Multidisciplinary approach for the management of term pregnancy complicated by Eisenmenger syndrome

Multidisciplinary approach for the management of term pregnancy complicated by Eisenmenger syndrome 足月妊娠合并艾森曼格综合征的多学科治疗 1 2 equal first-author 1 equal 3 1 1 1 corresp Jianhua LIN, linjhuarj@126.com Jianhua LIN, linjhuarj@126.com linjhuarj@126.com https://orcid.org/0000-0002-2121-3473 1 2 corresp Ning ZHANG, ningning1723@126.com Ning ZHANG, ningning1723@126.com ningning1723@126.com https://orcid.org/0000-0001-6306-4819 上海交通大学医学院附属仁济医院妇产科， 中国 上海， 200127 上海交通大学医学院附属仁济医院妇产科， 中国 上海， 200127 Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China 上海交通大学医学院附属仁济医院上海市妇科肿瘤重点实验室， 中国 上海， 200127 上海交通大学医学院附属仁济医院上海市妇科肿瘤重点实验室， 中国 上海， 200127 Shanghai Key Laboratory of Gynecologic Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China Shanghai Key Laboratory of Gynecologic Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China 天普大学医院内科， 美国 宾夕法尼亚， 19140 天普大学医院内科， 美国 宾夕法尼亚， 19140 Department of Medicine, Temple University Hospital, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA Department of Medicine, Temple University Hospital, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA 妊娠合并心脏病的发病率为0.5%~3.0%，占据导致孕产妇死亡的非产科病因首位。而重度肺动脉高压的处理最为棘手，合并艾森曼格综合征的孕产妇死亡率高达30%~50%，剖宫产患者甚至达65%~75%。妊娠合并重度肺动脉高压属于妊娠禁忌，一旦诊断需尽快终止妊娠，能达足月妊娠者临床非常罕见。本文报道1例足月妊娠合并重度肺动脉高压和艾森曼格综合征患者的成功诊治，旨在提高产科医师对该合并症的重视和多学科管理，并提高对该疾病围手术期的精细诊疗水平。 足月妊娠 艾森曼格综合征 重度肺动脉高压 多学科团队(MDT) Pregnancy in patients with Eisenmenger syndrome (ES) is associated with high maternal mortality rates of 30%‒50%, or even up to 65% in the case of a cesarean section ( Yuan, 2016 Yuan, 2016 ). Here, we report a case of term pregnancy complicated with ES and severe pulmonary artery hypertension (PAH), which was managed by a multidisciplinary team (MDT) and resulted in an uncomplicated delivery via elective cesarean section. The goal of this study is to emphasize the importance of multidisciplinary approach in the management of pregnancy with ES, which can profoundly improve maternal and infant outcomes. A 32-year-old female (gravida 3, para 0) at 36(+6)‍-week gestation was transferred to our institution (Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China) for further evaluation of hypoxemia and bilateral lower extremity edema. She first received prenatal care at an outside hospital in December 2019, and remained asymptomatic during that time. She was unaware of any cardiac diseases, diabetes, surgery, or trauma. Her obstetric history was significant for a spontaneous miscarriage in 2003 and an induced abortion in 2014. As a result of the corona virus disease 2019 (COVID-19)‍ pandemic, she was lost to follow-up and did not present to the hospital until 36(+6) weeks, when she developed progressive bilateral lower extremity edema. On presentation, she was hypoxic with an oxygen saturation (SpO 2 ) of 72% on ambient air, and showed digital clubbing. She was transferred to our institution for further evaluation and management. Upon transfer, her vital signs were as follows: heart rate of 80 beats per minute, blood pressure of 130/70 mmHg (1 mmHg=0.133 kPa), respiratory rate of 21 breaths per minute, and SpO 2 of 77% on ambient air. The cardiac exam revealed a loud P2 and a pansystolic murmur heard over the left sternal border. The lungs were clear to auscultation without rales or crackles. She was noted to have central cyanosis, digital clubbing, and 3+ pitting edema of the bilateral lower extremities. Obstetric exam findings showed a uterine height of 33 cm, maternal abdominal circumference (AC) of 101 cm, responsive non-stress test (NST) without contraction, and a Bishop score of 4 points. Transabdominal ultrasound revealed a biparietal diameter (BPD) of 86 mm, AC of 306 mm, femur length (FL) of 67 mm, and amniotic fluid volume (AFV) of 40 mm. The arterial blood gas test revealed pH 7.43, partial pressure of oxygen (PaO 2 ) at 47 mmHg, and SpO 2 at 80%. Significant laboratory findings included elevated