Complete resolution of arrhythmia-induced hydrops fetalis in utero

Abstract

A 21-year-old G3P2011 Caucasian woman at 27 weeks’ gestation presented with fetal tachyarrhythmia between 240 and 270 beats per minute. Fetal supraventricular tachycardia, abdominal ascites, pleural effusion and pericardial effusion indicated hydrops fetalis. Management with digoxin and flecainide converted the fetus to sinus rhythm and resolved the ascites and pleural effusion within 4 days of treatment. Flecainide was discontinued at 31 weeks’ gestation due to elevated liver enzymes. Intrahepatic cholestasis was treated with ursodiol. Caesarean section was performed at 37 weeks’ gestation. Neonatal echocardiogram revealed a bicuspid aortic valve with mild regurgitation and a patent foramen ovale, and the infant showed no subsequent evidence of tachyarrhythmia or hydrops after delivery. Treatment of hydrops fetalis in the antenatal period is complex, and early diagnosis and treatment can quickly resolve supraventricular tachycardia-induced hydrops fetalis.

Background

Hydrops fetalis is defined as the collection of fluid in at least two extravascular cavities of the fetus and can be manifested by abdominal ascites, pleural effusions, pericardial effusions and/or skin oedema. The aetiology of this presentation is complex and incompletely understood, but current literature classifies hydrops as either an immune-driven process due to red cell alloimmunisation or as non-immune.¹ Non-immune hydrops fetalis (NIHF), the more common aetiology, is primarily a result of cardiac pathology, including structural cardiac defects and arrhythmias. Less commonly, NIHF can result from chromosomal abnormalities, maternal or fetal infection, fetal skeletal dysplasia, fetomaternal haemorrhage or haematologic abnormalities.² Due to a combination of increased central venous pressure, decreased vascular oncotic pressure, increased capillary permeability and/or decreased lymphatic drainage, fluid extravasates into the interstitial spaces of the fetal body. With expanded use of ultrasonography and echocardiography, the diagnosis may be made early, allowing time for diagnostic procedures and treatment plans. However, despite these measures, hydrops has a poor prognosis and results in fetal death in 40%–50% of cases. Advancements in medicine have found treatments to help alleviate hydrops, but it is rare to see a complete regression of the often fatal disease process.¹ In this report, we present an extraordinary case of complete prenatal resolution of hydrops in a fetus with supraventricular tachycardia (SVT) following maternal medical management with digoxin and flecainide.

Case presentation

A 21-year-old G3P2011 Caucasian woman at 27 weeks’ gestation was transferred to Texas Tech University Health Science Center School of Medicine in Amarillo with fetal tachyarrhythmia between 240 and 270 beats per minute (bpm). The patient has an obstetrical history of spontaneous abortion at 17 weeks’ gestation due to hydrops of unknown aetiology and a history of shoulder dystocia at the delivery of an intrauterine fetal demise at 37 weeks’ gestational age. Her medical history was notable for Henoch-Schonlein purpura, IgA nephropathy and iron-deficiency anaemia.

Investigations

Initial ultrasonogram and echocardiogram of the fetus performed at 27 weeks’ gestation showed fetal SVT (figure 1), with abdominal ascites, pleural effusion and pericardial effusion indicating a clear picture of hydrops fetalis. The specific measurements were 13 mm for the abdominal ascites (figure 2), 5.8 mm for the pericardial effusion (figure 3) and 5 mm for the pleural effusion.

Figure 1.

Fetal tachycardia of 268 beats per minute on fetal echocardiogram at 26 weeks’ gestation.

Figure 2.

Ascites measuring 13 mm on ultrasonogram at 26 weeks’ gestation.

Figure 3.

Pericardial effusion measuring 5.8 mm on ultrasonogram at 26 weeks’ gestation.

Following consultation with paediatric cardiology, concomitant treatment with digoxin and flecainide converted the fetus to sinus rhythm (figure 4). After 1 day of treatment, abdominal ascites reduced to 7 mm, pericardial effusion diminished to 2.6 mm and the pleural effusion was no longer visualised by ultrasonography. Resolution of ascites (figure 5) was noted by the 4th day of treatment with the pericardial effusion remaining at 3 mm (figure 6).

Figure 4.

Fetal sinus rhythm of 124 beats per minute on fetal echocardiogram at 27 weeks’ gestation.

Figure 5.

Resolution of ascites on ultrasonogram at 27 weeks’ gestation.

Figure 6.

Pericardial effusion measuring 3 mm on ultrasonogram at 27 weeks’ gestation.

