Supraventricular tachycardia is the most common and clinically significant form of sustained fetal tachyarrhythmia in pregnancy; depending on duration and high rate variability heart failure and nonimmune hydrops may develop which are associated with a high incidence of perinatal mortality. Doppler/echo diagnosis is usually accidental during second and third trimester of pregnancy. Therapeutic goals are cardioconversion to sinus rhythm and recovery of heart failure. We present a case of fetal supraventricualr tachycardia diagnosed at 29 weeks of gestation with nonimmune hydrops. Treatment with digoxin and amiodarone was successful. The heart rate restored to sinus rhythm and nonimmune hydrops resolved within three weeks of treatment. Therapy with two drugs that act synergistically may be more efficient than monotherapy in blocking likely atrio-ventricular reentry mechanism by accessory pathway in sustained supraventricular tachycardia, thus allowing resolution of hydrops with favorable management outcome.Supraventrikularna tahikardija je najčešći i klinički najznačajniji oblik fetalne tahiaritmije u trudnoći, a ovisno o trajanju i visini srčane aktivnosti mogu se razviti zatajenje srca i neimuni fetalni hidrops, oboje povezani s lošim perinatalnim ishodom. Tijekom drugog i trećeg tromjesečja dijagnoza se često slučajno postavlja ultrazvučnim doplerskim nalazom. Terapijski cilj je konverzija u sinus ritam i oporavak srčane funkcije. Donosimo prikaz slučaja fetalne supraventrikularne tahikardije s neimunim hidropsom, dijagnosticirane u 29. tjednu trudnoće. Terapija digoksinom i amiodaronom bila je uspješna. Ponovo je uspostavljen sinusni ritam srčane frekvencije, a neimuni hidrops se povukao unutar tri tjedna liječenja. Terapija dvama lijekovima sa sinergističkim djelovanjem može biti učinkovitija od monoterapije u blokiranju vjerojatno ponovnog ulaska atrio-ventrikularnog impulsa pomoću sporednog puta u supraventrikularnoj tahikardiji, time dopuštajući povlačenje hidropsa te bolji ishod

Ivan Malčić

Josip Juras

Jozo Blajić

Marina Ivanišević

Vesna Sokol

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44Gynaecol Perinatol 2011;20(1):44–47University Medical School of Zagreb,*Clinical Hospital Centre Zagreb, Department of Obstetrics and Gynecology,**Department of pediatrics***DIGOXIN AND AMIODARONIN FETAL SUSTAINED SUPRAVENTRICULAR TACHYCARDIAAND NONIMMUNE HYDROPSDIGOXIN I AMIODARONKOD TRAJNE FETALNE SUPRAVENTRIKULARNE TAHIKARDIJEI NEIMUNOLO[KOG FETALNOG HIDROPSAVesna Sokol,** Josip Juras,* Ivan Mal~i},*** Jozo Blaji},** Marina Ivani{evi}**Case reportKey words: fetalus, tachycardia supraventricular, fetal hydrops, digoxin, amiodaroneSUMMARY. Supraventricular tachycardia is the most common and clinically significant form of sustained fetal tachyar-rhythmia in pregnancy; depending on duration and high rate variability heart failure and nonimmune hydrops may de-velop which are associated with a high incidence of perinatal mortality. Doppler/echo diagnosis is usually accidental during second and third trimester of pregnancy. Therapeutic goals are cardioconversion to sinus rhythm and recovery of heart failure. We present a case of fetal supraventricualr tachycardia diagnosed at 29 weeks of gestation with nonimmune hydrops. Treatment with digoxin and amiodarone was successful. The heart rate restored to sinus rhythm and nonim-mune hydrops resolved within three weeks of treatment. Therapy with two drugs that act synergistically may be more efficient than monotherapy in blocking likely atrio-ventricular reentry mechanism by accessory pathway in sustained supraventricular tachycardia, thus allowing resolution of hydrops with favorable management outcome.Prikaz bolesniceKlju~ne rije~i: fetus, tahikardija supraventrikularna, fetalni hidrops, digoksin, amiodaronSA`ETAK. Supraventrikularna tahikardija je naj~e{}i i klini~ki najzna~ajniji oblik fetalne tahiaritmije u trudno}i, a ovi-sno o trajanju i visini sr~ane aktivnosti mogu se razviti zatajenje srca i neimuni fetalni hidrops, oboje povezani s lo{im perinatalnim ishodom. Tijekom drugog i tre}eg tromjese~ja dijagnoza se ~esto slu~ajno postavlja ultrazvu~nim dopler-skim nalazom. Terapijski cilj je konverzija u sinus ritam i oporavak sr~ane funkcije. Donosimo prikaz slu~aja fetalne supraventrikularne tahikardije s neimunim hidropsom, dijagnosticirane u 29. tjednu trudno}e. Terapija digoksinom i amiodaronom bila je uspje{na. Ponovo je uspostavljen sinusni ritam sr~ane frekvencije, a neimuni hidrops se povukao unutar tri tjedna lije~enja. Terapija dvama lijekovima sa sinergisti~kim djelovanjem mo`e biti u~inkovitija od