Publications by authors named "Jun Yoshimatsu"

103 Publications

Cardiovascular disease among pregnant women after anticancer therapy.

J Obstet Gynaecol Res 2021 Jul 4;47(7):2278-2290. Epub 2021 May 4.

Department of Obstetrics and Gynecology, National Cerebral and Cardiovascular Center, Osaka, Japan.

Recent advances in cancer therapies have enabled many women diagnosed with malignancies during childhood and adolescence to survive longer and therefore to reach an age where they wish to conceive. When providing cancer treatment such as anticancer drugs and radiotherapy, attention is often paid to preserving future fertility, but little is known about maternal pregnancy risks, and in particular cardiovascular complications. Recent studies have shown that cardiovascular diseases such as cardiomyopathy, heart failure, and arrhythmias often occur during and soon after anticancer therapy. This has led to the emergence of the specialized field of "onco-cardiology" or "cardio-oncology," in which oncologists and cardiologists collaborate, as well as the publication of multiple clinical practice guidelines. The interdisciplinary onco-cardiology team plays an important role in further improving the prognosis of cancer survivors. The current recommendation for women after anticancer therapy who wish to conceive is to undergo cardiovascular screening, regardless of whether there is a history of cardiovascular complications or not, in order to provide preconception counseling. Pregnancies in cancer-survivors, who experience cardiovascular complications, should be managed perinatally by a multidisciplinary team including obstetricians and cardiologists. Absence of cardiovascular disease on screening does not preclude the possibility that new cardiac dysfunction may occur during the perinatal period, especially in women with a history of high-dose anthracycline drug administration and/or radiation therapy. In such high-risk cases, follow-up of cardiac function throughout the perinatal period is required.
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http://dx.doi.org/10.1111/jog.14812DOI Listing
July 2021

Short-term prediction of preeclampsia using the sFlt-1/PlGF ratio: a subanalysis of pregnant Japanese women from the PROGNOSIS Asia study.

Hypertens Res 2021 Jul 17;44(7):813-821. Epub 2021 Mar 17.

Roche Diagnostics International Ltd, Rotkreuz, Switzerland.

Two prospective multicenter studies demonstrated that a soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio cutoff of ≤38 can rule out preeclampsia within 1 week with a negative predictive value (NPV) of 99.3% (PROGNOSIS) and 98.6% (PROGNOSIS Asia). We report a subanalysis of the Japanese cohort from the PROGNOSIS Asia study. Pregnant women with suspected preeclampsia between gestational weeks 18 + 0 days and 36 + 6 days were enrolled at eight Japanese sites. Primary objectives: Assess the performance of the Elecsys sFlt-1/PlGF ratio cutoff ≤38 to rule out preeclampsia within 1 week and of the cutoff >38 to rule in preeclampsia within 4 weeks. Key secondary objectives: Prediction of maternal and fetal adverse outcomes (MAOs/FAOs) and their relationship with duration of pregnancy. Of 192 women enrolled, 180 (93.8%)/175 (91.1%) were evaluable for primary/combined endpoint analyses. Overall preeclampsia prevalence was 13.3%. A sFlt-1/PlGF ratio of ≤38 provided an NPV of 100% (95% confidence interval [CI], 97.5-100) for ruling out preeclampsia within 1 week, and a ratio of >38 provided a positive predictive value of 32.4% (95% CI, 18.0-49.8) for ruling in preeclampsia within 4 weeks. The area under the curve for the prediction of preeclampsia/maternal/fetal adverse outcomes within 1 week was 94.2% (95% CI, 89.3-97.8). After adjusting for gestational age and final preeclampsia status, Cox regression indicated a 2.8-fold greater risk of imminent delivery for women with a sFlt-1/PlGF ratio >38 versus ≤38. This subanalysis of Japanese women with suspicion of preeclampsia showed high predictive value for a Elecsys sFlt-1/PlGF ratio cutoff of 38 for short-term prediction of preeclampsia.
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http://dx.doi.org/10.1038/s41440-021-00629-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255209PMC
July 2021

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

J Perinat Med 2020 Dec 2;49(1):111-115. Epub 2020 Dec 2.

Department of Obstetrics and Gynaecology, Fetal Medicine Unit, Maternal and Child Health and Development Network, University Hospital 12 de Octubre, Complutense University of Madrid, Madrid, Spain.

