Nghiên cứu đặc điểm lâm sàng, cận lâm sàng, thái độ xử trí với thai phụ giảm tiểu cầu trong thai kỳ tại bệnh viện phụ sản trung ương TT TIENG ANH

MINISTRY OF EDUCATION MINISTRY OF HEALTH AND TRAINING HANOI MEDICAL UNIVERSITY DAO THI THANH HUONG INNITAL STUDY ON CLINICAL FEATURE, LABORATORY AND TREATMENT BEHAVIOR IN PREGNANCY WOMEN WITH THROMBOCYTOPENIA Speciality Code : Obstetrics and Gynaecology : 62720131 PH.D THESIS SUMMARY HANOI - 2022 THE THESIS WAS FULFILLED AT HANOI MEDICAL UNIVERSITY Principal Supervisors: Prof Dr.Tran Danh Cuong Prof Dr.Le Xuan Hai Opponent 1: Opponent 2: Opponent 3: The thesis will be defended at Board of Examiners of Hanoi Medical University At: 14:00 Date: 10/ 09 / 2022 The thesis can be found at: - National Library - Hanoi medical University Library LIST OF RESEARCH WORKS PUBLISHED RELATED TO THE THESIS Đao Thi Thanh Huong (2015) “A case report on the thrombocytopenia in pregnancy and newborn Journal of Obstetrics and Gynecology; volume 13(01), 05-2015, page 74-76 Đao Thi Thanh Huong (2015) “Comments on management during labor for pregnancy with indopathic thrombocytopenia in the National hospital of Obstetrics and Gynecology 2012” Journal of Obstetrics and Gynecology; volume 13(02), 05-2015, page 86-88 Đao Thi Thanh Huong, Tran Danh Cuong (2016) “Clinical, characteristics, subclinical, access management for thrombocytopenia pregnancy during labor in the National hospital of Obstetrics and Gynecology 2015” Journal of Obstetrics and Gynecology; volume 14(01), 05-2016, page 56-60 Đao Thi Thanh Huong, Tran Danh Cuong (2017) “Impact of maternal thrombocytopenia in pregnancy to neonates” Obstetrics and Gynecology; volume 15(02), 05-2076, page 70-74 Đao Thi Thanh Huong, Tran Danh Cuong (2015) “Clinical, characteristics, subclinical, access management for thrombocytopenia pregnancy during labor in the National hospital of Obstetrics and Gynecology 2014-2015” Doctor of Philosophy students meeting, page 160-161 Đao Thi Thanh Huong, Tran Danh Cuong, Le Xuan Hai (2020) “Impact of maternal thrombocytopenia in pregnancy to neonates” Việt Nam medical journal; volume 496, page 510-513 INTRODUCTION Thrombocytopenia is one of the causes leads to postpartum bleeding even maternal and neonatal mortality due to hemostasis disorder Thrombocytopenia is caused not only by medical condition but also by pregnancy Thrombocytopenia in pregnancy includes: 70-80% due to pregnancy (gestational thrombocytopenia), 20% due to preeclampsia /eclampsia, HELLP (Hemolysis: hemolysis, EL (elevated liver enzymes), LP (low platelet count) and about 3-4% immune thrombocytopenia Gestationalthrombocytopenia(GT)is themost common cause of thrombocytopenia during pregnancy Platelet value is usually above 80G/l and returns toal levelwithin the first three months postpartum The pathophysiology of gestational thrombocytopenia is unknown, but it might relate to increased blood volume during pregnancy The diagnosis is sometimes made after having a test result The treatment of thrombocytopenia in pregnancy is complicated due to maternal and fetal safety concerns and having a tough choice between the intervention or followup monitoring Thrombocytopenia in pregnancy has been mentioned since the 1980s around the world Many researches on the management of thrombocytopenia in pregnancy during delivery and the follow up monitoring of newborns have been done The relationship between maternal conditions and the degree of fetal thrombocytopenia has been also assessed and this matter remains challenging to obstetricians In Vietnam, there have been few studies on thrombocytopenia, therefore this study is set to explore: Clinical and subclinical characteristics of pregnant women with thrombocytopenia The management of thrombocytopenia in pregnancy Estimation of hematologic value of new-borns whose mothers diagnosed with thrombocytopenia during pregnancy New contributions from the thesis  This is the first thesis in Vietnam to access the effect of pregnant thrombocytopenia to the number of thrombocytes in newborns whose mothers are diagnosed with thrombocytopenia in pregnancy  This study gives initial insight on the difference of thrombocytopenia in pregnancy and ITP  This study also is the first study in Vietnam, which uses antiplates antibodies test in pregnant women and newborns In addition, antiplates antibodies test is screened by flow cytometric Thesis outline The thesis consists of 145 pages, covering: introduction (2 pages), overview (35 pages), object and method of research (19 pages), results (34 pages), discussion (52 pages), conclusion (2 pages), proposal (1 page) It has 34 tables, 12 figures, 12 charts 163 Referecnce, including English and Vietnamese