After initiation of treatment, the fetal heart rate (FHR) was assessed three times per week and non-stress testing and biophysical profile were performed two times per week. After 5 weeks of treatment, the patient was noted to have elevated liver enzymes, and flecainide was discontinued. Further hepatic testing at that time showed elevated bile acids of 327.6 µmol/L, consistent with severe intrahepatic cholestasis of pregnancy (ICP), which is diagnosed with bile acid levels over 40 µmol/L. The patient was assessed periodically for evidence of digoxin toxicity via serum levels and maternal electrocardiography.

Due to patient’s history of IgA nephropathy, the patient underwent periodic assessment of renal function with 24-hour protein collections and spot protein/creatinine ratios. The patient was also evaluated for pre-eclampsia and mirror syndrome due to IgA nephropathy.

Differential diagnosis

While the diagnosis of hydrops fetalis was relatively clear due to multiple fetal fluid collections, the aetiology is critical to deduce. Due to the elevated FHR, a cardiac aetiology was suspected. The prompt resolution of symptoms with antiarrhythmic treatment confirmed that the hydrops was induced by the SVT. After birth, testing was completed to rule out other potential aetiologies, as delineated in the Outcome section.

The cause of the patient’s elevated liver enzymes, however, was not as clear initially. Hepatotoxicity is a very rare side effect of flecainide with cholestatic hepatitis usually occurring within 1–6 weeks of initiating flecainide.³ In this case, discontinuation of the medication did result in normalisation of liver enzymes. The patient had persistence of elevated bile acids, consistent with ICP. Ursodiol treatment reduced circulating bile acid levels prior to delivery.

Treatment

When the patient initially presented, she was treated with intramuscular betamethasone for fetal lung maturation and an antiarrhythmic regimen of oral digoxin 0.25 mg three times per day and flecainide 100 mg two times per day that successfully converted the fetus to sinus rhythm. During the initial admission, maternal ECG was closely followed for QRS and QT intervals, and the patient’s serum digoxin trough level was measured 6 hours after dosing and found to be within the target range. However, when the patient was readmitted at 31 weeks due to chest pain later diagnosed as costochondritis, the digoxin level measured 2.3 ng/mL on day 4 of admission greater than 6 hours after the last digoxin dose. Due to required maintenance of therapeutic serum digoxin concentration between 1 ng/mL and 2 ng/mL, digoxin dose was reduced to 0.25 mg two times per day, and this dose was maintained until delivery as the minimum therapeutic dose for appropriate control of SVT.⁴ Flecainide was also discontinued at 31 weeks’ gestation due to elevated liver enzymes. Ursodiol 300 mg two times per day was started for intrahepatic cholestasis of pregnancy.

Outcome and follow-up

Because the patient had ICP and a history of shoulder dystocia, caesarean section was performed at 37 weeks’ gestation. The neonate had a temperature of 37.7°C, a respiratory rate of 40 breaths per minute and a heart rate of 136 bpm. Auscultatory findings included regular rate and rhythm with no murmurs, rubs or gallops. The neonate was admitted to the neonatal intensive care unit (NICU) for 4 days due to respiratory distress secondary to possible meconium aspiration versus transient tachypnea and required constant positive airway pressure treatment. Neonatal ECG showed normal sinus rhythm with a heart rate of 153 bpm and possible right ventricular hypertrophy with no evidence of ectopic beats or pre-excitation (figure 7). The neonate was monitored on oxy-cardiorespirogram monitoring over the course of the NICU stay which showed no evidence of ectopic beats or tachyarrhythmia. Accordingly, no antiarrhythmic medical management was started. Negative antibody screening ruled out red cell alloimmunisation or any other minor blood group incompatibilities. A TORCH (toxoplasmosis, syphilis, rubella, cytomegalovirus, herpes simplex) infection panel was negative, and the patient had no known exposure to parvovirus. Newborn screening and critical congenital heart disease screening were also negative. Transthoracic echocardiogram (TTE) revealed bicuspid aortic valve with mild aortic regurgitation and a patent foramen ovale. Based on these findings, the cause of the hydrops was determined to be a cardiac pathology with SVT. The neonate did not have ascites, pleural effusion or pericardial effusion on X-ray or on two subsequent TTEs performed the first week of life (figure 8). Follow-up with paediatric cardiology at 4 weeks of life showed no evidence of postnatal arrhythmia on ECG, and thus no antiarrhythmic management was prescribed. The family was counselled on monitoring the infant for signs and symptoms of SVT, how to measure the infant’s heart rate and the importance of seeking early prenatal care in future pregnancies to assess for risk of hydrops fetalis.

Figure 7.

Neonatal ECG exhibiting normal rate and rhythm.

Figure 8.

No evidence of hydrops fetalis on neonatal X-ray after delivery.