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http://dx.doi.org/10.1515/jpm-2020-0539DOI Listing
December 2020

Anesthesia for Cesarean Section and Postpartum Cardiovascular Events in Congenital Heart Disease: A Retrospective Cohort Study.

J Cardiothorac Vasc Anesth 2021 Jul 24;35(7):2108-2114. Epub 2020 Nov 24.

Department of Anesthesiology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.

Objective: To clarify the association between anesthetic technique and maternal and neonatal outcomes in parturients with congenital heart disease (CHD).

Design: Retrospective, observational cohort study.

Setting: An academic hospital.

Participants: A total of 263 consecutive parturients with CHD who underwent cesarean section from 1994 to 2019.

Interventions: None.

Measurements And Main Results: The authors compared postpartum cardiovascular events (composite of heart failure, pulmonary hypertension, arrhythmia, and thromboembolic complications) and neonatal outcomes (intubation and Apgar score <7 at one or five minutes) by anesthetic technique. Among 263 cesarean sections, general anesthesia was performed in 47 (17.9%) parturients and neuraxial anesthesia in 214 (81.3%) parturients. Cardiovascular events were more common in the general anesthesia group (n = 7; 14.9%) than in the neuraxial anesthesia group (n = 17; 7.9%). Generalized linear mixed models assuming a binomial distribution (ie, mixed-effects logistic regression), with a random intercept for each modified World Health Organization classification for maternal cardiovascular risk, revealed that general anesthesia was not significantly associated with cardiovascular events (odds ratio [OR], 1.00; 95% confidence interval [CI], 0.30-3.29). In addition, general anesthesia was associated with composite neonatal outcomes (Apgar score <7 at one or five minutes or need for neonatal intubation; OR, 13.3; 95% CI, 5.52-32.0).

Conclusion: Anesthetic technique is not significantly associated with postpartum composite cardiovascular events. General anesthesia is significantly associated with increased need for neonatal intubation and lower Apgar scores.
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http://dx.doi.org/10.1053/j.jvca.2020.11.042DOI Listing
July 2021

Discrepancy Between Pre- and Postnatal Diagnoses of Congenital Heart Disease and Impact on Neonatal Clinical Course - A Retrospective Study at a Japanese Tertiary Institution.

Circ J 2020 11 3;84(12):2275-2285. Epub 2020 Nov 3.

Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center.

Background: Congenital heart disease (CHD) is often diagnosed prenatally using fetal echocardiography, but few studies have evaluated the accuracy of these fetal cardiac diagnoses in detail. We investigated the discrepancy between pre- and postnatal diagnoses of CHD and the impact of discrepant diagnoses.Methods and Results:This retrospective study at a tertiary institution included data from the medical records of 207 neonates with prenatally diagnosed CHD admitted to the cardiac neonatal intensive care unit between January 2011 and December 2016. Pre- and postnatal diagnoses of CHD differed in 12% of neonates. Coarctation of the aorta and ventricular septal defects were the most frequent causes of discrepant diagnosis. Unexpected treatments were added to 38% of discrepant diagnostic cases. However, discrepant diagnoses did not adversely affect the clinical course. The 9% of the 207 neonates who required invasive intervention within 24 h of delivery were accurately diagnosed prenatally.

Conclusions: Pre- and postnatal diagnoses differed in only a few neonates, with differences not adversely affecting the clinical course. Neonates who required invasive intervention immediately after delivery were accurately diagnosed prenatally. Prenatal diagnosis thus seems to contribute to improved prognosis in neonates with CHD.
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http://dx.doi.org/10.1253/circj.CJ-20-0316DOI Listing
November 2020

Clinical management of coagulation status and placenta previa in a pregnant woman with Marfan's syndrome after mitral and aortic mechanical heart valve replacement.

Gen Thorac Cardiovasc Surg 2021 Mar 27;69(3):550-554. Epub 2020 Sep 27.

Department of Obstetrics and Gynecology, National Cerebral and Cardiovascular Center, 6-1, Kishibeshinmachi, Suita City, Osaka Prefecture, Japan.