B-type natriuretic peptide (BNP) of 278 ng/L and N-terminal pro-BNP (NT-pBNP) of 1192 ng/L. The complete blood count, hepatic and renal function, thyroid function, serum chemistries, and coagulation results were within normal limits. The thrombophilia screening (protein C, protein S, and homocysteine) and autoimmune findings were normal. Computed tomography (CT) of the chest revealed no acute pulmonary embolism or pleural effusion, and a complete abdominal ultrasound demonstrated no intraabdominal process or peritoneal effusion. The electrocardiogram discovered a sinus rhythm with right ventricular hypertrophy, and the echocardiogram showed a large arterial septal defect (ASD) measuring 30 mm with bidirectional and mainly right-to-left shunt, severe pulmonary hypertension with a systolic pressure of 135 mmHg, moderate tricuspid regurgitation, and left ventricular ejective fraction (LVEF) of 67%. Given the medical history, physical, laboratory, and imaging findings, she was diagnosed with pregnancy complicated with ES. Her hypoxemia was attributed to a right-to-left shunt secondary to a large ASD and severe pulmonary hypertension. An MDT was assembled to provide expertise for close hemodynamic and fetal monitoring, with a plan to optimize preoperative hemodynamic status bridging to elective cesarean section. The recommendations from different specialists were described below. (1) Cardiothoracic surgery and cardiology: given the extent of severe pulmonary hypertension, the patient was deemed not a surgical candidate for ASD closure. She was given oxygen therapy to maintain SpO 2 > 90%. PAH-specific therapies including sildenafil and treprostinil were initiated. The central line and arterial line were placed under close hemodynamic monitoring. (2) Anesthesiology: the decision was made to perform general anesthesia and endotracheal intubation. Epidural anesthesia was avoided as sympathetic blockade could reduce systemic vascular resistance, leading to worsening right-to-left shunt and hypoxemia. (3) Mechanical circulatory support: extracorporeal membrane oxygenation (ECMO) was planned for rescue in the event of decompensation. Femoral vein and artery were cannulated intraoperatively as needed for ECMO. (4) Obstetrics: as acute blood loss during delivery could pose a high risk for cardiopulmonary decompensation, the decision was made to proceed with judicious use of oxytocin in small and intermittent dose to augment contraction and prevent postpartum hemorrhage. (5) Neonatology: as hypoxemia in maternal circulation could lead to fetal hypoxia, neonatologists were standby in the event of newborn resuscitation. (6) Intensive care: the intensive care unit (ICU) level of care was deemed necessary to provide close monitoring, supportive care, and PAH-specific therapy. After optimization and finalization of the management plan, we conducted caesarean section under general anesthesia at 37(+2)‍-week gestation. A floating catheter was inserted to dynamically monitor the pulmonary artery pressure, and the pre-cannulation of the femoral vein and artery were prepared for the availability of standby ECMO. A live baby girl with an Apgar score of 4 points at 1 min, 7 at 5 min, 9 at 10 min, and 10 at 20 min, weighing 2495 g, was delivered and immediately resuscitated by the neonatologist. After delivery, intravenous oxytocin 5 U was given immediately and 10 min after delivery. The ligation of bilateral ascending branches of uterine artery and B-lynch suture was subsequently performed due to the concern of uterine inertia and postpartum hemorrhage. The estimated blood loss was 400 mL. Intraoperatively, vasopressors and inotropes including dopamine and norepinephrine were used and titrated as needed to maintain adequate systemic vascular resistance. Continuous treprostinil infusion was titrated to sustain a low pulmonary vascular resistance in order to prevent an increase in the right-to-left shunt. The patient was transferred to ICU for close hemodynamic