monotera-pije u blokiranju vjerojatno ponovnog ulaska atrio-ventrikularnog impulsa pomo}u sporednog puta u supraventrikular-noj tahikardiji, time dopu{taju}i povla~enje hidropsa te bolji ishod.IntroductionSupraventricular tachycardia is the most common and clinically significant form of sustained fetal tachyar-rhythmia in pregnancy. Depending on duration and high rate variability, heart failure and nonimmune hydrops may develop, that are associated with a high incidence of perinatal mortality. Therapeutic goals are cardiocon-version to sinus rhythm and recovery of heart failure, most frequently by digoxin and sotalol.Case reportA 28 year old primigravida at 29 weeks of gestation (with ultrasound analysis the pregnancy was 2 weeks younger) was referred to our antenatal clinic because of fetal tachycardia detected during her routine antenatal scan. She was transferred from another clinical hospital where she was treated with sotalol on which she devel-oped allergic reaction. Her antenatal period was une-ventful till 26 weeks when Doppler/M-echocardiogra-phy showed fetal supraventricular tachycardia (SVT) with minimal pericardial effusion. There was no history of fever or thyrotoxicosis. In family history, her mother has angina pectoris and arterial hypertension. The pa-tient was admitted to our hospital for administration of antiarrhythmic therapy. At admission patient’s height was 168 cms and weight 73(+9) kg. Blood pressure was 110/60 mmHg. ECG: sinus rhythm with 76 bpm.Fetal echocardiography showed normal heart posi-tion in left hemithorax with higher cardiothoracic index of 0.42 (normal 0.25–0.35), enlarged heart silhouette underlying both dilated atria with normal ventricles and valvular morphology, normal atrioventricular concord-ance and relations to surrounding internal organs. Pul-monary veins and vv.cavae were of normal anatomy and inflow. Patent foramen ovale with r-l shunt and ductus Botalli with communications between pulmonary artery and aorta corresponded with the mildly decreased same pressures in both pulmonal artery and aorta of 0.4m/s (normal 0.6–07m/s). Doppler/M-mode echocardiogra-phy demonstrated paroxysms of SVT in the range of 237–260 beats per minute intermittently falling down to 45Gynaecol Perinatol 2011;20(1):44–47 Sokol V. et al. Digoxin and amiodaron in fetal sustained supraventricular tachycardia and nonimmune hydrops131 beats per minute, but only rare and transitory. There were no signs of hydrops.The patient was started on digoxin 3×0.5 mg i.v. per day for three days and continued 3×0.5 mg per os daily. During complete treatment, serum electrolytes and elec-trocardiography were monitored. Three days after ini-tial therapy with digoxin the patient developed symp-toms of digoxin toxicity with epigastric pain, vomiting and nausea and ECG–changes showed intermittent first degree and second degree Mobitz II AV block and ST denivelation. Serum digoxin levels were elevated up to 5.3 mmol/L (normal 0.7–2.5 mmol/L). Fetal heart rate was found to be normal. She stopped taking digoxin three days till clinical and ECG normalization and after that she again continued digoxin treatment in dose 3×0.5 mg per os daily with expected maintenance dose (serum range 2.0–2.5 mmol/L). Fetal heart rate was found to be between 214–129/min with prevalence of tachycardia. Two weeks later Doppler/M-echocardiography showed the signs of fetal hydrops, the most probable because of underlying heart decompensation. As there were no signs of maternal digoxin intoxication and fetal heart rate was still high and unstable, amiodarone in a dose of 3×200 mgs was added as second line therapy. The dose of digoxin was reduced to 2×0.10 mg per day and amio-darone, after one week of therapy was gradually reduced to 2×200 mg per day without any adverse effects. Fetal cardiac decompensation and fetal hydrops disappeared three weeks after starting antiarrhythmic drugs. The fe-tal heart rate remained stable at 120–140 bpm till deliv-ery with only a few exacerbations. Last fetal ultrasound showed breech presentation. Patient’s autoimmune workup and TORCH screening were negative. Her thy-roid function tests were normal.At 38 week and 6 days of gestation (on ultrasound 36+6 weeks) she underwent elective cesarean section. The 2920 gs male infant with Apgar score 10/10 was delivered. The baby boy was transferred to Clinic of ne-onatology for further observation. On second day of hospitalization, the baby boy developed RDS, which was treated with oxygen and i.v. antibiotics with gradu-al respiratory improvement. During hospitalization ba-by’s heart was monitored and was treated with digoxin