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MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEATH HANOI MEDICAL UNIVERSITY ====== NGUYEN THI THANH BINH CLINICAL, PARACLINICAL CHARACTERISTICS AND RELATED FACTORS OF EPILEPTIC WOMEN IN PREGNANCY Sp[.]
MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEATH HANOI MEDICAL UNIVERSITY ====== NGUYEN THI THANH BINH CLINICAL, PARACLINICAL CHARACTERISTICS AND RELATED FACTORS OF EPILEPTIC WOMEN IN PREGNANCY Specialism : Neurology Code : 9720107 ABSTRACT OF THESIS HA NOI – 2022 The thesis has been completed at HANOI MEDICAL UNIVERSITY Supervisors: Supervisor 1: PROF.DR LÊ VĂN THÍNH Reviewer 1: Reviewer 2: Reviewer 3: The thesis will be present in front of board of university examiner and reviewer lever at… on ….20 This thesis can be found at: National Library: National Medical Informatics Library Library of Hanoi Medical University THE LIST OF WORKS HAS PUBLISHED AND RELATED TO THE THESIS Nguyễn Thị Thanh Bình, Lê Văn Thính (2019), Women with epilepsy in pregnancy: Clincal, Para-clinical characteristics and the role of preconception counseling in controlling seizures, Journal of Clinical Medicine, N April, pp 47-52 Nguyễn Thị Thanh Bình, Lê Văn Thính (2019), Clinical characteristics and some related factors to seizure activity during pregnancy of epileptic women, Viet Nam Medical Journal, volume 483, pp 44-48 1 Necessity of the subject Epilepsy is a common disease with abundant clinical manifestations and greatly effects on the quality of patient’s life It is necessary to have a special monitoring and treatment in epileptic women of childbearing age The risks during pregnancy as well as the antiepileptic drug treatment’s harm on the fetus and child at birth are interesting topics for clinicians The risk of obstetric complications and congenital malformations is higher in the group of epileptic women who use antiepileptic drugs Pre-pregnancy counseling has been recognized to have a positive effect on controlling pre-pregnancy seizure activities thereby reducing the risks during pregnancy for both the mother and the fetus; giving each patient a safe pregnancy In Vietnam, there are not many studies on this issue Therefore, the subject has a practical and scientific quality New contributions of the thesis The results show clinical characteristics, drugs treatment, obstetric outcomes; magnetic resonance imaging of brain and electroencephalogram of epileptic-pregnant women This study also insist on the role of prenatal counseling in reducing maternal-fetal complications as well as seizure enhancement during the pregnancy The absence of seizures for at least year prior to pregnancy is an independent prognostic factor for the occurrence of enhanced seizures during pregnancy Seizure-free during pregnancy and birth weight are two independent factors associated with the decision to have a cesarean delivery The study contributes to clinicians some experiences in the management of epileptic women at reproductive age, especially in drug selection; preconception-counseling; followup in pregnancy and postpartum period Aim of the study Describe the clinical and para-clinical characteristics of epileptic women in two groups who were consulted and not consulted in preconception and pregnancy Evaluate some factors related to seizure activity and pregnancy outcomes of epileptic women Content of the study: Thesis consists of 125 pages; Introduction pages; Chapter 1: Literature review 43 pages; Chapter 2: Research objects and method 13 pages; Chapter 3: Results 24 pages; Chapter 4: Discussion 42 pages; Recomendation page This thesis had 32 tables, charts, 24 images, 155 references Chapter 1: LITERATURE REVIEW 1.1 Epilepsy and epilepsy diagnosis in pregnant women An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain Epilepsy is a disease characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition Epilepsy: according to the International League Against Epilepsy (ILAE) in 2014, a person is considered to have epilepsy if they meet any of the following conditions: (1)At least two unprovoked (or reflex) seizures occurring greater than 24 hours apart (2)One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years (3)Diagnosis of an epilepsy syndrome (Epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but are now past the applicable age or those who have remained seizure-free for the last 10 years, with no seizure medicines for the last years) Classification of epileptic seizure: Seizures are clinically classified according to the ILAE‘s Classification of Seizures in 1981 and revised