monitoring and postpartum management. She was extubated 6 h postoperatively and placed on high flow oxygen to maintain SpO 2 at 95%‒98%. Macitentan was added as a third agent for PAH on postoperative Day 1. Dopamine and norepinephrine were eventually weaned off one weeks and three weeks post partum, respectively. Treprostinil was transitioned from intravenous injection to subcutaneous injection at postpartum Week 4. Subcutaneous weight-adjusted low-molecular-weight heparin (LMWH) was started within 12‒24 h postoperatively for venous thromboembolism (VTE) prophylaxis. To minimize the risk of infection, patient was treated with intravenous antibiotics prophylactically and lines were removed one week postoperatively. In addition, the patient received bromocriptine for lactation suppression to ensure adequate bedrest and sleep. On postoperative Day 37, a repeat echocardiogram showed a pulmonary arterial pressure of 124 mmHg. She was discharged on postoperative Week 6 on oral sildenafil, macitentan, and subcutaneous trepostinil, with a plan to follow up with cardiology. Contraception was started to avoid pregnancy. On 12-month follow-up, her overall condition was satisfactory and her daughter was healthy. Fig. 1 Fig. 1 demonstrated the outline of postoperative MDT management. Fig. 2 Fig. 2 demonstrated the trend of relevant laboratory indicators during the perioperative and puerperal periods. Term pregnancy complicated with ES and severe PAH is a rare and potentially life-threatening condition. According to the 2018 European Society of Cardiology (ESC) Guidelines, pregnancy is contraindicated in patients with ES, as PAH has the highest risk level (modified World Health Organization classification of maternal cardiovascular risk level IV (mWHO IV)) ( Regitz-Zagrosek et al., 2018 Regitz-Zagrosek et al., 2018 ). Women who become pregnant should receive counseling and early pregnancy termination should be discussed. For patients who opt to continue with the pregnancy, referral to a tertiary center with expertise in PAH should be made as soon as possible. When this patient was emergently transferred to our institution at 36(+6)‍-week gestation for the further evaluation of severe hypoxemia, the differential diagnosis of pulmonary embolism due to the hypercoagulable state of pregnancy was excluded by CT scan. Using any of the present techniques, the fetal dose is well below the dose levels above that proposed for a significantly increased risk for congenital abnormality ( Schaefer-Prokop and Prokop, 2008 Schaefer-Prokop and Prokop, 2008 ). Once the diagnosis of pregnancy complicated with PAH and ES is established, treatment strategy is further discussed by MDT: based on the guidance for assessing operability in PAH associated with congenital heart disease ( Simonneau et al., 2019 Simonneau et al., 2019 ), patients with severe residual PAH after the closure of shunts may have more rapid progression of disease and worse outcome. Our patient was not suitable for the management of ASD, and PAH-specific therapy was planned, as recommended in pregnancy with PAH. There are four major classes of PAH-specific therapy: prostaglandins (e.‍g., treprostinil), phosphodiesterase-5 (PDE-5) inhibitors (e.‍g., sildenafil), endothelin receptor antagonists (e.‍g., macitentan), and soluble guanylate cyclase stimulators ( Ballard et al., 2021 Ballard et al., 2021 ). Sildenafil and treprostinil are associated with risk category B in pregnancy by the United States Food and Drug Administration, while macitentan has been shown to have teratogenic effects and thus is contraindicated during pregnancy ( Yang et al., 2021 Yang et al., 2021 ). Of note, sildenafil is an oral medication that has been shown to exert beneficial effects on symptoms and exercise tolerance in patients with ES ( Lopez et al., 2020 Lopez et al., 2020 ); early initiation or continuation of PDE-5 inhibitors in women with PAH who choose to continue pregnancy is recommended ( Yuan, 2016 Yuan, 