Three Cases of Unprovoked Venous Thromboembolism with Prothrombin p.Arg596Gln Variant and a Literature Review of Antithrombin Resistance.

Antithrombin resistance (ATR) is a newly identified strong genetic predisposition to venous thromboembolism (VTE) caused by genetic variations in prothrombin with substitutions of Arg at position 596 with either Leu, Gln, or Trp. In the present report, we identified a missense variant p.Arg596Gln in 3 patients from 2 families with unprovoked VTE who each experienced their first VTE event at 19, 67, and 19 years old. The three patients did not show any positive markers for thrombophilia on routine testing, suggesting that patients with unprovoked VTE who have negative findings on thrombophilia tests may carry a prothrombin variant with ATR.

Evaluation of the clinical performance of noninvasive prenatal testing at a Japanese laboratory.

AIM: We aimed to evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of noninvasive prenatal testing (NIPT) in high-risk pregnant women. METHODS: Pregnant women who underwent GeneTech NIPT, the most commonly used NIPT in Japan, between January 2015 and March 2019, at Japan NIPT Consortium medical sites were recruited for this study. The exclusion criteria were as follows: pregnant women with missing survey items, multiple pregnancy/vanishing twins, chromosomal abnormalities in the fetus other than the NIPT target disease, and nonreportable NIPT results. Sensitivity and specificity were calculated from the obtained data, and maternal age-specific PPV and NPV were estimated. RESULTS: Of the 45 504 cases, 44 263 cases fulfilling the study criteria were included. The mean maternal age and gestational weeks at the time of procedure were 38.5 years and 13.1 weeks, respectively. Sensitivities were 99.78% (95% confidence interval [95% CI]: 98.78-99.96), 99.12% (95% CI: 96.83-99.76), and 100% (95% CI: 88.30-100) for trisomies 21, 18, and 13, respectively. Specificities were more than 99.9% for trisomies 21, 18, and 13, respectively. Maternal age-specific PPVs were more than 93%, 77%, and 43% at the age of 35 years for trisomies 21, 18, and 13, respectively. CONCLUSION: The GeneTech NIPT data showed high sensitivity and specificity in the detection of fetal trisomies 21, 18, and 13 in high-risk pregnant women, and maternal age-specific PPVs were obtained. These results could provide more accurate and improved information regarding NIPT for genetic counseling in Japan.

Clinical guidance for peripartum management of patients with hereditary thrombophilia.

Hereditary thrombophilia is a condition in which individuals are susceptible to the formation of thrombi due to a hereditary deficiency in anticoagulant factors, antithrombin (AT), protein C (PC), or protein S (PS). Many Japanese thrombophilia patients have PS deficiency, especially PS p.K196E (also called as PS Tokushima), which is exclusive to the Japanese population, and thrombosis sometimes occurs during pregnancy. At present, no management guidelines for pregnancy and delivery in thrombophilia patients have been developed. The Study Group for Hereditary Thrombophilia, one of the research groups of blood coagulation abnormalities in the Research Program on Rare and Intractable Diseases supported with the Research Grants of the Ministry of Health, Labour and Welfare Science, has therefore developed this clinical guidance to provide healthcare workers with necessary information on safe pregnancy, parturition and neonatal management, adopting a format of responses to seven clinical questions (CQ). At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated.

Stroke during pregnancy and puerperium among Japanese women: a single-center registry.

BACKGROUND: Stroke is one of the major causes of maternal death. This study aimed to analyze the maternal and fetal outcomes of stroke occurred during pregnancy and puerperium. METHODS: We conducted a retrospective analysis of patients admitted to our perinatology center between 1982 and 2012 with a diagnosis of acute cerebral stroke during pregnancy or within 6 weeks postpartum. RESULTS: Thirty-four patients were registered and all the patients had never been diagnosed as stroke nor detected cerebrovascular abnormalities before the current pregnancies. They were divided into 8 ischemic strokes (ISs) and 26 intracranial hemorrhage group. In the hemorrhage group, there was a spontaneous abortion and two patients chose artificial abortions to avoid rehemorrhage, and there were another three intrauterine fetal deaths (IUFDs) in the acute stage of maternal stroke. More patients in hemorrhage group delivered in preterm than in IS group for the treatment of stroke, 10/23 (43%) versus 0/8 (0%), p < .05. More patients in hemorrhage group had low Glasgow Coma Scale (GCS) (3-8) than in IS group at the onset of the stroke, 12/26 (46%) versus 0/8 (0%), p < .05. There were three maternal deaths and 6/23 (26%) were neurologically dependent in hemorrhage group in the chronic stage, whereas 87% were independent in IS group, p < .05. CONCLUSIONS: Hemorrhagic stroke was more common etiology of stroke related to pregnancy than IS in this study. Intensive and multidisciplinary care was needed especially in hemorrhagic stroke related to pregnancy as in the hemorrhagic stroke the fetal survival rate was lower, and maternal conscious levels at the onset of the stroke and neurological outcomes in the chronic stage were worse than IS.