edition in 2017 Essentially, there are three types of epileptic seizure: focal, generalized and unknown Epilepsy includes focal, generalized, combined generalized and focal and unknown epilepsy Causes of epilepsy: Based on the ILAE’s classification in 2017, the etiology of epilepsy is divided into six causes: structural, genetics, immune, metabolics, infectious and unknown 1.2 Additional testing in epilepsy diagnosis of pregnant women Additional testing used in epilepsy diagnosis of pregnant women include electroencephalography (EEG) and magnetic resonance imaging (MRI) The majority of pregnant women with epilepsy had been diagnosed and treated their epilepsy before pregnancy, so the tests were not different from other epileptic patients According to the "Guidelines for Diagnostic Imaging in Pregnancy and Lactation" of the American College of Obstetricians and Gynecologists (ACOG) in 2017, MRI ≤ Tesla in head and neck is safe for pregnant women and fetuses, therefore MRI is preferred for detection epileptic causes in pregnant patients who have seizures in pregnancy [25] 1.3 Studies on epilepsy in pregnant women Women with epilepsy are at increased risk for a range of medical comorbidities, life-threatening complications of pregnancy and seizure-related complications compared with the general population Several studies have found that perinatal complications including preeclampsia, premature delivery, hemorrhage, fetal growth restriction, stillbirth are 1.1-1.5 fold higher in pregnant women with epilepsy and a dramatically increased risk of maternal mortality (approximately 10-fold higher) [32],[33],[34],[35] The frequency of seizures in most women with epilepsy does not increase during pregnancy However, insomnia or non-compliance to treatment as well as changes in the pharmacokinetics of antiepileptic drugs during pregnancy also contribute to change seizure activity during pregnancy [46],[47] There is an increased risk of birth defects in the fetus when the mother uses antiepileptic drugs during pregnancy (the incidence of malformations is 4-6% compared to this rate of the general population is only 2-3%) The most common congenital malformations associated with antiepileptic drugs are neural tube, congenital heart, urinary tract defects, skeletal abnormalities and oral clefts [3],[41],[48],[49],[50],[51],[52],[54] Valproate is associated with the highest risk of major congenital malformations, while phenobarbital and topiramate are associated with an intermediate risk, and lamotrigine and levetiracetam are associated with the lowest Valproate is the most strongly associated with adverse neurodevelopmental outcomes Phenytoin, primidone and phenobarbital exposures with impaired cognitive performance later in life In contrast, carbamazepine, lamotrigine and levetiracetam are associated with a low or no risk of adverse neurobehavioral or cognitive outcomes [3],[4],[64] 1.4 Management for epileptic women at childbearing age during preconception, pregnancy and the postpartum period Women with epilepsy are more likely to have a higher risks of complications during pregnancy compared with the general population Therefore, it is necessary to manage of epilepsy during preconception, pregnancy and the postpartum period 1.4.1 Pre-pregnancy management Counseling all epileptic women of childbearing age include information about birth control, the potential of antiseizure drugs to cause contraceptive failure, the risks of antiepileptic drugs on pregnancy outcomes, possible changes needed to optimize the drug regimen, and the importance of early folic acid supplementation to prevent neural tube defects Lamotrigine or levetiracetam is the first choice for women with epilepsy of childbearing age who have a plan for pregnancy Valproate should not be used if the seizure is controlled by other drugs [3] 1.4.2 Management during pregnancy and delivery Antiseizure drugs using and dose adjustment: Pregnancy is accompanied by many alterations in drug metabolism, therefore drug level may decrease in plasma leading to deteriorate seizures Some drugs are required to close monitoring: levetiracetam, lamotrigine, oxcarbazepine, phenytoin, phenobarbital, topiramate and zonisamide If the drug levels are not available, a 2019 report from the International League Against Epilepsy (ILAE) notes that it is reasonable to increase the dose after the first trimester for epileptic women when the following conditions apply: (1)The treatment involves antiepleptic drugs that are prone to marked changes in clearance (lamotrigine, levetiracetam, and oxcarbazepine) with