Pregnancy with a mechanical heart valve (MHV) is high risk for valve thrombosis because pregnancy is a hyper-coagulation state. In addition, warfarin use during pregnancy is restricted due to its fetotoxicity, and postpartum bleeding may be increased with anticoagulation. In particular, placenta previa under anticoagulation may cause massive postpartum bleeding. The optimal anticoagulation for a pregnant woman with mitral and aortic double MHVs is not known. In addition, suitable techniques for control of bleeding in a case of placenta previa under anticoagulation are not known. Thus, a case of a pregnant woman with mitral and aortic double MHVs and placenta previa is presented. The case was managed without valve thrombosis through precise unfractionated heparin dose adjustment and frequent activated partial thromboplastin time monitoring, along with maintenance of antithrombin levels. Compression sutures were found to be effective for controlling bleeding from the attachment site of placenta previa even under anticoagulation.
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http://dx.doi.org/10.1007/s11748-020-01494-0DOI Listing
March 2021

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

J Perinat Med 2020 11;48(9):950-958

Department of Obstetrics and Gynaecology, Ospedale di San Leonardo, Castellammare di Stabia, Italy.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6±9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; p<0.001), birthweight (OR: 1.17, 95% CI 1.09-1.12.7 per 100 g decrease; p=0.012) and maternal ventilatory support, including either need for oxygen or CPAP (OR: 4.12, 95% CI 2.3-7.9; p=0.001) were independently associated with composite adverse fetal outcome. Conclusions Early gestational age at infection, maternal ventilatory supports and low birthweight are the main determinants of adverse perinatal outcomes in fetuses with maternal COVID-19 infection. Conversely, the risk of vertical transmission seems negligible.
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http://dx.doi.org/10.1515/jpm-2020-0355DOI Listing
November 2020

Management of pregnancy and delivery in women with Kawasaki disease and residual coronary artery lesion with detailed analysis of labor analgesia: combined experience of 13 cases in two institutions.

JA Clin Rep 2020 Sep 7;6(1):67. Epub 2020 Sep 7.

Division of Obstetric Anesthesia, Department of Anesthesiology, Saitama Medical Center, Saitama Medical University, Saitama, Japan.

Introduction: Approximately half of Kawasaki disease patients are expected to have transitioned to adulthood, and an increasing number of patients with cardiovascular sequelae have gotten pregnant. Management of women with Kawasaki disease who have residual coronary artery disease is poorly established. Thus, we conducted detailed analysis of these cases.

Methods: We reviewed 19 pregnancies in 13 such women in two tertiary perinatal facilities, Saitama Medical Center and National Cardiovascular Center. The medical records were reviewed in all women with Kawasaki disease and coronary artery lesion between 1998 and 2015, with regard to age of diagnosis, types of coronary artery lesion, location, previous treatment, pregnancy course and medical management for coronary lesion, cardiac function, and planned mode of delivery.

Results: Fourteen parturients attempted vaginal delivery, and all but one received neuraxial analgesia, providing stable hemodynamics. Four elective and two emergency cesarean deliveries were performed due to obstetric indications, while one woman required cesarean delivery at preterm due to maternal cardiac indication. Among 14 attempted vaginal deliveries, instrumental vaginal delivery was performed in 50%. Cardiac events were noted in four women, all in post-partum period, such as non-sustained ventricular tachycardia or chest discomfort without ECG changes. Antithrombotic medication was exclusively low dose aspirin in 11 of 19 pregnancies (58%), and none received anticoagulation during pregnancy or delivery.

Conclusion: Our case series support the practice of preferred vaginal delivery, with neuraxial labor analgesia in indicated patients, while highlighting the need for vigilance in the post-partum period.
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http://dx.doi.org/10.1186/s40981-020-00375-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477027PMC
September 2020

Pregnancy outcomes in women with dilated cardiomyopathy: Peripartum cardiovascular events predict post delivery prognosis.

J Cardiol 2021 Mar 30;77(3):217-223. Epub 2020 Jul 30.

Department of Obstetrics and Gynecology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.

Background: The number of pregnant women with dilated cardiomyopathy (DCM) is relatively small, and therefore their prognosis after pregnancy is unknown. This study aims to elucidate pregnancy outcomes among women with DCM, as well as the long-term prognosis after pregnancy.

Methods: Thirty-five pregnancies and deliveries in 30 women, diagnosed with DCM before pregnancy, were retrospectively analyzed.