2016 ). Both cesarean and vaginal delivery in women with ES are associated with high cardiovascular risk. Compared to cesarean section, vaginal delivery is linked to reduced blood loss, lower risk of infection, VTE, and sudden hemodynamic changes ( Lopez et al., 2020 Lopez et al., 2020 ). However, the prolonged delivery course and pain can lead to increased pulmonary arterial pressure ( Yang et al., 2021 Yang et al., 2021 ). As for caesarean section, the placement of a pulmonary artery catheter in delivery may be helpful to assess hemodynamic status and adjust medication ( Zhang et al., 2018 Zhang et al., 2018 ). The selection of the method and timing of delivery remains debatable and should be individualized ( Slaibi et al., 2021 Slaibi et al., 2021 ). Postpartum monitoring and management are vital in the first 10 d post partum, which is associated with the highest mortality due to hypovolemia, VTE, and preeclampsia ( Maciejewski et al., 2019 Maciejewski et al., 2019 ). PAH patients complicated with right-to-left shunt are at high risk of VTE, and therapeutic anticoagulation is recommended in pregnancy with ES ( Karsenty et al., 2021 Karsenty et al., 2021 ). In our case, weight-based LMWH at full anticoagulation dose was started within 12‍‒‍24 h post partum after the risk of postpartum hemorrhage was deemed to be low. According to the recommendation, vasopressors and inotropes should be used with caution. In our case, vasopressors were continued postpartum but eventually weaned off. A third agent (macitentan) was added for PAH and intravenous trepostinil was transitioned to subcutaneous injection at postoperative Weeks 4 and 5. Lastly, psychological support, lactation suppression, and postpartum contraception were all important measures for comprehensive care during the postpartum period. All the above measures resulted in an uneventful delivery under precise management by a coordinated and experienced MDT. Early screening for heart disease during pregnancy and appropriate referral have crucial importance. Pregnant patients with ES should be treated carefully by an experienced MDT. PAH-specific therapy should be initiated or continued during pregnancy. In our case, precise and standardized management by MDT profoundly improved maternal and fetal outcomes. References Ballard W III , Dixon B , McEvoy CA , et al. , 2021 . Pulmonary arterial hypertension in pregnancy . Cardiol Clin , 39 ( 1 ): 109 - 118 . https://doi.org/10.1016/j.ccl.2020.09.007 https://doi.org/10.1016/j.ccl.2020.09.007 Pulmonary arterial hypertension in pregnancy Karsenty C , Waldmann V , Mulder B , et al. , 2021 . Thromboembolic complications in adult congenital heart disease: the knowns and the unknowns . Clin Res Cardiol , 110 ( 9 ): 1380 - 1391 . https://doi.org/10.1007/s00392-020-01746-2 https://doi.org/10.1007/s00392-020-01746-2 Thromboembolic complications in adult congenital heart disease: the knowns and the unknowns Lopez BM , Malhamé I , Davies LK , et al. , 2020 . Eisenmenger syndrome in pregnancy: a management conundrum . J Cardiothorac Vasc Anesth , 34 ( 10 ): 2813 - 2822 . https://doi.org/10.1053/j.jvca.2020.02.053 https://doi.org/10.1053/j.jvca.2020.02.053 Eisenmenger syndrome in pregnancy: a management conundrum Maciejewski T , Darocha T , Kiermasz K , et al. , 2019 . Emergency caesarean section delivery and puerperium in a patient with severe idiopathic pulmonary arterial hypertension—a case report . Anaesthesiol Intensive Ther , 51 ( 1 ):‍ 70 - 71 . https://doi.org/10.5603/AIT.a2019.0001 https://doi.org/10.5603/AIT.a2019.0001 Emergency caesarean section delivery and puerperium in a patient with severe idiopathic pulmonary arterial hypertension—a case report Regitz-Zagrosek V , Roos-Hesselink JW , Bauersachs J , et al. , 2018 . 