pregnancy (2)The seizures include focal to bilateral or generalized tonic-clonic seizures (3)The seizure control was sensitive to changes in drug levels before pregnancy (4)The patient entered pregnancy on the lowest effective anti seizure medication dose [3] Screening methods for congenital malformations are measurement of the serum alpha-fetoprotein (AFP) concentration and fetal ultrasound [119],[120] To prevent the risk of serious bleeding in the newborn, vitamin K is required at oral dose 10-20 mg/day during the last month of pregnancy for women taking polytherapy or enzyme inducers (phenobarbital, phenytoin and carbamazepine), patients at risk of preterm delivery and alcoholic patients [3],[109] Management at delivery: Cesarean delivery should be applied to patient who have multiple seizures during in the trimester of pregnancy or have a severe status epilepticus in the past [3] When convulsions occur during labor and delivery, prompt administration of intravenous benzodiazepines, monitor continuously the fetal heart rate during the seizure as well as for at least hour after the seizure occurs [36] 1.4.3 Management of the postpartum period in epileptic women It is necessary to re-administer the pre-pregnancy dose within the first few weeks after delivery, prevent of seizure worsening due to sleep deprivation, have safety precautions with the newborn and breastfeeding Most experts believe that women taking antiepileptic drugs have no contraindications to breastfeeding [3],[121] Chapter 2: RESEARCH OBJECTS AND METHOD 2.1 Research subject There were 92 epileptic women with 97 pregnancies who had visited to the Department of Neurology at Bach Mai Hospital in period from October 2015 to October 2020 2.1.1 Patient selection criteria Female patients who were diagnosed with epilepsy before pregnancy as well as were pregnant Patients and their family had agreed to participate in the study Diagnostic criteria for epilepsy: Based on the ILAE’s classification of seizures in 1981 and revised edition in 2017 Diagnosis criteria for pregnancy: Based on blood tests, urinalysis and obstetric ultrasound Blood test: the earliest time to take blood is 6-8 days after conception, the patient is pregnant if the result of hCG concentration in blood more than 25 mIU/ml Urine test: to detect the presence of hCG hormone, tested weeks after the patient's last period, with an accuracy of 97% Obstetric ultrasound: can detect pregnancy in the uterus (at least 7-10 days after late period) 2.1.2 Elimination criteria: Patients had a systemic medical conditions such as thyroid disease, cancer, autoimmune diseases, etc 2.2 Research method 2.2.1 Research design It is a descriptive study and follow-up a cluster of cases Patients were divided into groups: Group 1: Epileptic patients had a pre-pregnancy counseling and management during pregnancy (consulted group) Group 2: Epileptic patients visited to neurologist after becoming pregnant (non-consulted group) 2.2.2 Research procedure All patient informations were collected with a research medical record form Patients in group (consulted group) were examined and collected at least twice in pre-pregnancy, times during pregnancy and once after delivery Patients in group (non-consulted group) were examined and collected at least once during pregnancy and once after delivery Data was imported and processed by using SPSS Statistic 23 software 2.3 Procedure of the management in preconception, pregnancydelivery and postpartum period Procedure for pre-pregnancy counseling − Consultation time: patients in childbearing age intend to become pregnant, patients visit to Neurological Clinic at least months before conception − Number of visits: at least once per months − Content of consultation and examination: based on recommendations of the ILAE for management of epilepsy in preconception: birth control, potential of antiseizure medications to cause contraceptive failure; preconception planning; optimize the drug regimen; seizure activity; early folic acid supplementation Procedure for monitoring during pregnancy-delivery - Number of visits: At least once per trimester during pregnancy, arranged suitable with the schedule of the obstetrician as well as ensuring the patient’s convenience - Content of consultation and examination: Folic acid supplementation; controlling and adjusting antiepileptic drugs, detection of hyper-activity of seizure; screening for fetus malformations; collaboration between the obstetrician and neurologist as a multidisciplinary team to manage childbirth Procedure for postpartum period 11 premature birth (33.3%) and abortion (33.3%) were most common The average of birth weight in the consulted group was 0.16 kg heavier compared to non-consulted group (t=2,005, T-test; p=0.047) 3.1.2 Para-clinical characteristics Multiple-lesions were most common (13.04 %), the CNS inflammatory sequelae was 12.37%, focal cortical dysplasia was 2.05% and hippocampal atrophy was 1.03% The percentage of patients having abnormal EEG was 32% Slow waves on both hemipheres were most common (20/31), the rate of epiletic discharges at non-attacks group was 5/31 The rate of abnormal EEG was 1.95 fold higher in group compared to group (RR=1.95; 95% CI=1.05-2.05; p=0.038) (Table 3.15) Table 3.15 Distribution of abnormal EEG and MRI Group Group OR (95% CI) No 32 34 Yes 11 20 No Yes 34 32 22 1.71 (0.714.13) 2.6 (1.04-6.5) Variable Abnorrmal MRI Abnormal EEG RR (95% CI) p 1.37 _ (0.8-2.34) 0.229 , 95 (1.05-2.05) 0.038 3.2.Factors related to seizure activity in pregnancy and pregnancy outcomes 3.2.1 Factors associated with seizure activity during pregnancy In the active-seizure group in pregnancy, the rate of patiens having active seizures in pre-pregnancy was 3,1 fold higher (p=0.001); non-preconception counseling was 1,75 fold higher (p=0.001); having polytherapy was 1,39 fold higher (p=0.022); noncompliance was 1,41 fold higher (p=0.03); abnormal EEG was 1,55 12 fold higher (p=0.003) and abnormal MRI was 1,36 fold higher (p=0,037) compared to non-active seizure group during pregnancy Patient having seizure free for at least year before the preconception was an independent factor affecting the occurrence of seizures in pregnancy (Table 3.22) Table 3.22 Binary Logistic Regression Analysis of free seizure in pregnancy Factor Preconception counseling Polytherapy Drug compliance Abnormal EEG Number of attacks per month in pre-pregnancy Seizure free for year OR 2.05 1.11 0.66 3.59 95% CI 0.62-6.86 0.31-3.94 0.12-3.79 0.71-18.13 P 0.24 0.87 0.66 0.121 1.44 0.5-4.12 0.501 8.68 1.15-65.23 0.036 In the enhanced-seizure group in pregnancy, the rate of patiens having non- preconception counseling was 2,48 fold higher (p=0.02); having focal epilepsy was 1,26 fold higher (p=0.007); having polytherapy was 1,72 fold higher (p=0,036); non-compliance was 1,96 fold higher (p=0.009); abnormal EEG was 2,02 fold higher (p=0.006) and abnormal MRI was 1,36 fold higher (p=0,037) compared to non-enhanced seizure group during pregnancy Preconception counseling was an independent factor affecting the intensification of seizures in pregnancy (table 3.23) Table 3.23 Binary Logistic Regression Analysis of enhanced seirures in pregnancy Factor Polytherapy Drug compliance Focal epilepsy Abnormal EEG Preconception counseling OR 0.71 1.44 0.46 1.85 2.86 95% CI 0.27-1.89 0.45-4.61 0.18-1.17 0.61-5.61 1.02-8.05 P 0.49 0.54 0.101 0.28 0.046 13 Number of seizures/month in prepregnancy 0.98 0.65-1.48 0.94 3.2.2 Factors influence on pregnancy outcomes In the group having maternal-fetal events, the frequency of seizures during pregnancy was significantly higher than in non-event group (p=0,005) Results showed that: The rate of patients having enhanced seizures during pregnancy in this group was 2,06 fold (p=0.092); non-preconception counseling was 6,37 fold higher (p=0.002); non-compliance was 2,88 fold higher (p=0.009) compared to the non- event group Preception counseling was an independent factor affecting the maternal-fetal events (OR=6.07; CI 95%=1.21-30.31; p= 0,028) (table 3.25) Table 3.25 Binary Logistic Regression Analysis of maternal-fetal events Factor OR 95%CI P Drug compliance Pre-pregnancy counseling Enhanced seizure in pregnancy Average of seizures per month 2.23 6.07 1.12 0.69-7.19 1.21-30.31 0.25-5.15 0.18 0.028 0.881 1.08 0.68-17.1 0.749 The cesarean delivery group had the average of seizures per month and the average of birth weight significant higher than the vaginal delivery group (p=0,021 and p=0,005 respectively) The rate of patients having tonic-clonic seizures in this group was 1,49 fold higher (p=0,009); having enhanced seizures during pregnancy was 1,47 fold higher (p=0.008) compared to the vaginal delivery group 14 Seizure-free during pregnancy and birth weight were two independent factors related to mother's decision having a cesarean delivery (table 3.27) Table 3.27 Binary Logistic Regression Analysis of cesarean delivery decision Odds Ratio Factor 95% CI P (OR) Seizure free in 5.21 1.78-15.2 0.003 pregnancy Birth weight 6.98 1.52-31.94 0.012 Chapter : DISCUSSION 4.1 Clinical and paraclinical characteristics 4.1.1 Clinical characteristics General characteristics Epileptic