versions Chapter OVERVIEW 1.1 Platelet Figure 1.1.Diagram of platelet growth and maturation 1.2 Thrombocytopenia and the causes 1.3 Thrombocytopenia in pregnancy Thrombocytopenia in pregnancy is caused by medicine conditions or decreased platelet count associated with pregnancy The main causes of it relating to pregnancy are gestational thrombocytopenia (75%), the secondary diseasesdue to hypertensive and immune disorder in pregnant women Other causes such as preeclampsia, HELLP syndrome, acute fatty liver of pregnancy, disseminated intravascular coagulation, im-mune thrombocytopenic purpura, and hemolytic uremic syndrome may be founded based on clinical and laboratory abnormal findings Furthermore, thrombocytopenia can also be as a manifestation of viral infections or adverse effects related to drugs and supplements and it requires careful differential diagnosis by history and laboratory tests Nevertheless, ITP that first appears in pregnancy is often confused with gestational thrombo-cytopenia in a clinical setting In case of asymptomatic thrombocytopenia for the first time of pregnancy, lumbar puncture procedure is not routine Hematologist and obstetrician distinguish ITP from GT by the onset time and platelet count 1.3.1 Gestational thrombocytopenia In pregnancy, there is significant physiological changes in the body of mothers for adaptation and being able to provide nutrition sufficiently to fetus In terms of hematological system, plasma volume has increased, and coagulation factors has changed For the latter, these changes are mild thrombocytopenia, an increase in coagulation factors and decrease in fibrinogen 1.3.2 Immune thrombocytopenic purpura The pathophysiology of ITP is autoimmune mechanism It is demonstrated that the lifespan of intravascular platelet of ITP is shortened and primary mechanism is the platelet destruction in peripheral tissue Even nowadays, initial factors producing anti-platelet antibodies are still unknown, but it is the fact that antiplatelet antibodies from lymphocyte B is specificallyresponded to glycoprotein in platelet membrane and theyweredestroyed by macrophages or dendritic cells in the liver and spleen via receptor Fcy Activated cytokine like IL-2 results in lymphocyte TCD4 proliferation (Th1, Th2) Lymphocyte TCD4s stimulate lymphocyte B to produce anti-platelet glycoprotein antibodies 1.3.3 Neonatal thrombocytopenia (NT) Neonatal thrombocytopenia is not caused by thrombocytopenia in pregnancy, but it could be by ITP with antiplatelet antibodies passing through placental barrier (IgG) It is the standard of diagnose of GT or immune thrombocytopenia Nevertheless, not all cases of ITP cause neonatal thrombocytopenia Hemorrhage in NT are the common immune pathologies This disease is characterized by platelet in peripheral vascular destroyed in the reticuloendothelial system associated with ant- platelet antibodies Although the correlation between the magnitude of platelet level decline and the occurrence of neonatal thrombocytopenia is unfound, some studies show that themoderate and server neonatal diseasesrelated to ITP mothers account for 10% and 4%, respectively and the hemorrhage rate approx 1% Evaluation of prenatal fetal platelet count through fetal blood sampling or fetal scalp blood sampling is not routine due to the high rates of complications and fetal loss In clinical practice, the best predictable factor of neonatal thrombocytopenia is based on the history of GT with thrombocytopenia of preceding infants 1.4 Anti- platelet antibodies 1.4.1 Platelet Antigen 1.4.2 Platelet Antibodies  Autoantibody Autoantibodies is an antibody (immune proteins) that mistakenly targets and reacts to a person’s own tissues or organs One or more autoanti-bodies may be produced by a person’s immune system that fails to distinguish between “self” and “non- self” Usually, when foreign substances infiltrate into body, for example bacteria, viruses and parasite, the lymphocyte will produce antibodies against them In the autoimmune disease, the body mistakenly discriminate its own organ as strange things and may produce antibodies reacting to its own cells, tissues or organs  Anti- platelet alloantibody Alloimmunity is an immune response to non-self antigens from members of the same species, commonly due to blood infusion or transplanted tissues andpregnancy The reaction is caused by the role of alloantibody HPA with HPA1a antibody approximately 80% specific HPA anti platelet antibody Alloantibodies against HPAs and HLA is related to platelet disorders via immune mediation Hemorrhage in fetal immune thrombocytopenia is due to fetal HPA that stimulates the immune system of mother and produces antibodies against