ALBERT

Description: 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.

Description: Background Using oftyrosine kinase inhibitors (TKIs) in women with chronic myeloid leukemia (CML) at pregnancy is risky due to possible teratogenecity. Absence of TKIs for whole pregnancy is risky for remission loss and disease progression. Particular situations may warrant TKI usage at pregnancy for potential benefits despite potential risks although no precise indications have been developed. Rareness of cases and ethical issues make significant difficulties in decision making. Aim To develop and evaluate the treatment approach for CML and pregnancy considering leukemic burden and pregnancy terms. Materials and methods During years 2011-2015 we monitored prospectively 29 cases of pregnancy in 28 women with CML chronic phase developing the treatment scheme step by step (picture 1). In 16 cases molecular response (MR) at pregnancy start was the following: MR4 in 8 cases (BCR-ABL 1% and CHR. All women insisted to keep pregnancy in spite of risks. We recommended 1) immediate discontinuation of TKIs if they were taken 2) monthly follow-up of complete blood count (CBC) and BCR-ABL level by reverse quantitative polymerase chain reaction (RQ-PCR) 3) careful evaluation for developmental defects 4)possibility of using TKIs in cases of high leukemic burden starting from 15th pregnancy week as comparatively safe late term when main organogenesis is completed and blood-placental barrier (BPB) exists knowing that TKIs have limited BPB crossing ability. High leukemic burden was considered BCR-ABL〉1% as this level correlates with complete cytogenetic response (CCyR) absence and increased progression risk. The absence and/or loss of CHR was crucial to warrant TKIs. Alternative approaches including interferon, leukapheresis and staying without treatment were weighted in all cases. Dasatinib (DAS) was avoided due to multitargeted action, high fetal/maternal (F:M) concentrations and known possibility of hydrops fetalis. All patients were informed about possible risks at every stage of pregnancy. Results In 19 of 29 cases TKIs taken at conception were discontinued at 4th -10th week: imatinib (IM) in 17 and nilotinib (NIL) in 2. Evaluation for BCR-ABL level was done regularly but not monthly. Practically significant timepoints for BCR-ABL evaluation were pregnancy start, week 15th and pregnancy end. In 17 cases TKIs were reinitiated or started first: 4 newly diagnosed cases, 2 with CHR loss, 11 with BCR-ABL〉1% (high level at pregnancy start or MR loss). The TKIs taken were IM in 14 cases (dose 400 mg), NIL in 3 (1-400 mg, 1-600 mg 1- 800mg). In 1 woman NIL was taken from week 10th due to CHR loss and resistance to IM. In 12 other cases no TKIs were reinitiated at pregnancy as 11 had BCR-ABL

Description: Background Myeloproliferative diseases (MPD) rarely occur in women of reproductive age. But in recent years it becomes more often that young women suffer from these diseases. The development of new drugs and therapeutic strategies provides good results in survival rate and life prognosis for these patients. All this requires special options for management of pregnancy in women with MPD. Aims To develop the protocol of preconception planning and pregnancy management and to evaluate pregnancy outcomes and complications in women with MPD. Methods We have analyzed 110 pregnancies in 90 women. The prospective group (group 1) included 67 women who were treated according to our algorithm. Retrospectively we have analyzed 43pregnancies in 23 women (group 2) who did not receive a special treatment of MPD during pregnancy. Our trial included women with main MPD: essential thrombocythemia, polycythemia vera, primary myelofibrosis. Pregnancy management included examination of blood cell count and hemostasis system twice a month, besides this the inherited trombophylia testing, lupus anticoagulant, homocystein level, antiphospholipid syndrome diagnostics and hematologic examination including trepanobiopsy and JAK2V617F mutation. Besides thorough laboratory examination our algorithm of pregnancy planning and management included cytoreductive therapy, antiaggregants, low molecular weight