Results: All women had a left ventricular ejection fraction (LVEF) over 30% and belonged to the New York Heart Association (NYHA) class I or II before pregnancy. The mean gestational age at delivery was 36 weeks with 15 (43%) preterm deliveries. Eight pregnancies (23%) were complicated by peripartum cardiac events including 1 ventricular arrhythmia, 6 heart failures, and 1 significant deterioration in LVEF requiring termination of pregnancy. NYHA class II, pre-pregnancy use of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker/diuretics, elevated brain natriuretic peptide (BNP), and advanced diastolic dysfunction assessed by Doppler echocardiography were defined as risk factors for cardiac events. Although the more severe cases took beta-blockers during pregnancy, the rates of cardiac events and decreasing LVEF did not differ significantly between those taking beta-blockers and those who were not. Values of LVEF decreased by almost 10% after the average 4-year post-delivery follow-up period. The long-term event-free survival was considerably worse among women with peripartum cardiac events than in those without (p<0.0001).

Conclusions: DCM women with pre-pregnancy LVEF over 30% tolerated pregnancy, but the rate of preterm delivery was high. Peripartum cardiovascular events occurred more often in women with NYHA class II, as well as those who received medications before and during pregnancy and showed more elevated BNP and advanced diastolic dysfunction before pregnancy. Beta-blockers likely allowed similar outcomes for DCM patients with lower initial LVEFs. Close monitoring later in life is required, particularly among the women with peripartum cardiac events.
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http://dx.doi.org/10.1016/j.jjcc.2020.07.007DOI Listing
March 2021

Perinatal outcome in case of maternal death for cerebrovascular acute disorders: a nationwide study in Japan.

J Matern Fetal Neonatal Med 2020 Jul 16:1-6. Epub 2020 Jul 16.

Department of Obstetrics and Gynecology, Mie University School of Medicine, Mie, Japan.

Objective: The goal of this study is to find clues to improve perinatal outcomes in the case of cerebrovascular acute disorders during pregnancy.

Study Design: We analyzed 35 cases of cerebrovascular diseases related to maternal deaths in Japan those that occurred during pregnancy and reported to the Committee of the Ministry of Health, Labor, and Welfare from 2010 to 2018.

Results: Cerebrovascular acute disorders occurred at 34.6 ± 6.6 gestational weeks. There were seven intrauterine fetal deaths (IUFD), and eight cases showed neonatal asphyxia with umbilical arterial pH between 6.7 and 7.0 (asphyxia cases,  = 15). In two of eight newborns, brain hypothermia therapy was given, and all survived without neurological sequelae. Maternal dyspnea was significantly related to severe prolonged decelerations of the fetus ( < .05), and asphyxia cases ( < .005). Median time from maternal onset to delivery (OD time) was significantly longer in asphyxia cases than in the non-asphyxia cases (84 vs 29 min,  < .05). OD time over 30 min was significantly related to the antepartum occurrence, cervical dilatation <5 cm ( < .05), onset outside of the hospital ( < .001), and maternal transfer before delivery ( < .001).

Conclusion: More than 40% of cases experienced fetal asphyxia, and 20% ended in IUFD in maternal deaths related to cerebrovascular acute disorders. Maternal respiratory support and rapid delivery would be the keys to improve perinatal outcomes in case of cerebrovascular acute disorders during pregnancy.
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http://dx.doi.org/10.1080/14767058.2020.1786511DOI Listing
July 2020

Predictive value of protein S-specific activity and ELISA testing in patients with the protein S K196E mutation.

Thromb Res 2020 01 31;185:1-4. Epub 2019 Oct 31.

Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.

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http://dx.doi.org/10.1016/j.thromres.2019.10.026DOI Listing
January 2020

Deficiency of Cardiac Natriuretic Peptide Signaling Promotes Peripartum Cardiomyopathy-Like Remodeling in the Mouse Heart.

Circulation 2020 02 31;141(7):571-588. Epub 2019 Oct 31.

National Cerebral and Cardiovascular Center (K.K.), Osaka, Japan.

Background: The maternal circulatory system and hormone balance both change dynamically during pregnancy, delivery, and the postpartum period. Although atrial natriuretic peptides and brain natriuretic peptides produced in the heart control circulatory homeostasis through their common receptor, NPR1, the physiologic and pathophysiologic roles of endogenous atrial natriuretic peptide/brain natriuretic peptide in the perinatal period are not fully understood.

Methods: To clarify the physiologic and pathophysiologic roles of the endogenous atrial natriuretic peptide/brain natriuretic peptide-NPR1 system during the perinatal period, the phenotype of female wild-type and conventional or tissue-specific Npr1-knockout mice during the perinatal period was examined, especially focusing on maternal heart weight, blood pressure, and cardiac function.