postnatally.DiscussionCardiac arrhythmias develop from impairment of im-pulse generation, impulse conduction or both. It is, however, difficult to establish the exact mechanism for many clinical arrhythmias that can appear as response to ischemia, inflammation, electrolyte disturbances, al-tered load states, structural heart defects, inherited ge-netic conditions and other causes.1 Approximately 1% of all pregnancies are complicated by a fetal arrhyth-mia. Although, in most of the cases they are benign and of short duration, 1–3 % is complicated and can lead to fetal death.2There are three different types of fetal arrhythmias that can be seen in pregnancy such as fetal tachycardia with baseline fetal heart rate over 160/min (SVT, atrial flutter or fibrillation, ventricular tachycardia), fetal bra-dycardia with baseline heart rate less than 110/min., and the most common, premature beats as atrial and ventricular extrasystoles. An initiating premature beat caused by abnormal automaticity can precipitate an epi-sode of SVT sustained by AV reentry mechanism and accessory pathway with AV conduction 1:1 up to 220 to 260 bpm (accounts for 93% of total SVT with 1:1 AV conduction).3,4 It is the most commonly encountered fe-tal cardiac arrhythmia in pregnancy that may be associ-ated with adverse perinatal outcome if untreated.5 Fetal SVT can be presented like non sustained (tachycardia with intermittent sinus rhythm) and sustained (pro-longed uninterrupted tachycardia of >12h), which is he-modynamically more dangerous for fetal life.4 In this case, sustained SVT with 1:1 atrioventricular conduc-tion was diagnosed prenatally by the presence of 1:1 atrioventricular contraction sequence during tachycar-dia, abrupt onset and terminations with minimal heart rate variability. Our patient was without favorite risk factors for development of arrhythmia like smoking, caffeine and illicit drugs. Fetal Doppler/M-echocardi-ography showed structurally normal heart with only mildly enlarged cardiac silhouette and both atria.In addition, there are some newer methods used today for the diagnosis of SVT such as magnetocardiogram (MCG) and Doppler myocardial deformation analy-sis.6,7The prognosis and treatment of this kind of arrhyth-mia depend on the presence or absence of fetal hemody-namic compromise, gestational age of fetus at which the tachycardia occurs, the ventricular rate, the percentage of the time that the tachycardia is present and the site of origin of the tachycardia.5,8 Spontaneous resolution of SVT has been reported in some cases to occur in utero or later, during neonatal period.9,10 In fetus with a nor-mal anatomical survey, the management depends upon the gestational age and the presence or absence of hy-drops. In our case we demonstrated nonimmune hy-drops fetalis secondary to sustained SVT that appeared 2 weeks after its initiation to develop heart failure from multiple episodes of tachycardia and recurring at rela-tively »slow heart rates«.5,11The most important goal of treatment is the preven-tion or resolution of hemodynamic compromise. Today, numerous antiarrhythmic drugs have been prescribed for the treatment of fetal tachycardia as digoxin, sotalol, amiodarone and flecainide. We began the treatment transplacentally with digoxin which is the drug of first choice for the treatment of SVT and two weeks later in the sense of developing hydrops phenomenon, we in-cluded in the treatment additionally oral amiodarone, preserving myocardial contractility, because the treat-ment and prognosis of SVT depends not only of sup-pression rate of SVT but recovery from fetal congestive 46Gynaecol Perinatol 2011;20(1):44–47 Sokol V. et al. Digoxin and amiodaron in fetal sustained supraventricular tachycardia and nonimmune hydropsheart failure and hydrops as well.12 Digoxin is cardiac glycoside and for a long time prominent drug in the therapy of congestive heart failure. It has positive ino-tropic and negative chronotropic properties that increase cardiac output and decrease heart rate. With these char-acteristics, digoxin prolongs the refractoriness of the AV node and terminates the circular movements within re-entrant circuit so that aberrant wave of excitation reaches depolarized tissue.5 Digoxin is effective and nontoxic in relatively narrow serum range (0.8 – 2.0 ng/mL), so the optimum therapy for pregnant women or fetus requires an accurate measurement of serum dig-oxin levels.13 During pregnancy increased digoxin dos-age may be necessary because of enhanced renal clear-ance and expanded blood volume. Reported fetal : ma-ternal (F:M) plasma concentration ratios vary from 0.4 