A less-intensive anticoagulation protocol of therapeutic unfractionated heparin administration for pregnant patients.

Heparin anticoagulant therapy for thromboembolic disorders during pregnancy is problematic due to unexpected adverse bleeding. To avoid bleeding, we have used a less-intensive anticoagulation protocol of unfractionated heparin (UFH). The protocol had a therapeutic activated partial thromboplastin time (APTT) ratio of 1.5-2.0 with the control value, a UFH dose of ≤ 30,000 U/day, and an antithrombin (AT) activity target of ≥ 70%. In the present study, we evaluated this protocol using an anti-Xa assay. We collected UFH-treated plasma samples from ten consecutive pregnant Japanese patients with current or previous thromboembolic disorders. Seven patients remained in the therapeutic APTT ratio range (heparin-sensitive [HS] group). The other three patients had difficulty remaining within the therapeutic range (heparin-resistant [HR] group). In the HR group, two had AT deficiency and one had congenital absence of the inferior vena cava. Of the HS and HR samples, 73% and 31%, respectively, were within the therapeutic anti-Xa activity range 0.3-0.7 U/mL, indicating difficulty for the HR group to remain within the therapeutic range. Neither major bleeding nor symptomatic thromboembolic episodes occurred in either group. These findings suggest that the less-intensive anticoagulation protocol is permissive and may be beneficial in the HS group.

Predicting postpartum cardiac events in pregnant women with complete atrioventricular block.

BACKGROUND: Women with complete atrioventricular block (CAVB) can tolerate hemodynamic changes during pregnancy; however, the incidence of cardiac events in women with CAVB may increase after delivery. The aim of this study was to investigate predictive factors for postpartum cardiac events in pregnant women with CAVB. METHODS AND RESULTS: Pregnant women with CAVB who received perinatal management at a tertiary cardiac center from 1981 to 2015 were retrospectively reviewed. Univariate and multivariate logistic analyses of postpartum cardiac events were performed. Postpartum cardiac event was defined as cardiopulmonary arrest, cardiac failure, or the need for permanent pacemaker implantation (p-PMI) within 3 months after delivery. A total of 63 pregnancies in 36 women with CAVB were included in this study; 25 had undergone p-PMI before pregnancy. Regardless of p-PMI status, women with CAVB had no further increases in heart rate during the second and third trimesters. No heart failure was found during pregnancy and delivery. Postpartum cardiac events occurred in 9 pregnancies (14.3%) in 8 women with CAVB; 3 had cardiac failure and p-PMI, 3 had cardiac failure, 2 required p-PMI, and 1 had cardiopulmonary arrest. Multivariate analysis showed that perinatal ventricular pause (odds ratio 11.60, 95% confidence interval 1.90-82.18, p<0.01) and family history of CAVB (odds ratio 10.59, 95% confidence interval 1.36-90.56, p=0.03) were associated with postpartum cardiac events. CONCLUSIONS: All cardiac events occurred during the postpartum period among women with CAVB, and ventricular pause during the perinatal period and a family history of CAVB were predictors of postpartum cardiac events. Close follow-up should be considered during the postpartum period for women with high-risk CAVB.

Cardiovascular profile and biophysical profile scores predict short-term prognosis in infants with congenital heart defect.