Results: In wild-type mice, lactation but not pregnancy induced reversible cardiac hypertrophy accompanied by increases in fetal cardiac gene mRNAs and ERK1/2 (extracellular signaling-regulated kinase) phosphorylation. Npr1-knockout mice exhibited significantly higher plasma aldosterone level than did wild-type mice, severe cardiac hypertrophy accompanied by fibrosis, and left ventricular dysfunction in the lactation period. Npr1-knockout mice showed a high mortality rate over consecutive pregnancy-lactation cycles. In the hearts of Npr1-knockout mice during or after the lactation period, an increase in interleukin-6 mRNA expression, phosphorylation of signal transducer and activator of transcription 3, and activation of the calcineurin-nuclear factor of the activated T cells pathway were observed. Pharmacologic inhibition of the mineralocorticoid receptor or neuron-specific deletion of the mineralocorticoid receptor gene significantly ameliorated cardiac hypertrophy in lactating Npr1-knockout mice. Anti-interleukin-6 receptor antibody administration tended to reduce cardiac hypertrophy in lactating Npr1-knockout mice.

Conclusions: These results suggest that the characteristics of lactation-induced cardiac hypertrophy in wild-type mice are different from exercise-induced cardiac hypertrophy, and that the endogenous atrial natriuretic peptide/brain natriuretic peptide-NPR1 system plays an important role in protecting the maternal heart from interleukin-6-induced inflammation and remodeling in the lactation period, a condition mimicking peripartum cardiomyopathy.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.039761DOI Listing
February 2020

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

J Matern Fetal Neonatal Med 2021 Sep 9;34(18):2957-2964. Epub 2019 Oct 9.

Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center, Suita, Japan.

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%) 0/8 (0%),  < .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%) 0/8 (0%),  < .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,  < .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.
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http://dx.doi.org/10.1080/14767058.2019.1675626DOI Listing
September 2021

Metabolism of atrial and brain natriuretic peptides in the fetoplacental circulation of fetuses with congenital heart diseases.

Placenta 2019 08 25;83:26-32. Epub 2019 Jun 25.

Omics Research Center (NM), National Cerebral and Cardiovascular Center, Japan.

Introduction: Natriuretic peptides (NPs) play a pivotal role in maintaining fetal circulation; however, little is known about their metabolism. The aim of the present study was to elucidate the metabolism of plasma NPs in the fetoplacental circulation.

Methods: Plasma NP concentrations in maternal vein and umbilical artery (UA) and vein (UV) samples from fetuses with congenital heart defect (n = 86) or arrhythmia (n = 31) and controls (n = 127) were analyzed.

Results: Levels of plasma atrial NP (ANP) and brain NP (BNP) showed good correlation between UV versus UA samples (p < 0.01). In all three fetus groups, the regression coefficients between UV and UA plasma ANP levels were close to 0.5, while those between UV and UA plasma BNP levels were close to 1. The molecular forms of immunoreactive ANP in UA plasma showed a single peak corresponding to mature ANP, while those of immunoreactive BNP in UA plasma showed two major peaks and several minor peaks corresponding to mature BNP-32 and its partially digested peptides, as well as glycosylated and non-glycosylated BNP precursors (proBNP). No correlation was found between fetuses and mothers in terms of either plasma ANP or BNP levels.

Conclusions: The mother and fetus independently secrete and metabolize both ANP and BNP. Fetal plasma ANP consists exclusively of the mature form, and the placenta and umbilical vessels are possible major sites of ANP metabolism. In contrast, fetal plasma BNP consists predominantly of the precursor forms, which may contribute to protecting BNP from metabolism in the fetoplacental circulation.
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http://dx.doi.org/10.1016/j.placenta.2019.06.382DOI Listing
August 2019

Peripartum Management of Pregnant Women With Congenital Heart Disease.

Circ J 2019 10 29;83(11):2257-2264. Epub 2019 Aug 29.

Department of Health Sciences, Kyushu University Graduate School of Medical Sciences.