Discussion

The reported mortality rate of hydrops fetalis is nearly 50%. Cardiac anomalies (including structural defects, arrhythmias and tumours) and infections are responsible for at least 10%–20% of prenatally diagnosed cases of NIHF. SVT, which is the focus of this case report, elevates the atrial pressure, decreases cardiac output and may lead to congestive heart failure. Thirty-five per cent to 60% of fetuses with SVT will develop NIHF, and the mortality rate is approximately 27%.^{5 6} Those who live often require continued treatment after birth.

A few cases of SVT-induced hydrops fetalis have been published but with crucial differences from this case. A majority of cases were diagnosed at an earlier gestational age yet had findings leading to poorer outcomes such as persistent hydropic features at birth and postnatal arrhythmias which required interventions such as emergency caesarean section, premature delivery and postnatal antiarrhythmic management. Another published case also demonstrated maternal cholestatic hepatitis with no fetal complications after treatment; however, both transplacental and direct fetal antiarrhythmic treatments were used to control the heart rhythm.⁷ Additionally, the fetal tachycardia in these cases was not as severe and was recorded between 200 and 250 bpm, except one notably at 292 bpm.⁸ These cases also implemented varied medication management of SVT, including digoxin alone, flecainide alone, digoxin with flecainide and digoxin with sotalol. Even with these varied regimens, the hydrops often took longer to resolve than the 5 days required in this case.^7–12

The case presented is unusual in that the patient presented at a later gestational age with a severe fetal tachyarrhythmia, delivered at 37 weeks’ gestation, and had no need for postnatal antiarrhythmic treatment. The positive outcome in this case highlights the importance of proper diagnosis and treatment of hydrops in utero.

Diagnosis of hydrops is usually made by ultrasound between 19 and 36 weeks’ gestation.⁴ To deduce the aetiology of the hydrops fetalis, initial work-up including anatomical ultrasound and fetal echocardiogram should be performed to rule out cardiac abnormalities before extensive work-up for other non-immune causes. Periodic FHR assessment should be performed. FHR >200 requires consultation with a paediatric cardiologist, but if heart structure and function are normal, the patient can be monitored with fetal heart doppler, biophysical profile and non-stress tests alone. If FHR >220, the fetus is likely to develop hydrops with increased duration of SVT. In such cases, inpatient maternal assessment and 24-hour monitoring is warranted to determine the frequency of the arrhythmia.⁴

If, as in this case, when SVT and hydrops fetalis are diagnosed concurrently, immediate treatment is indicated. Antiarrhythmic medications are the main course of treatment, and digoxin is usually the first line. If this is insufficient in converting the SVT to normal sinus rhythm, sotalol or flecainide can be added to the treatment protocol as second line agents. All three of these medications are cleared by the renal system, and due to the increased glomerular filtration rate associated with pregnancy, dosing is often initiated three times per day compared with two times per day dosing. Additionally, achieving therapeutic fetal concentration of antiarrhythmic drugs is complicated by the low level of placental transfer. Maternal serum digoxin levels should be maintained between 1 ng/mL and 2 ng/mL for efficacy in reducing FHR.⁴ However, flecainide has been shown to have superior transplacental transfer and effectiveness in hydrops compared with digoxin, but the first line agent for treatment is debated.¹³ In this case, due to the profound fetal tachycardia up to 270 bpm, the patient was started on a concomitant digoxin and flecainide regimen which was successful in converting the abnormal rhythm to a sinus rhythm and resolving the hydrops. After 5 weeks of treatment, the patient developed elevated liver enzymes. Flecainide was discontinued due to possible hepatoxicity with the potential for subsequent hepatic failure. While taking ursodiol, aspartate aminotransferase and alanine aminotransferase levels returned to normal prior to delivery.

Determining the plan for delivery for the fetus was influenced by several factors. Due to rapid resolution of the hydrops and the preterm gestation, delivery was not indicated at the time of diagnosis. The Society of Maternal–Fetal Medicine reports that elective preterm deliveries of fetuses with NIHF do not improve outcomes. Additionally, the fetus should be delivered at 34 weeks if the hydrops is worsening, but it can be delayed to 37–38 weeks if there is no change or alternative reason for early intervention.¹⁴

Learning points.

• It is crucial to conduct a complete work-up for all aetiologies of hydrops fetalis both prenatally and postnatally, with a focus on cardiac pathology including structural cardiac defects and arrhythmias, congenital infections and haematologic abnormalities.

• Either digoxin or flecainide is suitable for medical management of supraventricular tachycardia depending on patient tolerance.

• Coordinated care between obstetrics and paediatric cardiology is critical for in utero management of hydrops.