fetal platelet  The correlation between antiplatelet antibodies and thrombocytopenia Now, anti-HPA antibody can be detectable by highly sensitive measures However, ani-HPA antibody evidence did not demonstrate that these antibodies led to decrease in platelet count In clinical practice, it is clearly important to determine whether antibody leading to thrombocytopenia present or not Few reports showed that very low antibody titer may lead to declined platelet count in animal There is strong evidence that antibody may make platelet decrease, even the antibody level is lower than the detectable limitones by common measures 1.4.3.Antibody tests Some measures such as available taget cell help to detect anti–HPA antibodies Common measures today are MAIPA-Monoclonal antibody-specific immobilisation of platelet antigens, PAC-platelet antigen capture immunoassay), MPHA-mixed passive haemagglutination), flwcytometry analysis, ELISA, Luminex lab test These attribute are abstracted in table Anti–HLA antibody may create problems with platelet antibody test, such as MPHA and flow cytometry but, not specific test like MAIPA MAIPA is highly sensitive and specific, therefore, it is considered to golden standard CHAPTER MATERIALS AND METHOD 2.1 Studyparticipants This descriptive study was conducted at National Hospital of Obstetrics and Gynacology in the period from March 2014 to December 2018 The study protocol was approved by the Ethics Committee of Nation hospital for Obstetrics and Gynecology Informed written consent was provided from all participants All participants was diagnosis with thrombocytopenia at one of the hospitals including: National Hospital of Obstetrics and Gynecology, Bach Mai Hospital, and National Institute of Haematology and Blood Tranfusion and thier newborn 2.1.1 Inclusion Pregnant women included in the study had to fulfil all of the following criteria: - Normal health history - Platelet counts is below 150G/l - Not been diagnosed with thrombocytopenia due to bone marrow failure, viral infection, cancers, or drugs,… 2.1.2 Exclusion criteria Women were excluded if they: not end their pregnancy at National Hospital of Obstetrics and Gynecology 2.2 Setting and time The study was conducted at all three hospitals include: National hospital of Obstetrics and Gynecology, Bach Mai Hospital, and National Institute of Haematology and Blood Tranfusion from March 2014 to December 2018 2.3 Study Method 2.3.1 Study Design Descriptive study 2.3.2 Sample Size We use non-probability sampling to collect those who met all the criteria In fact, 58 patients and their newborns were recruited into our study 2.3.3 Data collection + Patients who met all the criteria will be chosen to our study + All of them will be examined thoroughly and carefully and have their blood sample taken + Haematological consultation to decide when we should terminate pregnancy + Pediatric consultation to decide 2.4 Variables 2.4.1 Basic characteristics of participants + Age: divided into aged groups: under 18 years old, 18-34 year-old group, above 35 year-old group + Career: officer, worker, farmer and others + Parity: 1, or more than + A history of thrombocytopenia in previous pregnancy: yes or no + Timing of thrombocytopenia diagnosed: ≤ 14-week gestation, 15-28 week gestation, or ≥28 week gestation 2.4.2 Clinical, subclinical characteristics and causes of thrombocytopenia in pregnant women + Haemorrhage: no symptom, cutaneous bleeding, mucosa bleeding, internal bleeding + Timing of haemorrhage: admission, before the termination of pregnancy, or before discharge + Haematological status: before the termination of pregnancy, or before discharge + Platelet count at the time of diagnosis + Platelet count at the time of delivery + Anti-platelet antibodies: negative or positive + The level of anemia: + Postpartum follow-up: yes or no 2.4.3 The evaluation of neonatal hematological status whose mothers are diagnosed with thrombocytopenia + Gestation + Weight + Platelet counts: 100G/l + Anti platelet antibodies: positive or negative 2.4.4 Management of thrombocytopenia in pregnancy + Delivery: vaginal delivery, C – section + Analgesic methods: + Medicine: Corticoid 2.5 Assessment Criteria and Techniques 2.5.1 Assessment criteria 2.5.2 Testing procedures for platelet antibodies 2.5.2.1 Principle Human platelet antigens are presented on the surface of platelet cells Patients might produce platele antibodies when they are administered plalelet transfusion(this type of antibodies partly attach to platelet surface or be free in the blood serum) The nature of these antibodies is IgG, therefore we can detect the antibodies which attach to platelet surface by using fluorescent