Background: The average maternal age at delivery, and thus the associated maternal risk are increasing including in women with congenital heart disease (CHD). A comprehensive management approach is therefore required for pregnant women with CHD. The present study aimed to investigate the factors determining peripartum safety in women with CHD.Methods and Results:We retrospectively collected multicenter data for 217 pregnant women with CHD (age at delivery: 31.4±5.6 years; NYHA classifications I and II: 88.9% and 7.4%, respectively). CHD severity was classified according to the American College of Cardiology/American Heart Association guidelines as simple (n=116), moderate complexity (n=69), or great complexity (n=32). Cardiovascular (CV) events (heart failure: n=24, arrhythmia: n=9) occurred in 30 women during the peripartum period. Moderate or great complexity CHD was associated with more CV events during gestation than simple CHD. CV events occurred earlier in women with moderate or great complexity compared with simple CHD. Number of deliveries (multiparity), NYHA functional class, and severity of CHD were predictors of CV events.

Conclusions: This study identified not only the severity of CHD according to the ACC/AHA and NYHA classifications, but also the number of deliveries, as important predictive factors of CV events in women with CHD. This information should be made available to women with CHD and medical personnel to promote safe deliveries.
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http://dx.doi.org/10.1253/circj.CJ-19-0369DOI Listing
October 2019

Plasma natriuretic peptide levels reflect the status of the heart failure in fetuses with arrhythmia.

J Matern Fetal Neonatal Med 2021 Jun 15;34(12):1883-1889. Epub 2019 Aug 15.

Omics Research Center, National Cerebral and Cardiovascular Center, Suita, Japan.

Objectives: To evaluate the significance of natriuretic peptide (NP) levels in fetal arrhythmia.

Study Design: Cardiovascular profile (CVP) scores and umbilical vein (UV) NP levels at birth were compared by different fetal arrhythmia statuses.

Results: Fetal tachyarrhythmia ( = 22), bradyarrhythmia ( = 12), extrasystole ( = 12) and controls ( = 127) were enrolled in this study. Fetal antiarrhythmic therapy was performed in fetuses with tachyarrhythmia ( = 18) and bradyarrhythmia ( = 5). Fetal arrhythmias were divided into three groups: group A (arrhythmia controlled at birth,  = 17), Group B (arrhythmia uncontrolled at birth,  = 9) and Group C (fetal therapy not indicated,  = 20). Group B had significantly lower CVP scores and higher NP levels than the other two groups and controls ( < .01). Groups A and C had significantly lower CVP scores than controls, but NP levels in Groups A and C showed no differences compared with controls.

Conclusions: UV NP concentrations reflect the severity of fetal arrhythmia and responses to fetal therapy.
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http://dx.doi.org/10.1080/14767058.2019.1651271DOI Listing
June 2021

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

Int J Hematol 2019 Nov 25;110(5):550-558. Epub 2019 Jul 25.

Department of Obstetrics and Gynecology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.

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.
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http://dx.doi.org/10.1007/s12185-019-02712-zDOI Listing
November 2019

Safety of Amlodipine in Early Pregnancy.

J Am Heart Assoc 2019 08 26;8(15):e012093. Epub 2019 Jul 26.

Motherisk Program Division of Clinical Pharmacology and Toxicology Department of Paediatrics The Hospital for Sick Children University of Toronto Toronto Canada.

Background Amlodipine is used for the treatment of hypertension, but reports on its use in early pregnancy are limited. Methods and Results In the present study, we recruited 231 women with chronic hypertension, including those who received amlodipine or other antihypertensives during early pregnancy, and investigated frequencies of morphologic abnormalities in their 231 offspring. Specifically, we evaluated 48 neonates exposed to amlodipine in the first trimester (amlodipine group, Group A), 54 neonates exposed to antihypertensives other than amlodipine (other antihypertensive group, Group O), and 129 neonates not exposed to antihypertensives (no-antihypertensive group, Group N). The number of morphologic abnormalities of offspring in each group were 2 in Group A (4.2%; 95% CI, 0.51-14.25); 3 in Group O (5.6%; 95% CI, 1.16-15.39) and 6 in Group N (4.7%; 95% CI, 1.73-9.85). The odds ratio of the primary outcome comparing Group A and Group O was 0.74 (95% CI: 0.118-4.621) and Group A and Group N was 0.89 (95% CI: 0.174-4.575). Conclusions The odds of birth defects in Group A in the first trimester were not significantly different from those with or without other antihypertensives.
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http://dx.doi.org/10.1161/JAHA.119.012093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761676PMC
August 2019

Impact of Pregnancy on Aortic Root in Women with Repaired Conotruncal Anomalies.

Pediatr Cardiol 2019 Aug 13;40(6):1134-1143. Epub 2019 May 13.

