Chemotherapy-Induced Cardiomyopathy in Pregnancy: A Multidisciplinary Approach.

History of Presentation
A 38-year-old gravida 4 para 3 woman at 10 weeks’ gestation palpated a right axillary mass while breastfeeding her infant. Breast magnetic resonance imaging and ultrasound confirmed a mass. Biopsy of the right breast mass with lymph node dissection revealed triple-negative, stage IIIB breast cancer.
Take-Home Messages
•Gestational cancer requires multidisciplinary cardio-obstetric and oncologic coordination to optimize maternal and fetal outcomes, balancing the timing and safety of cancer therapy with pregnancy-related physiological changes and fetal risks.

•Chemotherapy-related cardiac dysfunction during pregnancy demands vigilant cardiac surveillance and tailored therapy during pregnancy, precise labor and delivery planning, and individualized postpartum care to optimize maternal and fetal risks.

After a thorough risk versus benefit discussion that included the options of pregnancy termination, postponement of treatment, surgery, or chemotherapy during pregnancy, the shared decision was to initiate anthracycline and cyclophosphamide therapy during the second trimester of pregnancy. After 3 cycles of chemotherapy, a transthoracic echocardiogram (TTE) demonstrated left ventricular dilation with mildly reduced left ventricular ejection fraction (LVEF) of 41%, at 21 weeks’ gestation. She was referred to a multidisciplinary cardio-obstetric center of excellence for coordinated management of her active malignancy and suspected chemotherapy-induced cardiomyopathy during pregnancy. She reported daily palpitations that occurred intermittently without identifiable triggers. During these paroxysmal episodes, she experienced shortness of breath and lightheadedness. She denied chest pain, syncope, lower extremity edema, orthopnea, or paroxysmal nocturnal dyspnea.

Past Medical History
Medical history was remarkable for BRCA1 mutation diagnosed at 37 years of age, before pregnancy. She had no prior cardiac history. Her obstetric history was notable for 3 prior full-term pregnancies delivered via cesarean section.

Differential Diagnosis
Given recent anthracycline exposure, the leading diagnosis was cancer therapy–related cardiac dysfunction secondary to anthracycline. Peripartum cardiomyopathy and arrhythmia-mediated cardiomyopathy were also considered. Peripartum cardiomyopathy was thought to be less likely given the temporal association between the cardiotoxic chemotherapy exposure and cardiomyopathy, and presentation in the second trimester because peripartum cardiomyopathy typically presents in the late third trimester or postpartum. Given the onset of cardiomyopathy before development of ventricular arrythmias, arrythmia-induced cardiomyopathy was less likely the primary etiology.

Investigations
Prechemotherapy cardiac evaluation was significant for normal resting 12-lead electrocardiogram (ECG), normal troponin, brain natriuretic peptide (BNP), and TTE with normal LVEF of 55%, normal right ventricular (RV) size and function, and no valvular heart disease. After 3 cycles of doxorubicin and cyclophosphamide chemotherapy, a TTE at 21 weeks’ gestation demonstrated a dilated left ventricle: left ventricular internal diastolic dimension (LVIDd) 6.3 cm, reduced LVEF of 41%, left ventricular global longitudinal strain of −16%, and normal RV size and function. BNP was 141 pg/mL. A noncontrast cardiac magnetic resonance showed a dilated left ventricle with end-diastolic volume of 265.5 mL, depressed LVEF of 47%, moderate mitral regurgitation with regurgitant volume of 34 mL, and normal RV size and RV ejection fraction (50.9%) (Video 1). An ECG showed normal sinus rhythm (NSR), QTc interval of 478 milliseconds, and polymorphic premature ventricular contractions (PVCs) (Figure 1A). Ambulatory electrocardiography monitoring revealed NSR with PVC burden of 32%, with 812 frequent, nonsustained ventricular tachycardia (NSVT) episodes (Figure 1B). Follow-up TTE at 30 weeks’ gestation demonstrated further dilation (LVIDd up to 7.0 cm), decrement in LVEF to 35% to 40%, and normal RV size and function (Video 2). Repeat BNP was 86 pg/mL.

Management
The patient was referred to a tertiary center of excellence for multidisciplinary cardio-obstetric management of cardiomyopathy in context of active malignancy and pregnancy. After multidisciplinary patient-centered discussions with oncology, cardiology, and maternal fetal medicine, the patient chose to continue with current pregnancy with known maternal and fetal complications associated with malignancy, chemotherapy, and cardiomyopathy. Her chemotherapy regimen was transitioned from doxorubicin and cyclophosphamide to carboplatin and paclitaxel given concern for possible anthracycline-induced cardiotoxicity. She was monitored closely with serial ECGs, BNPs, and TTEs every 6 to 8 weeks, in addition to close fetal surveillance. Beta-blocker (BB) therapy for cardiomyopathy and coexistent symptomatic PVCs was initiated. She developed frequent, symptomatic NSVT refractory to beta-blockade, prompting admission at 30 weeks’ gestation for initiation of sotalol therapy. She continued active chemotherapy treatment throughout her pregnancy with close maternal and fetal monitoring. Surveillance fetal ultrasounds demonstrated normal intrauterine growth. Given her prior cesarean sections, a repeat cesarean section at term (>37 weeks) was recommended and planned in the cardiac operating room with support of cardiac and obstetric anesthesia, gynecology oncology, and maternal fetal medicine. In the setting of BRCA1 + status, gynecology-oncology recommended concomitant prophylactic bilateral salpingo-oophorectomy. The optimal timing of delivery was determined by maternal hemodynamic and fetal status, and last administered chemotherapy dose to allow for hematologic recovery, reduced infection risk, and improved wound healing, while minimizing delays in resumption of oncologic therapy.