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy: the Task Force for the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC) . Eur Heart J , 39 ( 34 ): 3165 - 3241 . https://doi.org/10.1093/eurheartj/ehy340 https://doi.org/10.1093/eurheartj/ehy340 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy: the Task Force for the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC) Schaefer-Prokop C , Prokop M , 2008 . CTPA for the diagnosis of acute pulmonary embolism during pregnancy . Eur Radiol , 18 ( 12 ): 2705 - 2708 . https://doi.org/10.1007/s00330-008-1158-8 https://doi.org/10.1007/s00330-008-1158-8 CTPA for the diagnosis of acute pulmonary embolism during pregnancy Simonneau G , Montani D , Celermajer DS , et al. , 2019 . Haemodynamic definitions and updated clinical classification of pulmonary hypertension . Eur Respir J , 53 : 1801913 . https://doi.org/10.1183/13993003.01913-2018 https://doi.org/10.1183/13993003.01913-2018 Haemodynamic definitions and updated clinical classification of pulmonary hypertension Slaibi A , Ibraheem B , Mohanna F , 2021 . Challenging management of a pregnancy complicated by eisenmenger syndrome; a case report . Ann Med Surg (Lond) , 69 : 102721 . https://doi.org/10.1016/j.amsu.2021.102721 https://doi.org/10.1016/j.amsu.2021.102721 Challenging management of a pregnancy complicated by eisenmenger syndrome; a case report Yang JZ , Fernandes TM , Kim NH , et al. , 2021 . Pregnancy and pulmonary arterial hypertension: a case series and litera Pregnancy and pulmonary arterial hypertension: a case series and litera ture review . Am J Obstet Gynecol MFM , 3 ( 4 ): 100358 . https://doi.org/10.1016/j.ajogmf.2021.100358 https://doi.org/10.1016/j.ajogmf.2021.100358 ture review Yuan SM , 2016 . Eisenmenger syndrome in pregnancy . Braz J Cardiovasc Surg , 31 ( 4 ): 325 - 329 . https://doi.org/10.5935/1678-9741.20160062 https://doi.org/10.5935/1678-9741.20160062 Eisenmenger syndrome in pregnancy Zhang JL , Lu JK , Zhou XR , et al. , 2018 . Perioperative management of pregnant women with idiopathic pulmonary arterial hypertension: an observational case series study from China . J Cardiothorac Vasc Anesth , 32 ( 6 ):‍ 2547 - 2559 . https://doi.org/10.1053/j.jvca.2018.01.043 https://doi.org/10.1053/j.jvca.2018.01.043 Perioperative management of pregnant women with idiopathic pulmonary arterial hypertension: an observational case series study from China Shibin HONG contributed to data analysis, writing and editing of the manuscript. Xin KANG contributed to data analysis. Ka U. LIO contributed to writing and editing of the manuscript. Yiping LE and Chuan WANG collected materials in the study. Jianhua LIN and Ning ZHANG conceived and designed the study, and revised the manuscript. The scientific guarantor of this publication is Ning ZHANG. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data. We acknowledge all the multidisciplinary members from Renji Hospital (Shanghai, China) for their dedication and support. This work was supported by the Natural Science Foundation of Science and Technology Commission of Shanghai Municipality (No. 22ZR1438700), China. 10.1631/jzus.B2200368 1673-1581（2023）01-0089-05 洪士彬,康昕,Ka U. LIO等.足月妊娠合并艾森曼格综合征的多学科治疗[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2023,24(01):89-93. 洪士彬,康昕,Ka U. LIO等.足月妊娠合并艾森曼格综合征的多学科治疗[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2023,24(01):89-93. 2022-07-10 2022-09-18 2023-01-15 2023-02-06 2022-12-08 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2022 2023 浙江大学出版社 Shibin HONG, Xin KANG, Ka U. LIO, Yiping LE, Chuan WANG, Jianhua LIN, and Ning ZHANG declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the Ethics Committee of Renji Hospital, Shanghai Jiao Tong University School of Medicine and with the Helsinki Declaration of 1975, as revised in 2008 (5). Ethical approval document was not required for the single case report in accordance with the Renji Hospital's requirement. Informed consent was obtained from the patient for being included in the study. Additional informed consent was obtained from the patient for which identifying information is included in this article. Compliance with ethics guidelines 浙江大学学报（英文版）（B辑：生物医学和生物技术） 1 24