Massive fetal cardiac rhabdomyoma treated with transplacental sirolimus

Introduction

Fetal cardiac rhabdomyomas, typically secondary to tuberous sclerosis complex, are generally noted in the second trimester and often grow until 30-32 weeks gestational age (GA), with spontaneous regression possible in the third trimester and after birth [1, 2]. Transplacental therapy with maternal oral mechanistic target of rapamycin inhibitor (mTORi) use initiated in the third trimester has been successful in several documented cases at reducing tumor size, with rare reports of fetal growth restriction and no serious adverse effects documented [1-5]. In this case, given findings of fetal hydrops with ventricular dysfunction and left ventricular outflow tract (LVOT) obstruction with concern for impending fetal demise, transplacental sirolimus was initiated with good tumor response.

Case report

A gravida 3 para 2 mother at 26 weeks GA with history of chronic hypertension, anxiety, and gestational diabetes presented to the fetal cardiology clinic for evaluation of cardiac masses progressing in size. Initial fetal echocardiogram showed a large 2.1 × 2.1 × 2.6 cm echogenic mass adherent to the interventricular septum extending from the left ventricular apex to base. The mass protruded into the LVOT and abutted the anterior leaflet of the mitral valve, causing severe LVOT obstruction. Systolic function of the left ventricular free wall was mildly depressed with moderate mitral regurgitation, mild to moderate tricuspid regurgitation, normal right ventricular systolic function, and no right ventricular outflow tract obstruction. There were no arrhythmias or pericardial effusion. At 27 weeks GA, a fetal magnetic resonance imaging study was performed, which demonstrated trace pericardial and pleural effusion, ascites, skin edema, and scrotal edema concerning for development of hydrops, confirmed on obstetric ultrasound. Consideration of maternal sirolimus therapy was discussed, however mother preferred to continue observation at that time. Weekly follow-up demonstrated progressive growth of the mass and hydrops. Amniotic fluid indices increased from 24.6 cm to 36.2 cm, consistent with polyhydramnios. Fetal biophysical profiles remained reassuring. By 30 weeks GA, the mass had increased in size to 4.4 × 4.4 cm with moderate to severe mitral and tricuspid regurgitation and severe hydrops (Figures 1 and 2).
Severe narrowing of the LVOT was still present, with preserved antegrade flow across the aortic valve and aortic arch. There was moderate to severe left ventricular and mild right ventricular systolic dysfunction. Sirolimus was initiated at a dose of 2 mg/m2/day divided twice daily. Trough levels were measured at 5 days, targeting 10-12 ng/ml. Complete metabolic panel, complete blood count, and lipid panel were obtained at initiation and weekly thereafter. Inpatient monitoring, twice weekly evaluation for fetal growth and well-being, and weekly fetal echocardiograms were performed. The fetal growth rate remained normal. A decrease in the size of the mass was noted 2 weeks after sirolimus initiation with subsequent decrease in the amount of hydrops. By 36 weeks GA, the mass size had significantly decreased with an increase in left ventricular cavity size (Figures 3 and 4).
Oligohydramnios was also noted at 36 weeks GA (amniotic fluid index decreased to 2.5 cm); thus, the fetus was delivered via repeat Cesarean section. The infant required intubation and prostaglandin initiation after delivery due to inadequate cardiac output that was due to left ventricular systolic dysfunction. Prostaglandin was discontinued by 24 hours of life, and the infant was maintained on low-dose epinephrine and milrinone along with oral everolimus with gradual transition to oral heart failure medications. The infant was discharged at 6 weeks of life. At 3 months of life, the mass measured 0.9 × 1.5 cm with no LVOT obstruction. There was mild dynamic right ventricular outflow tract obstruction, normal left ventricular size with mild left ventricular dysfunction (left ventricular ejection fraction of 51%), trivial mitral regurgitation, normal tricuspid valve function, and normal right heart size and function. Postnatal genetic testing confirmed diagnosis of tuberous sclerosis complex.

Conclusions

As demonstrated in this case, mTORi therapy is thought to reduce tumor size by slowing cell growth and proliferation. However, maternal use of mTORi therapy is also thought to increase risk of fetal growth restriction due to effects on transfer of substrates including fatty acids, glucose, and amino acids, and possible resulting placental insufficiency [6]. As mentioned in one large case series investigating prognostic factors relating to fetal cardiac tumors, use of mTORi therapy is still isolated and has an unknown safety profile [7]. Transplant Pregnancy Registry International data through 2020 does provide reassuring support that sirolimus exposure during all stages of pregnancy does not appear to correlate with congenital fetal anomalies [8]. Reported maternal sirolimus dosing regimens have ranged from 1 mg/day to 6 mg/day. A consensus dosing regimen for transplacental treatment of fetal cardiac rhabdomyoma has not yet been defined [1]. Our patient was treated with 2 mg/m2/day divided twice daily with excellent tumor response and fetal clinical improvement. Development of fetal oligohydramnios has never been reported in these cases and is an important clinical concern to be aware of in monitoring during transplacental sirolimus use. While data are still limited regarding maternal and fetal safety and efficaciousness, we report a single case of fetal cardiac rhabdomyoma with hemodynamic compromise that was safely and effectively treated via transplacental mTORi therapy.

Conflict of interest

The authors declare no conflict of interest.

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