antibodies in Flowcytomater 2.5.2.2 Sample +Whole blood sample + 2ml in blood collection tube containing EDTA +Send blood sample to laboratory to refine serum by using 3000 cycle centrifugal method + Take serum out of the blood sample (300µl) + Preserve serum sample at 2-8℃ + Serum samples are transferred to National Institute of Haematology and Blood Tranfusion to indirect anti-platelet antibodies test 2.5.2.3 Assessment Criteria + Platelets which are refined should not contain erythrocytes and lymphocytes + Negative sample or O sample are takes from donors who never had a platelets transfusion before + Assess platelets base on SS and FS + Blood collection tube should be sterilized + The number of antibodies should be adequate + The chemicals should not out of date + The timing for testing should be adequate 2.6 Data analysis +The statistical analyses were performed by using SPSS 22 package program + Categorical data were expressed as number and percentage For qualitative data, Chi-square test was used + P 80G/l was the highest (accounted for 62.5% comparing to other groups with 37.5% and 0%, respectively) and had forceps 3.4 The hematological indices in febrile newborn 3.4.1 The platelet count of neonatal Figure 3.11 Patient distribution stratified by the neonatal platelet count Comment: There was 16 among 58 pregnant women had a newborn with thrombocytopenia (27.6%) There was 10 for 16 neonatal thrombocytopenia with platelet count 100- 80G/l in Nguyen Trong Tuyen's study accounted for 27.7% while ours 46.5% (27/58-Figure 3.12) The vaginal delivery ratio in our study was 13.8% andit was lower than that of the studies by the other authors in the world, for example 60% pregnant women with ITP and87%from Fujita et al (2010) On the contrary, the caesarean section ratios in our study and studies done by the domestic authors was higher than theseof foreign authors’ (usually fluctuatedwithin the range of 40%) According to WHO, when the platelet count > 80G/l, all of indicated cesarean section was obstetric indicated →Going back to our research results, we found that the indicated cesarean sectiondue to the large drop in platelet count compared was a wide range of indication thanthe research results and the recommendation for that in the world So it was necessary to reconsider so that theindicated cesarean section was made more closely 4.3.2.3.Pain relief for cesarean section Up to now, there are no study guidelines which suggest specifically in terms of platelet count for the lower limit deemed safe for epidural or spinal anesthesia There was no data for supporting minimum platelet count specifically to regional anesthesia and as result, each case must be considered individually Other studies only provide limited data and retrospective to solve this problem Most experts consider a platelet count in the range of 80G/l is adequate for epidural or spinal anesthesia if the patient were without any acquired or other congenital coagulation disorder, his/her platelet level was stable and platelet function was normaland was not receiving any anti-platelet or anticoagulant therapy 21 This was also acceptable with the lower platelet count but there was not enough published evidence to make a recommendation for this time For patients with the platelet count less than 75G/l, an individual decision should be made based on risks and benefit analysis However, the other authors also recommended general anaesthesia to the mothers whose platelet count was 20-30G/l Absolute contraindication for epidural anesthesia for the cases of low platelet count and severe coagulation disorder However, the risks and benefits of epidural anesthesia should be evaluated individually on the patients who with low platelet countsand have no clinical sign of coagulation disorder According to the British Society for Haematology’s Guidelines that the platelet count should be at least 80G/l to need to achieve a safe epidural anesthesia on pregnant women with ITP However, most of the anesthesiologists and authors report that they had used nerve blockade techniques, especially spinal anesthesia in healthy pregnant women with ITP with platelet count above 50G/l →This problem was: should be indicated epidural anesthesia more closely than those another recommendations in the world 4.4 Neonatal conditions 4.4.1 Platelet * Platelet count in newborns: According to our study, the mean platelet count in infants was 208.4 ± 79.5G/l (20–393G/l) (Figure 3.7) Among 58 infants, there were 16 infants with thrombocytopenia (29.6%: table 3.30) including: 10 infants with platelet countsat 100–150G/l (62.5%); 5infants with platelet counts at 50–100G/l (31.25%) and one of them with platelet counts