Outcome and Follow-Up
Preterm delivery was planned due to worsening maternal cardiac status, declining left ventricular function, and chemotherapy timing. A detailed timeline of events can be found in Table 1. Her last carboplatin/paclitaxel dose was at 31 weeks, with delivery scheduled 4 weeks later to optimize wound healing and reduce infection risk. She underwent repeat cesarean section and bilateral salpingo-oophorectomy at 35 weeks 4 days’ gestation under epidural anesthesia. Her delivery and postpartum course were uncomplicated, with delivery of a healthy girl weighing 2,290 g. Guideline-directed medical therapy (GDMT) for heart failure was initiated postpartum with enalapril, metoprolol, and spironolactone given her desire to breastfeed. Sotalol was continued for the management of NSVT. Given successful suppression of arrhythmias with medical therapy, ventricular tachycardia ablation was deferred at the time. TTE at the time of discharge showed an LVEF of 35% to 40% with continued left ventricular cavity dilation but overall, no significant change. The patient self-discontinued breastfeeding in the early postpartum period allowing for transition of enalapril to sacubitril-valsartan and initiation of dapagliflozin, for maximal GDMT of her cardiomyopathy. She received one additional cycle of carboplatin and paclitaxel postpartum followed by initiation of pembrolizumab. She is pending bilateral mastectomy, radiation therapy, and initiation of olaparib.

Discussion
Gestational cancer is cancer that occurs during pregnancy or within 12 months postpartum and occurs in about 1 in 1,000 pregnancies, most frequently due to breast cancer.1 Patients with gestational cancer should be referred to a multidisciplinary cardio-obstetrical team for counseling on the potential effects of cancer and oncologic treatments on the pregnancy and the developing fetus. Chemotherapy is contraindicated in the first trimester of pregnancy, during organogenesis, due to the high risk of malformations and abortions.2 Chemotherapy can be safely administered during the second and third trimesters, until the 34th week of gestation, to avoid pancytopenia around the time of delivery. The risks associated with chemotherapy administration include premature birth and low birth weight. Chemotherapy regimens for breast cancer in pregnancy typically include combinations of 5-fluorouracil, anthracyclines, and cyclophosphamide. Doxorubicin and epirubicin have the lowest transplacental transfer among the anthracyclines, and no teratogenic effects have been observed with their use in the second and third trimesters.2,3
Anthracyclines are associated with type I chemotherapy-related cardiac dysfunction, in which iron-based oxygen free radicals induce myocardial necrosis.4 Doxorubicin-induced cardiomyopathy is dose-dependent, with incidence rates of approximately 5% at cumulative lifetime doses of 400 mg/m2, rising to 48% at 700 mg/m2, with heightened risk when combined with other cardiotoxic agents such as cyclophosphamide or trastuzumab.4,5 Although our patient received doses below this cumulative dose, acute cardiac toxicity has been reported at lower doses. Dexrazoxane has been used to prevent cardiac toxicity in patients with doxorubicin doses >300 mg/m2 and epirubicin doses >540 mg/m2, by preventing DNA double-strand breaks.4,6 However, dexrazoxane is contraindicated in pregnancy and lactation, and was therefore not recommended for use in this patient's care.
All patients undergoing chemotherapy in the context of pregnancy should undergo monthly or bimonthly ECG, TTE, and cardiac biomarkers to monitor for cancer therapy–related cardiac dysfunction.1 According to the 2014 American Society of Echocardiography guidelines, chemotherapy-induced cardiomyopathy is defined as a drop in LVEF of >10% to a value <53%.7 When TTE is nondiagnostic, alternative imaging such as noncontrast cardiac magnetic resonance may be used because gadolinium-based contrast agents cross the placenta and are retained in fetal tissues with limited long-term safety data.
Management of cancer therapy–related cardiac dysfunction follows GDMT for heart failure, including a BB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, mineralocorticoid receptor antagonist, and sodium-glucose cotransporter 2 inhibitor. Early initiation—within 2 months of diagnosis—of enalapril and carvedilol or bisoprolol has been shown to improve LVEF.4 However, angiotensin-converting enzyme inhibitors are contraindicated in pregnancy due to teratogenicity. In this case, BB therapy was used throughout pregnancy, and enalapril was initiated postpartum to support recovery and accommodate the patient's breastfeeding wishes.
Positive maternal and fetal outcomes in this case were largely attributed to the efforts of a dedicated multidisciplinary cardio-obstetric team, including maternal-fetal-medicine, cardio-obstetric providers, cardio-oncologists, electrophysiologists, heart failure specialists, oncologists, anesthesiologists, and nurse navigators whom maintained close communication with the patient and each other—coordinating treatment plans that balanced maternal and fetal safety, allowed continuation of cancer therapies, and allowed the desired pregnancy with ultimate carefully executed delivery and postpartum management.

Conclusions
This case highlights the complexity of managing pregnancy in patients with anthracycline-induced cardiomyopathy and active malignancy. Chemotherapy-induced cardiomyopathy can manifest with ventricular dysfunction and arrhythmia during pregnancy, a period characterized by increased hemodynamic stress. This case illustrates that a multidisciplinary cardio-obstetrics approach is essential for coordinated peripartum management, and that favorable maternal and neonatal outcomes can be achieved in high-risk pregnancies complicated by cancer therapy–related cardiac dysfunction.

Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.