heparin, plasmapheresis, vitamins of group B. For the cytoreductive therapy we prescribed Interferon alfa which is the safest option in preconception planning and pregnancy management for women with MPD. Results Termination of pregnancy was made in 2 (3%) women of group 1 and in 3 (6,9%) women of group 2 (OR – 2,44; 95% C.I.: 0,265; 30,109). In the group of women who were treated according to our algorithm 6% of women (4 pregnancies) developed spontaneous abortions. In group 2 without special treatment spontaneous miscarriages occurred in 62,8% in comparison with group 1 (OR – 16,88; 95% C.I.: 4,655; 74,177). First and second trimester spontaneous abortions in group 2 prevailed among all the miscarriages – 15 (34,9%) cases, stillbirth occurred in 12 (27,9%) cases. Preterm labor were in 5 (7,4%) and 6 (14%) pregnancies in 1 and 2 groups respectively (OR – 2,01; 95% C.I.: 0,471; 8,899). Full-term delivery occurred in 83,6% (56 pregnancies) and 16,3% of cases (7 pregnancies) in two groups (OR – 26,18; 95% C.I.: 8,441; 85,448). Complications of pregnancy were analysed in 61 and 13 women in 1 and 2 groups respectively. Pregnancy was uncomplicated in 21 (34,4%) and 2 (15,4%) cases in 1 and 2 groups respectively (OR – 2,89; 95% C.I.: 0,544; 28,852). The most often pregnancy complications were threatening miscarriage - 25 (41%) and 10 (76,9%) cases (OR – 0,21; 95% C.I.: 0,034; 0,937), anemia – 22 (36%) and 4 (30,8%) cases in 1 and 2 groups respectively (OR – 1,27; 95% C.I.: 0,307; 6,289). Although all pregnancies in group 1 were carefully observed and treated 14,8% of them (9 pregnancies) were complicated by placental isufficiency with IUGR in 5 (8,2%) cases. Placental insufficiency complicated 30,8% pregnancies (4 cases) including intrauterine growth retardation (IUGR) in 2 cases in group 2 (OR – 0,95; 95% C.I.: 0,161; 10,263). Conclusion Thus pregnancy losses in women suffering from MPD occur in 62,8% without special treatment and complications of pregnancy – in 84,6% cases. The development of algorithm for preconception planning and pregnancy management resulted in considerable decrease in miscarriages to 6% (P

Description: Background: Anemia is the most common hematological abnormality in pregnant women. The main cause of anemia in pregnancy and puerperium is the deficiency of iron. Iron requirements increase during pregnancy, and a failure to maintain sufficient levels of iron may result in adverse maternal-fetal consequences. Antenatal iron deficiency anemia (IDA) must be adequately and safely treated to avoid complications during the pregnancy. Other causes of anemia in pregnancy require early diagnosis and precise therapy. Aim. Establishment of algorithms for management of pregnancy, delivery and postpartum period in different types of anemia is crucial to pregnancy outcomes. We have been optimizing strategies for the management of pregnant patients with anemia. Results: From 2012 to 2014 we observed 1284 pregnant women aged 19-44 years. 312(24,3%) of them had decreased hemoglobin (Hb) during the pregnancy. IDA was diagnosed in 267(85,6%), myeloprolyferative neoplasms (MPN) –18(5,8%), hemoglobinopathies –7(2,2%), hematological malignancies (MHD) in remission –6(1,9%), folic acid or B12 deficiency –5(1,6%), paroxysmal nocturnal hemoglobinuria (PNH) –4(1,3%), aplastic anemia (AA) –3 (1%), myelodysplastic syndrome (MDS) –2(0,6%). Hb level was below 90 g/l in 58(18,6%) patients. The most of anemia cases were identified during the pregnancy -187(59,9%), others existed before that. For IDA diagnosis we used the serum ferritin level, ratio of serum iron and total iron-binding capacity and transferrin. 88 (33%) of IDA patients had already had IDA during their lifespan. IDA was treated with ferric carboxymaltose intravenously weekly after the first trimester of pregnancy in Hb up to 90 g/l (the course summary dose –1500-2000 mg). In other cases we administered ferric (III) hydroxide polymaltosate per os (100-200 mg daily during 1-3 months). Hb was normalized by delivery in 216 (80,9%) patients. We have analyzed the outcomes of pregnancy in IDA. The most common complaint was impaired physical performance (91%). Spontaneous miscarriages were registered in 2(0,8%) cases. We did not observe a neonatal mortality. 