Departments of Perinatology and Gynecology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, 565-8565, Osaka, Japan.

The effect of pregnancy on aortic root in women with repaired conotruncal anomalies (CTA) has not been clarified. This study examined aortic diameters during and after pregnancy in women with repaired CTA. A retrospective review of consecutive pregnant women with repaired CTA was performed for results of echocardiography from 1 year before pregnancy to 3 years after delivery and compared with findings from healthy pregnant volunteers. Participants comprised 42 subjects and 49 deliveries with repaired CTA (CTA group), and 47 healthy pregnant women (control group). Although no maternal aortic events were encountered, aortic diameters during pregnancy increased by 1.0 ± 2.2 mm (maximum, 7.0 mm) in the CTA group and 0.6 ± 1.3 mm (maximum, 3.4 mm) in the control group (p = 0.13). The CTA subgroup with increase in aortic diameter ≥ 3.5 mm during pregnancy showed no reversion to baseline diameter at follow-up > 6 months after delivery. Significant risk factors for increased aortic diameter and no reversal included pulmonary atresia, history of aortopulmonary shunt, older age at repair, and smaller left ventricular end-diastolic diameter pre-pregnancy. Women with repaired CTA tolerated pregnancy and delivery well. However, the aortic root progressively dilated during pregnancy and 1/4 of them, especially those with longstanding high aortic blood flow before repair, showed an increase of aortic root size of ≥ 3.5 mm during the peripartum period; this dilatation tended not to revert to the pre-pregnancy diameter. Therefore, serial measurement of the aortic root during pregnancy and after delivery is recommended in these women.
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http://dx.doi.org/10.1007/s00246-019-02112-4DOI Listing
August 2019

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

J Cardiol 2019 Oct 3;74(4):347-352. Epub 2019 May 3.

Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center, Suita, Japan.

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.
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http://dx.doi.org/10.1016/j.jjcc.2019.04.002DOI Listing
October 2019

Analysis of preventability of malignancy-related maternal death from the nationwide registration system of maternal deaths in Japan.

J Matern Fetal Neonatal Med 2021 Feb 2;34(3):432-438. Epub 2019 May 2.

Department of Obstetrics and Gynecology, Mie University School of Medicine, Mie, Japan.

We reviewed malignancy related maternal deaths in Japan to ascertain if there were avoidable factors. Malignancy-related maternal death in Japan reported to the Maternal Death Exploratory Committee, from 2010 to 2016 inclusive. There were 12 cases of maternal death caused by malignancy. There were four gastric cancers (two poorly differentiated adenocarcinoma, one signet ring cell carcinoma with adenocarcinoma, one histology not available), 3 leukemia (two acute myeloid leukemia, one aggressive NK cell leukemia), two ureteral cancers (histology not available), one malignant lymphoma (diffuse large B-cell lymphoma with translocation), one brain tumor (gliomatosis cerebri), and one cervical cancer (glassy cell carcinoma). Two gastric cancer patients had chronic gastric pain before conception. In two cases the physicians commented that they had avoided computed tomography and the brain biopsy needed for diagnosis because the patient was pregnant. At diagnosis, the clinical stages were II-IV in 9, and the performance status was 3-5 in 8. Indication for delivery was exacerbated maternal condition in 5, for treatment in 3, spontaneous labor in 3, and one patient declined elective delivery. Median [interquartile rage] (range) gestational weeks of delivery was 29 [24-30] (19-40). One cervical cancer patient had a radical hysterectomy and chemotherapy for 10 months. However, three leukemia and one gastric cancer patients had chemotherapy within 10 d because they deteriorated rapidly. Another seven cases did not have any treatment because of poor general condition or because they remained undiagnosed. In all cases, the Committee considered that there was no evidence of substandard care. In these cases, both the clinical stages and biological degree of malignancy were high. In two-thirds of cases, early termination of the pregnancy was indicated because of deteriorating maternal condition. Chemotherapy was not effective because of short available time for therapy and the advanced stage of the cancers when diagnosed. Encouraging women to have a thorough medical assessment before conception, and early diagnosis and treatment before pregnancy, appears to be the only practical way to reduce deaths from malignancy while a woman is pregnant.
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http://dx.doi.org/10.1080/14767058.2019.1609930DOI Listing
February 2021

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

J Obstet Gynaecol Res 2019 Jul 11;45(7):1268-1276. Epub 2019 Apr 11.

