequent blood transfusions. [7] It may be due to intravascular hemolysis which is frequently increased (due to activation of complement cascade in pregnancy),[5] episodic bone marrow failure and concurrent iron deficiency due to loss of hemoglobin in urine. Thrombocytopenia is also more common in pregnancy as compared to the non pregnant state. Pregnancy being a prothrombotic state appears to increase the risk of PNH related venous thrombosis both antenatally and in the postpartum period and is the most important cause of maternal mortality. Infections occur with an increased frequency during pregnancy, as evident by development of chickenpox in our patient.[2,6,7] Thus, these cases require careful clinical and laboratory evaluation during pregnancy for early detection and treatment of complications, as was done for our case. Although most of them can be delivered vaginally, one retrospective study has reported increased rates of cesarean sections, possibly due to increased incidence of planned inductions of labor and PNH related smooth muscle dystonia hampering the progress of normal labor.[2] There is an increased incidence of preterm induction of labor, major reasons being- a) worsening of hematological parameters, and b) associated obstetric complications viz. preeclampsia and intra uterine growth restriction.[2,8] Perinatal mortality in PNH ranges from 4%-9%, mostly due to iatrogenic prematurity. However, the surviving infants usually have a normal growth and development.[6]
Blood and blood product transfusion forms the mainstay of management of anemia/ thrombocytopenia in a pregnant woman with PNH. Hemolysis and subsequent hemoglobinuria leads to urinary iron loss and iron deficiency requiring iron supplementation. In classic PNH, the
iron loss is usually so large that iron overload is a rarity (inspite of repeated transfusions) and parenteral iron supplementation may be necessary.[6] Nonetheless, anemia in PNH is complex, requires complete hematological workup and consultation with hematologist for appropriate treatment. Oral folate supplementation is a must owing to the increased metabolic demands due to heightened erythropoiesis (secondary to hemolysis). Prophylactic anticoagulation with heparin is recommended, starting as soon as the pregnancy is confirmed and is continued for up to 6 weeks postpartum. Those women who develop thrombosis should receive therapeutic anticoagulation. Warfarin is contraindicated in pregnant PNH patients as it carries increased risk of hemorrhage (may be given in the postpartum period).[5-7] All the above recommendations were strictly followed in our case leading to a good maternal and fetal outcome without any complications. Eculizumab, a human monoclonal antibody directed against complement protein C5, has been increasingly used recently in the treatment of PNH with good results. Few published case reports have documented the safety and efficacy of eculizumab in pregnancy, however, this needs to be confirmed with larger studies.[5- 7]
Pregnancy is usually discouraged in patients with PNH. Patients should be counseled in detail about the increased feto-maternal risks and option of termination of pregnancy should be given to the patient. However, when patient desires pregnancy, a multidisciplinary management in a tertiary care hospital, involving experts in the field of obstetrics, hematology and intensive care is a must. [8, 9]
Conclusion
Pregnancy in a woman with PNH is a high risk situation with definite increase in the maternal and perinatal morbidity and mortality. It requires multidisciplinary management with careful monitoring, early diagnosis and prompt treatment of complications to prevent adverse events.
References
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- Sharma R, Keyzner A, Liu J, Bradley T, Allen S. Successful pregnancy outcome in paroxysmal nocturnal hemoglobinuria (PNH) following escalated eculizumab dosing to control breakthrough hemolysis. Leukemia Research Reports.2015;4(1):36-8.
- Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood.2005;106(12):3699- 709.
- Kelly R, Arnold L, Richards S, Hill A, Bomken C, Hanley J et al. The management of pregnancy in paroxysmal nocturnal hemoglobinuria on long term eculizumab. Br J Hematol.2010;149(3):446-50.
- Melo A, Gorgal-Carvalho R, Amaral J, Marques MC, Andrade J, Guimaraes JT, et al. Clinical management of paroxysmal nocturnal haemoglobinuria in pregnancy: three case reports. Blood Transfus. 2011;9(1):99–103.
- Bjørge L, Ernst P, Haram KO. Paroxysmal nocturnal hemoglobinuria in pregnancy. Acta Obstet Gynecol Scand. 2003;82(12):1067-71.
Citation
Kale KG, Deshmukh P, Chauhan AR. Paroxysmal Nocturnal Hemoglobinuria In Pregnancy. JPGO 2016. Volume 3 No. 8. Available from: http://www.jpgo.org/2016/08/paroxysmal-nocturnal-hemoglobinuria-in.html