242 (90,6%) pregnancies ended up with a birth of full-term healthy infants without birth defects. Preterm birth occurred in 23(8,6%) cases, IDA persisted in 19 (82,6%) of them. 38(14,3%) of patients with IDA in third trimester reported maternal and fetal complications, such as chronic placental insufficiency (36,8%), fetal growth retardation syndrome and low birth weight for gestational age (57,9%), placental abruption (5,3%), postpartum hemorrhage (10,5%). IDA was diagnosed in 14(5,3%) neonates and 26(9,8%) women noted the reduced lactation. Anemia in postpartum period was registered in 43(16,2%) patients. Also we have analyzed outcomes of 44 pregnancies in women with non-IDA anemia. The majority of them were patients remained in complete or partial remission of MHD, MPN, AA, PNH, MDS, who underwent the special treatment. Some of them required special treatment during the pregnancy (interferon in MPN, eculizumab in PNH). The non-severe types of hemoglobinopathies required observation and supportive care until postpartum period. Macrocytic anemia with folic or B12 deficiency was successfully treated with folic acid or cyanocobàlamin. The level of Hb by delivery was below 110 g/l in 32(72,7%) non-IDA women (blood transfusion required 2 patients). 40(90,9%) of pregnancies ended up with a birth of full-term infants. Preterm birth occurred in 4(9,1%) cases. In our study exposure to special therapy was not associated with congenital anomalies, and no spontaneous miscarriages were registered. The fetal growth retardation syndrome and low birth weight registered in 3(6,8%) patients. No hemorrhagic complications during labor or postpartum period have been observed. Conclusion: Despite the regular antenatal observation, maternal anemia is still high. Anemia during pregnancy is a diverse group of disorders with varied pathophysiology, treatment options and overall prognosis. IDA is the most frequent anemia reason. We have concluded that the prognosis for pregnant women timely treated for IDA is similar to that of healthy women. Mothers with persistent IDA reported different pregnancy complications. The modern IDA treatment approaches allow the majority of patients to achieve the effect in shortest time. Another anemia reasons require diagnosis and special treatment of underlying disease. Disclosures No relevant conflicts of interest to declare.

Description: Background The diagnosis of malignant hematological diseases (MHD) during pregnancy imposes major therapeutic decisions - optimal maternal treatment must be balanced against the risk to the fetus. The aim of therapy in this clinical situation is saving two lives – both a mother and a child. MHD treatment has some specific complications that may have special importance during pregnancy. Thus, management of pregnant patient with MHD is a difficult multidisciplinary problem. Furthermore, the issues of reproductive health in MHD patients are becoming very important in general because of survival improvement. Aim Evaluation of the disease prognosis and establishment of algorithms for management of pregnancy and delivery in MHD patients are crucial for quality of life. We have been developing the optimal strategy for management of pregnant patients with MHD. Results From 1986 to 2013 we observed 218 pregnancies in 207 pregnant women with MHD in total. We have analyzed outcomes in 36 cases disease presented in pregnancy, including 19 patients treated with chemotherapy for MHD during pregnancy (Hodgkin lymphoma (HL) was diagnosed in 21 patients, non-Hodgkin lymphomas (NHL) in 15). All of them exposed to chemotherapy in the second and third trimesters according to form of the disease. ABVD was the chemotherapy regimen given in HL. Pregnant women with NHL treated with CHOP, R-CHOP or VACOP-B. Also we have analyzed 182 pregnancies in 171 women remaining in remission after MHD, including 131 patients with HL, 24 patients with NHL and 16 patients with acute leukemia (AL). All of them underwent the treatment of hematological disease to achieve remission. The median time from the moment of achieving remission to the onset of pregnancy was 7,2 years in patients with HL, 4.3 years in patients with NHL and 7.8 years in patients with AL. 10-years overall survival of pregnant and non-pregnant HL patients has no significant difference: 86,4% vs 91,2% (p=0,27). 