Department of Obstetrics and Gynecology, Mie University, Tsu, Japan.

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.
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http://dx.doi.org/10.1111/jog.13970DOI Listing
July 2019

Maternal and fetal outcomes in pregnancy complicated with Eisenmenger syndrome.

Taiwan J Obstet Gynecol 2019 Mar;58(2):183-187

Department of Obstetrics and Gynecology, Mie University, Japan.

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, PaO, and SpO 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/cm). 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.
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http://dx.doi.org/10.1016/j.tjog.2019.01.002DOI Listing
March 2019

Effects of low-dose combined oral contraceptives and protein S K196E mutation on anticoagulation factors: a prospective observational study.

Int J Hematol 2019 Jun 19;109(6):641-649. Epub 2019 Mar 19.

Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.

The association between low-dose combined oral contraceptives (COCs) and anticoagulation factors in Japanese women has been rarely studied. A total of 394 Japanese women with a new beginning cycle of COC use were enrolled, of whom 335 women visited the clinic within 4 weeks after starting the first cycle of COC. Visits occurred in the active phase (272 women) and the placebo phase (63 women). Free protein S (PS) antigen and activity levels and antithrombin activity levels decreased significantly in both the active and placebo phase groups. Protein C (PC) activity levels increased significantly in both groups. Larger reductions in free PS antigen and activity levels occurred with COC comprising either 30 µg ethinylestradiol/desogestrel or 20 µg ethinylestradiol/drospirenone than that comprising 35 µg ethinylestradiol/norethisterone. In four women with the Japanese-specific PS K196E mutation, mean PS activity was 65% before COC use and 57% during COC use, indicating further decrease with COC use. In conclusion, decreased antigen and activity levels of PS and antithrombin and increased activity levels of PC were observed even during the first cycle of low-dose COC use. The effects on PS and PC activities were also observed in the hormone-free interval.
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http://dx.doi.org/10.1007/s12185-019-02633-xDOI Listing
June 2019

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

Pediatr Cardiol 2019 Apr 4;40(4):865-870. Epub 2019 Mar 4.

Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan.

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.
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http://dx.doi.org/10.1007/s00246-019-02083-6DOI Listing
April 2019

Pharmacological treatment for cardiovascular disease during pregnancy and lactation.

J Cardiol 2019 05 27;73(5):363-369. Epub 2019 Feb 27.

Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center, Osaka, Japan.

Maternal circulatory dynamics change drastically during pregnancy and delivery. Therefore, pregnancy with concomitant cardiovascular disease has risks, even for maternal death, in severe cases. This condition has tended to increase with advances in medical care and an increase in the age of pregnant women. Drug therapy during pregnancy and lactation should be administered if it is judged that this is necessary to improve the maternal pathology despite a risk of adverse effects. Fetuses and infants are exposed to maternal drugs, which is a specific concern in drug therapy for pregnant and lactating women. Care is needed because of the risk of adverse effects of teratogenicity in the organogenesis period and fetal toxicity thereafter. However, unstable maternal circulatory dynamics also inhibit fetal development and increase the risk of premature delivery, and stabilization of maternal physiologic condition by drug therapy often gives benefit to fetuses indirectly. Therefore, detailed knowledge of drug therapy during pregnancy should be acquired to manage the condition appropriately. Caution is also needed in using some obstetric drugs, such as tocolytic agents, which influence maternal circulatory dynamics. Therefore, drug therapy during pregnancy and lactation should only be used after full consideration of its benefit and possible harm to the mother and child, and after obtaining consent from the patient after giving a sufficient explanation. In this report, we review drug therapy for pregnant and lactating women with concomitant cardiovascular disease.
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http://dx.doi.org/10.1016/j.jjcc.2018.12.020DOI Listing
May 2019

Fetal paroxysmal atrial fibrillation during transplacental therapy for supraventricular tachycardia.

HeartRhythm Case Rep 2019 Jan 10;5(1):22-24. Epub 2018 Oct 10.

Department of Obstetrics and Gynecology, Mie University, Tsu, Japan.

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http://dx.doi.org/10.1016/j.hrcr.2018.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342607PMC
January 2019

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.

J Cardiol 2019 03 20;73(3):247-254. Epub 2018 Dec 20.

Departments of Perinatology and Gynecology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.

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.
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http://dx.doi.org/10.1016/j.jjcc.2018.11.007DOI Listing
March 2019
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