AIM: To predict the prognosis of infants with congenital heart disease, accurate prenatal diagnosis of structural abnormality and heart failure are both necessary. The aim of this study was to investigate whether cardiovascular profile (CVP) and biophysical profile (BP) scores are useful for predicting prognosis in infants with congenital heart defect (CHD). METHODS: A retrospective review of singletons prenatally diagnosed with CHD at a tertiary pediatric cardiac center between 2011 and 2015 was undertaken. RESULTS: A total of 202 patients with CHD were analyzed. Perinatal and infant deaths occurred in 16 (7.9%) and 10 cases (5.0%), respectively. Infants with the last CVP score ≤ 5 had 18.7-fold higher perinatal mortality than those with a last CVP score > 5 (P < 0.01). Infants with a last BP score ≤ 6 had 18.7-fold higher perinatal mortality than those with a last BP score > 6 (P < 0.01). Infants with a CVP score decrease in utero had 4.5-fold higher infant mortality than those with an increase or no change (P < 0.01). Multivariate analysis showed that single-ventricle physiology, pre-term birth at <37 weeks of gestation, last CVP score ≤ 5, and last BP score ≤ 6 were independent predictors of perinatal mortality. Single-ventricle physiology and a CVP score decrease were independent predictors of infant mortality. CONCLUSION: CVP and BP scores are useful for predicting perinatal prognosis in infants with CHD. A CVP score decrease in utero is associated with infant mortality, suggesting that serial CVP score assessment may be useful for management planning.

Recurrent Congenital Heart Diseases Among Neonates Born to Mothers with Congenital Heart Diseases.

The frequency of newborns with congenital heart disease (CHD) is approximately 1% in the general population; however, the recurrence rate of CHD in mothers with CHD differs in ethnicity and reports. We therefore aimed to determine the prevalence of CHD among neonates born to mothers with CHD in our institute in Japan. We reviewed the medical charts of 803 neonates delivered by 529 women with CHD at the National Cerebral and Cardiovascular Center from 1982 to 2016. They included isolated ventricular septal defect (VSD,31.4%), isolated atrial septal defect (ASD, 23.3%), tetralogy of Fallot (TOF,10.6%). We defined CHD in neonates as being diagnosed within 1 month of birth. We estimated that the average rate of the CHD recurrence was 3.1%. The recurrence ratios in each maternal CHD were 8.6%, 7.1%, 6.2%, 4.8%, 3.6%, and 1.5% for PS, CoA, TOF, atrioventricular septal defect, VSD, and ASD, respectively. The rate of CHD in offsprings whose mothers have CHD was 3 times greater than that of mothers with healthy hearts. Almost half of neonates with CHD had the same phenotype as their mother in our series. Especially, PS and CoA were closely related to the type of maternal CHD.

Maternal and fetal outcomes in pregnancy complicated with Eisenmenger syndrome.

OBJECTIVE: The goal of the study was to clarify the risk factors for pregnancy complicated with Eisenmenger syndrome (ES). MATERIALS AND METHODS: A retrospective study was performed in 15 patients with ES who were managed throughout pregnancy at one institution from 1982 to 2013. Cases associated with congenital heart diseases other than atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus (PDA) were excluded. RESULTS: The congenital heart diseases in ES included ASD (n = 3), VSD (n = 9), and PDA (n = 3). Ten women chose termination and 5 continued with their pregnancies. In the 5 continuation cases (PDA 1, VSD 4), worsening of cyanosis, exertional fatigue and dyspnea appeared between 25 and 30 weeks gestation and cesarean section was performed at 30 (28-33) weeks. LVEF, PaO2, and SpO2 decreased and heart rate increased significantly from before pregnancy to 25-30 weeks gestation. From before to during the pregnancy, there were no significant changes in mean PABP or pulmonary vascular resistance (PVR) in four cases with data (582-592, 885 to 868, 1280 to 1291, 1476-1522 dyn × s/cm2). PVR at conception had a negative relationship with delivery weeks. NYHA classes before, during and 1 year after pregnancy were II, III and II. In one recent case, epoprostenol and tadalafil were administered during pregnancy. CONCLUSIONS: Pregnancy with ES has a high risk due to hypooxygenation, cyanosis, and cardiac failure, which can appear as common complications as early as the 2nd trimester. Early interventions with meticulous care are required for these complications during pregnancy and delivery.