10-years disease free survival rate of 70 vs 72% (p=0,34) respectively. We did not observe any maternal life-threatening complications during pregnancy. Most common complications in the group of women exposed chemotherapy during pregnancy were different infections (viral infections -10,5%, pyelonephritis – 4,2%, pneumonia – 3,3%) and thrombotic events (16,2%). All of thrombotic complications registered during chemotherapy for NHL and were successfully treated. In pregnant women with full MHD remission the progression of the disease was registered in 23% patients with AL and in 1.7% patients with HL. All patients with diagnosed disease relapse needed the resumption of chemotherapy. 196 (89,9%) pregnancies ended up with a birth of full-term healthy infants without birth defects. Premature birth occurred in 16 (7.3%) cases. Neonatal mortality occurred in 1 (0.5%) newborn. In 2 (0.9%) patients pregnancy was terminated for medical reasons in the 2nd trimester. The mode of delivery was determined by the obstetrician in all cases. In our study exposure to chemotherapy was not associated with congenital anomalies, and no spontaneous miscarriages were registered. When early stage disease is diagnosed in the first trimester, chemotherapy is commenced in the second trimester. In advanced-stage disease in the first trimester there were 3 (1,4%) cases of abortion because of delay in treatment may adversely affect maternal outcome. No hemorrhagic complications during labor or postpartum period have been observed. Conclusion The MHD is a diverse group, with varied presenting features, pathophysiology, treatment options, levels of urgency to commence treatment in pregnancy, affect upon maternal and fetal outcome in pregnancy and overall prognosis. We conclude that prognosis of pregnant women treated for Hodgkin's lymphoma is similar to non-pregnant women. Treatment of MHD in pregnancy must conform to the protocol for type of disease and must include sufficient supportive care. We recommend patients with lymphomas to plan a pregnancy 3 years after achieving the remission. Pregnant women in remission after AL are at a considerably higher risk for relapse, hence, the pregnancy planning in this category of patients is feasible but no sooner than in 5 years after achieving full remission, and only after detailed examination including MRD testing. There is no difference in health between infants born by mothers with MHD and the newborns from general population. Disclosures: No relevant conflicts of interest to declare.

Description: Magnetic resonance imaging (MRI) and ultrasound methods used for the diagnosis of an abnormally invasive placenta (AIP) have a wide range of sensitivity (Se, 33–93%) and specificity (Sp, 71–100%) levels, which results in a high risk of unfavorable maternal and perinatal outcomes. The relevance of optimizing the diagnosis of AIP is beyond doubt. Given the epigenetic nature of trophoblast invasion, we aimed to quantitate microRNAs and proteins of their target genes that are potentially associated with AIP in blood plasma samples from 64 pregnant women at gestation weeks 30–34 by reverse transcription coupled with polymerase chain reaction (RT-PCR) and Western blotting, respectively. Statistically significant increases in the expression levels of hsa-miR-17-5p, hsa-miR-21-5p, hsa-miR-25-3p, hsa-miR-92a-3p, and hsa-miR-320a-3p were revealed in the groups of women with AIP (accreta, increta, percreta) relative to the group of women with scars on the uterus or to the group with placenta previa. Opposite changes in the expression level of “gene–target protein/miRNA” pairs were found for the α-subunit of the clusterin secretory form and any of the hsa-miR-21-5p, hsa-miR-25-3p, hsa-miR-92a-3p, hsa-miR-320a-3p, and hsa-miR-17-5p in all cases of AIP. The developed logistic regression models to diagnose AIP cases of various severity gave Se values of 88.8–100% and Sp values of 91.6–100% using a combination of hsa-miR-21-5p, hsa-miR-92a-3p, hsa-miR-320a-3p, or clusterin levels.