Pregnancy in Paroxysmal Nocturnal Hemoglobinuria
Authors: Vinogradova Maria A. , Shmakov Roman G. , Fidarova Zalina T. , Polushkina Eugenia S. , Mikhailova Elena A. 
Published: October 2019

Abstract
Pregnancy and childbirth associated with a high risk of severe maternal and fetal complications in women with paroxysmal nocturnal hemoglobinuria (PNH). Recently the management of PNH during pregnancy has been challenging and childbearing was practically contraindicated in these patients. Eculizumab treatment improved the prognosis in PNH and made it possible to minimize complications during pregnancy. Establishment of effective and safe algorithms for the management of pregnancy, delivery and postpartum period in PNH patients is crucial to their lives.
Since 1999, we have analyzed 15 pregnancies in six women with PNH. The median age at PNH diagnosis was 22 years (18-27), the median age at the start of pregnancy - 25 years (21-34). All of them were diagnosed with PNH following treatment for aplastic anemia (AA) with antithymocyte globulin, cyclosporine A and splenectomy in two cases before pregnancy. The median of PNH granulocyte clone at the start of pregnancy was 74,7% (17,8-94,1). Pregnancy occurred during complete remission of AA with PNH clinical signs in 5 (33,3%) cases. Most patients were in partial remission at the time of pregnancy-7 (46,7%) or continued to receive immunosuppressive therapy with minimal effect-3 (20%). Progression of aplasia observed during 4 (26,7%) pregnancies, but it was not severe and special treatment delayed until the completion of pregnancy. Two patients exposed to eculizumab before conceiving and remained on the treatment during pregnancy. Other women received only symptomatic therapy. Anticoagulation with low molecular weight heparin was used in 5 (33,3%) pregnancies. No thrombotic events during pregnancy and postpartum have been observed. Skin hemorrhages were revealed in 2 (13,3%) patients. During 4 (26,7%) gestations patients underwent erythrocytes and/or platelets transfusion. Pregnancies resulted in the birth of healthy infants in 7 (46,7%) cases - two girls and five boys. There were no adverse effects in the newborns from PNH patients both on eculizumab and without it. Successful outcomes were in 2/2 pregnancies on eculizumab treatment and in 5/13 (38,5%) cases without the drug. Caesarean sections were performed in all of births, early surgical delivery (30-34 weeks)-in 4/7 cases (preeclampsia-2, placenta previa-1, breakthrough hemolysis-1). Adverse pregnancy outcomes occurred only in patients not receiving eculizumab and amounted to 8/13 (61,5%). Only three patients had planned the pregnancy, other 12 cases were unplanned. Consequently, in 4 (30,8%) cases of pregnancy in the midst of illness was performed the abortion for medical reasons. Spontaneous miscarriage was registered in 2 (15,4%) patients. Two pregnancies (15,4%) ended in fetal death on 27th and 20th gestation weeks. Transfusion requirements increased in two pregnancies with symptomatic therapy, but did not increase on eculizumab. One of patients had first pregnancy without eculizumab and developed complications such as preeclampsia, postpartum severe epistaxis and high transfusion requirement (an average of 1,2 units per month). During second pregnancy on eculizumab she had no obstetric complications and transfusion requirements were less (0,5 units monthly). Second patient continued to have evidence of intravascular hemolysis despite the treatment, and so received eculizumab more frequent (one time in 10 days) in the third trimester. PNH granulocyte clone size decreased in both cases of eculizumab treatment during pregnancy.
The risk of complications in PNH patients during pregnancy may be minimized by applying the management algorithm with eculizumab treatment. Despite the small number of observations, we can safely conclude that pregnancy outcomes in PNH patients with eculizumab are better than with only symptomatic therapy. Our experience confirms that eculizumab can be safely used in PNH throughout pregnancy to reduce the risk of complications and adverse outcomes. There is no difference in health between infants born by mothers with PNH and the newborns from general population.

Disclosures
No relevant conflicts of interest to declare.