Prediction of postnatal arrhythmia in fetuses with cardiac rhabdomyoma.

OBJECTIVES: Fetal cardiac rhabdomyomas are rare but well-known to be associated with arrhythmia or conduction abnormalities. However, since in utero electrophysiological information is quite limited, it remains unclear which type of rhabdomyoma will develop arrhythmia after birth. The aim of this study is to identify factors that predict postnatal arrhythmia requiring therapy in fetuses with cardiac rhabdomyoma. STUDY DESIGN: A retrospective review of infants prenatally diagnosed with cardiac rhabdomyoma was performed at our tertiary pediatric cardiac center between 1990 and 2016. Fetal arrhythmia was diagnosed using fetal echocardiography and magnetocardiography. We compared the characteristics of cases with and without antiarrhythmic therapy after birth. Cases without antiarrhythmic therapy after birth consisted of those who had postnatal arrhythmia but did not require antiarrhythmic therapy and those who had no postnatal arrhythmia. RESULTS: A total of 20 fetuses with cardiac rhabdomyoma were included in this study. Ten cases (50%) were confirmed as having tuberous sclerosis after birth. The mean gestational week at diagnosis and delivery were 32.1 ± 2.7 and 37.6 ± 2.8 weeks, respectively. Mean cardiac tumor size in utero was 21 ± 11 mm (range, 7-54 mm) in diameter. Fetal arrhythmia was found in six cases; three resolved in utero with transplacental antiarrhythmic therapy. Postnatal arrhythmia or conduction abnormalities were found in 12 cases; 7 required antiarrhythmic therapy. Cases with antiarrhythmic therapy after birth had larger cardiac tumor in utero than those without therapy (29.6 ± 12.8 mm versus 16.3 ± 5.8 mm, p < .01). Cardiac tumor size >30 mm in diameter predicted postnatal arrhythmia requiring therapy with sensitivity of 57.1% and specificity of 100%. Location and number of cardiac tumor and presence of arrhythmia or conduction abnormalities in utero were similar between the two groups. CONCLUSIONS: Cardiac rhabdomyomas >30 mm in diameter are associated with postnatal arrhythmia requiring therapy regardless of number and location.

Safety and efficacy of a 52-mg levonorgestrel-releasing intrauterine system in women with cardiovascular disease.

AIM: We sought to examine the safety and efficacy of a 52-mg levonorgestrel-releasing intrauterine system (LNG-IUS), and to evaluate the changes in biomarkers of infection, anemia and cardiovascular conditions after LNG-IUS insertion in women with cardiovascular disease. METHODS: We prospectively followed women with a cardiovascular disease in whom a 52-mg LNG-IUS was inserted between 2009 and 2015. The primary outcome was the frequency of cardiovascular and gynecologic side effects due to the LNG-IUS over the year after LNG-IUS insertion. The secondary outcomes were the changes in menstrual blood loss and biomarkers, e.g., white blood cell count and the levels of C-reactive protein, hemoglobin and brain natriuretic peptide. We also evaluated the 24-month continuation rate of LNG-IUS. RESULTS: A total of 34 women were prospectively followed-up, including two women with pulmonary hypertension. No cardiovascular side effects were identified during the 1 year after LNG-IUS insertion, other than one case of mild vasovagal reaction at insertion. Neither the white blood cell count nor the C-reactive protein value increased after LNG-IUS insertion. The menstrual blood loss was decreased in most subjects and the median hemoglobin levels increased significantly within 1 year after insertion (P < 0.001 and P = 0.002). Moreover, brain natriuretic peptide levels tended to decrease in correspondence with the hemoglobin elevation (P = 0.074). The 24-month LNG-IUS continuation rate was 97% (95% confidence interval 85-100). CONCLUSION: No clinically significant cardiovascular event was identified during the 1 year after 52-mg LNG-IUS insertion among women with cardiovascular disease. The 52-mg LNG-IUS may have specific favorable effects by decreasing the risk of iron deficiency anemia in these women.

Classification of factors involved in nonreportable results of noninvasive prenatal testing (NIPT) and prediction of success rate of second NIPT.