women often get married later than other women, therefore, the average age of epileptic women at first pregnancy is higher than the general population Most of patients in consulted group came to the neurological clinic in the first trimester, in contrast, non-consulted patients visited to neurologist when they had a deterioration of seizures during pregnancy Folic acid supplementation was widely recommended in preconception and during pregnancy to reduce the risk of fetal spinal defects The rate of patients using folic acid at least months in preconception of the counseling group (65.1%) was 2.07 times higher than unconsulted group (p=0.002 ) Characteristics of seizure activity and seizure control in prepregnancy Features of seizure’s activity in preconception 15 The percentage of patients having less than attacks per month was in a range 70-76%, result in this study was similar (total group 70.1%, 79.1% in group and 62.9% in group 2) Consulted group had a seizure activity in preconception more stable than nonconsulted group: The rate of patients having a seizure-free at least year was higher; the average of seizures per month in pre-pregnancy was significantly lower in group than group Features of using antiepileptic drugs in preconception Pre-pregnancy drug discontinuation and risk of relapse Group had 04 patients who did not take medication before pregnancy as well as seizure-free for at least years and all of these patients had recurrent seizures during pregnancy The counseling group included 15 patients who had seizure-free for more than years, but none of them stopped using drugs Retrospective study shown that one-third of recurrent seizures occur within 6-12 months of drug discontinuation, so that epileptic patients with stable seizures who want to conceive and stop taking the antiepileptic drug in pregnancy need to accept these risks Use of antiepileptic drugs in pre- pregnancy A three-quarters of patients had a monotherapy as well as an drug compliance, this result reflected the progress in epilepsy treatment, which was a reduction of polytherapy, an optimization in drug selection to minimize medication side effects for patients and fetus [3] 4.1.2 Characteristics in pregnancy A Characteristics of seizure activity in pregnancy Almost two-thirds of patients had generalized seizures, moreover the percentage of tonic-clonic seizures (including generalized and partial-onset seizures) was 78.35% The distribution of epilepsy types was inconsistent, the rate of generalized seizures 16 was in a range 60-80% and focal seizure was limited in 30-72 %) as well as the rate of generalized seizure in low-income countries’ studies was higher than high-income countries 17 Features of seizure activity in pregnancy Most patients with an average seizure monthly less than attacks in preconception had milder seizures during pregnancy The rate of recurrent seizure during pregnancy in group having free seizure for months was 25% and this rate was 10-20% in group having seizure-free at least year during the preconception Similar results has been shown in this study Seizure-free for at least year before pregnancy was a guarantee for a safe pregnancy Seizure activity during pregnancy in consulted group had more stable than non-consulted group: the rate of patients having seizurefree, having non-enhanced seizure in group was significant higher; average of seizures per month was lower than group Furthermore, majority of consulted patients had seizures with shorter duration as well as a commitment to maintain their medication regimen and a reasonable lifestyle according to their doctor’s advice Data from multi-center studies have shown that the rate of patients having free seizure and having enhanced seizures during pregnancy was in a range 29-45% and 20-50%, respectively Recently, the rate of patients having stable seizures and having enhanced seizures during pregnancy in cohort studies was over than 67% and less than 20%, respectively These progressive results were from the collaboration as a multidisciplinary team to manage preconception, pregnancy and delivery effectively One point of consensus among studies: counseling in preconception as well as management in pregnancy for epileptic patient appropriately made a positive impact on seizure control B Characteristics of drug use in epileptic women during pregnancy Antiepileptic drug adjustment and compliance The percentage of patients having a drug adjustment in consulted group was 34.9%, contributed by patients with increased seizure activity; still having generalized tonic-clonic seizures