OBJECTIVE: To evaluate the reasons for nonreportable cell-free DNA (cfDNA) results in noninvasive prenatal testing (NIPT), we retrospectively studied maternal characteristics and other details associated with the results. METHODS: A multicenter retrospective cohort study in pregnant women undergoing NIPT by massively parallel sequencing (MPS) with failed cfDNA tests was performed between April 2013 and March 2017. The women's data and MPS results were analyzed in terms of maternal characteristics, test performance, fetal fraction (FF), z scores, anticoagulation therapy, and other details of the nonreportable cases. RESULTS: Overall, 110 (0.32%) of 34 626 pregnant women had nonreportable cfDNA test results after an initial blood sampling; 22 (20.0%) cases had a low FF (<4%), and 18 (16.4%) cases including those with a maternal malignancy, were found to have altered genomic profile. Approximately half of the cases with nonreportable results had borderline z score. Among the women with nonreportable results because of altered genomic profile, the success rate of retesting using a second blood sampling was relatively low (25.0%-33.3%). Thirteen (11.8%) of the women with nonreportable results had required hypodermic heparin injection. CONCLUSIONS: The classification of nonreportable results using cfDNA analysis is important to provide women with precise information and to reduce anxiety during pregnancy.

Pregnancy outcomes and mid-term prognosis in women after arterial switch operation for dextro-transposition of the great arteries - Tertiary hospital experiences and review of literature.

OBJECTIVE: Arterial switch operation (ASO) for dextro-transposition of the great arteries (d-TGA) has gradually replaced the atrial switch operation and has become the standard operation. To date, the outcomes of pregnant women with d-TGA after this new operation have not been investigated. In this study, we investigated the impact of ASO on pregnant outcomes and mid-term prognosis in women with d-TGA and compared with the atrial switch operation through the literature review. METHODS AND RESULTS: There were 20 pregnancies in 10 women with d-TGA after ASO and 6 resulted in abortion. Among 14 successful pregnancies in 10 women, 11 pregnancies achieved the term delivery and 3 pregnancies, including 1 twin pregnancy, resulted in preterm labor. Maternal cardiovascular events occurred in 4 (heart failure and arrhythmias in 3 and arrhythmia in 1), and all were controllable with medications. Risk factors for the peripartum cardiac events were older age at ASO and delivery, and higher concentration of brain natriuretic peptide (BNP) at first trimester (p<0.05). In 7-60 month-follow-up after delivery, no case showed deterioration of functional class and systemic ventricular function. According to the literature review, women after ASO demonstrated a better prognosis than those after the atrial switch operation. CONCLUSIONS: The majority of women with d-TGA after ASO tolerated pregnancy and delivery well. The older age at ASO, an elderly pregnancy, and higher BNP levels at the first trimester were possibly risk factors of peripartum cardiovascular events among the group. The literature reviews and this study may indicate the advantage of systemic left ventricle compared with systemic right ventricle in long-term outcomes after delivery.

Cardiomyopathy Phenotypes and Pregnancy Outcomes with Left Ventricular Noncompaction Cardiomyopathy.

Little is known about pregnancies of left ventricular noncompaction cardiomyopathy (LVNC), much less cases in which LVNC was definitively diagnosed prepregnancy. We report the cases of three pregnant Japanese women definitively diagnosed with LVNC prepregnancy. Case 1 presented LVNC with restrictive phenotype. Her pregnancy was terminated due to exacerbated pulmonary hypertension and low output status at 30 weeks' gestation. Case 2 presented isolated LVNC with nonsustained ventricle tachycardia. A cesarean section was performed at 36 weeks' gestation because of placenta previa. Case 3 presented dilated LVNC. Labor induction was performed because of decreased left ventricular ejection fraction, leading to a vaginal delivery at 37 weeks' gestation. In all cases, no thromboembolic event was identified during pregnancy; two patients received anticoagulants. We reviewed all English-literature cases of pregnant women definitively diagnosed with LVNC prepregnancy to analyze causes of adverse pregnancy outcomes and the necessity of anticoagulation. Four of the six pregnancies identified were terminated due to exacerbated cardiomyopathy phenotypes and not complications due to noncompaction itself, resulting in three cases' preterm deliveries. No thromboembolic event was identified by maintenance of the anticoagulation strategy determined prepregnancy. In pregnancies with LVNC, the possibility of a severe cardiac event and the indications for termination of the pregnancy can depend on the cardiomyopathy phenotypes, not noncompaction itself. Anticoagulation only because of the pregnancy itself may be redundant. In the management of LVNC during pregnancy, close monitoring of the condition of different phenotypes and reassessment of the necessity of anticoagulation can contribute to the pregnancy outcome.

Fetal cell-free DNA fraction in maternal plasma for the prediction of hypertensive disorders of pregnancy.

OBJECTIVE: The purpose of this study is to compare the fetal fractions during non-invasive prenatal testing (NIPT) in singleton pregnancies according to gestational age and maternal characteristics to evaluate the utility of this parameter for the prediction of pregnancy complications including gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP). STUDY DESIGN: This study was a multicenter prospective cohort study. The present data were collected from women whose NIPT results were negative. The relationships between the fetal fractions and the gestational age, maternal weight and height, and incidences of miscarriage, preterm delivery, and pregnancy complications including GDM, HDP and placental abruption were assessed. RESULTS: A total of 5582 pregnant women with verified NIPT negative results were registered in the study. The demographic characteristics of the study populations were statistically analyzed, and the women with HDP tended to have a low fetal fraction in samples taken during early gestation. The area under the curve (AUC) in a receiver operating characteristic curve (ROC) analysis was 0.608 for women with HDP. CONCLUSION: A low fetal fraction on NIPT might be correlated with future HDP. However, predicting HDP during early pregnancy in women with a low fetal fraction might be difficult.

Utility of Fluid Assessment Based on the Intrathoracic Impedance Monitoring in a Peripartum Woman with Heart Disease.

Recently, implantable cardioverter-defibrillators (ICD) have become capable of monitoring intrathoracic impedance to detect an increased fluid volume and heart failure. Pregnancy is a well-known cause of an increased body fluid volume; however, it is not clear whether the measurement of intrathoracic impedance by ICD is clinically useful for precisely detecting heart failure in pregnant women. We herein report the case of a 39-year-old woman with an ICD that had been implanted after an event of ventricular fibrillation due to severe aortic regurgitation with a bicuspid aortic valve. Elevated right ventricular pressure and brain natriuretic peptide levels were detected at 37 weeks of gestation and postpartum. At the same time, the ICD's stored fluid index gradually increased and exceeded the threshold on the 10th day after delivery. She was treated with diuretics and recovered from postpartum heart failure. The physiological volume changed in the perinatal period, but we were still able to detect heart failure by ICD. Intrathoracic impedance monitoring is effective in the perinatal field.

Management of pregnancy complicated with intracranial arteriovenous malformation.

AIM: To clarify the perinatal outcomes in pregnancy complicated with intracranial arteriovenous malformation (i-AVM). METHODS: A retrospective study was performed in 36 pregnancies complicated by i-AVM from 1981 to 2013 at one institution. RESULTS: In total, 6 women miscarried, and 30 had live births. The median (range) gestational age at delivery was 38 (24-40) weeks; 11 cases experienced initial i-AVM rupture during pregnancy (first, second and third trimester: 18%, 64% and 18%, respectively). At onset, 4 cases had a Glasgow Coma Scale ≤10, 10 cases needed emergency maternal transport, 4 underwent neurosurgery with the fetus in utero and 4 had termination of pregnancy in the second trimester for emergent treatment for i-AVM. Two cases delivered vaginally. Another 25 cases had already been diagnosed as i-AVM at conception. Of these, as an indication for epidural birth, 18 cases had either residual lesion of i-AVM or neurological symptoms, although 18 cases had received treatments of i-AVM before conception. Without rupture of i-AVM and worsening of symptoms, 15 cases succeeded in epidural birth. One case was delivered by cesarean section for residual i-AVM with indication of treatment. Another case who had refused treatment of i-AVM experienced rupture of i-AVM 1 year after delivery. CONCLUSION: Most of the cases with residual i-AVM lesion and neurological symptoms could deliver vaginally without worsening of symptoms. However, pregnancy with i-AVM can be complicated by rupture of i-AVM. In cases with a residual lesion with indication of treatment and rupture of i-AVM during pregnancy, meticulous care is required during pregnancy and after delivery.