to 0.9.14,15 However, in case of fetal hydrops, this ratio is reduced because the placental transfer of the digoxin is limited. In addition, conversion to sinus rhythm with di-goxin is achieved in 50% of nonhydropic fetuses and only in 15–25% in hydropic fetuses.5,16,17 Hence, medi-cation with good placental transfer, such as amiodarone, should be used from the beginning of fetal treatment for hydrops. Digoxin has a few maternal side effects which are related to overdosing like nausea, vomiting and headache.4 There also can be found maternal cardiac ad-verse effects such as ventricular extrasystoles or heart block that was seen in our case.Because of low conversion rate with digoxin, second line drugs are frequently required to achieve sinus rhythm as it was in our case with inclusion of amiodar-one in therapy.Amiodarone prolongs the repolarization of the myo-cardium. A large study by Strasburger et al.18 was pub-lished in which amiodarone had a 93% successful rate of conversion as second line therapy in fetal SVT tachy-cardia complicated with hydrops. Treatment with amio-darone has been associated with transient biochemical neonate hypothyroidism, maternal photosensitive skin rash and thrombocytopenia. In addition, amiodarone is a suitable second line treatment in hydropic SVT and because of unsignificant possibility of proarrhythmic events in distinction of flecainide and sotalol. Amiodar-one administration has been found to increase the steady-state digoxin concentration, and maintenance doses of digoxin should be decreased by ≥50%.19There is also a question whether to treat prenatally or postnatally. The decision mainly depends on gestational age and in early gestational weeks prenatal treatment is the reasonable management. However, if hydrops does not resolve in 2 weeks, postnatally treatment is recom-mended.2 Transplacental therapy is proper mode of therapy in nonhydropic fetuses and first choice in hy-dropic fetuses. But, when conversion to sinus rhythm is not achieved, direct fetal therapy should be recom-mended.After successful fetal rhythm conversion, dosage is maintained till delivery. If the heart rate is controlled, vaginal delivery is recommended and newborns are treated for at least 6–12 months.9 In the case of cesarean section, the maturity of fetal lungs must be verified to avoid neonatal adverse affects. One third or more ne-onates postnatally will be free of further SVT probably due to involution of the abnormal pathway.ConclusionSustained fetal SVT with instability rates of ventricu-lar rhythm and prolonged duration can be serious condi-tion in which the fetus is at significant risk for develop-ing congestive heart failure and hydrops, neurological damage and intrauterine death. Vigilant fetal heart rate control and ultrasound monitoring as well as adequate selection of antiarrhythmic drugs are crucial in tachyar-rhythmia suppression and hydrops resolution. Digoxin and oral amiodarone with its favorable effect on myo-cardial contractility and well known amiodarone high conversion rate in fetal SVT complicated by hydrops were proper option in terms of management outcome.References1. Strasburger JF, Wakai RT. Fetal cardiac arrhythmia detec-tion and in utero therapy. Nat Rev Cardiol 2010;7(5):277–90.2. Maeno Y, Hiroshe A, Kanabe T, Hori D. Fetal arrhythmia: prenatal diagnosis and perinatal management. J Obstet Gynaecol Res 2009;35(4):623–9.3. Rubart M, Zipes DP. Genes and cardiac repolarization: the challenge ahead. Circulation 2005;112(9):1242–4.4. Oudijk MA, Ambachtsheer EB, Stoutenbeek P, Meijboom EJ. Protocols for the treatment of supraventricular tachycardias in the fetus. Ned Tijdschr Geneeskd 2001;145(25):1218–9.5. Naheed ZJ, Strasburger JF, Deal BJ, Benson DW Jr, Gid-ding SS. Fetal tachycardia: mechanisms and predictors of hy-drops fetalis. J Am Coll Cardiol 1996;27(7):1736–40.6. Strasburger JF, Cheulkar B, Wichman HJ. Perinatal ar-rhythmias: diagnosis and management. Clin Perinatol 2007;34 (4):627–52.7. Jaeggi ET, Nii M. Fetal brady- and tachyarrhythmias: new and accepted diagnostic and treatment methods. Semin Fetal Neonatal Med 2005;10(6):504–14.8. Guntheroth WG, Cyr DR, Shields LE, Nghiem HV. Rate-based management of fetal supraventricular tachycardia. J Ultra-sound Med 1996;15(6):453–8.9. Suri V, Keepanaseril A, Aggarwal N, Vijayvergiya R. Pre-natal management with digoxin and sotalol combination for fetal supraventricular tachycardia: case report and review of litera-ture. Indian J Med Sci 2009;63(9):411–4.10. Cuneo BF, Strasburger JF. Management strategy for fetal tachycardia. Obstet Gynecol 2000;96(4):575–81.11. Zales VR, Dunnigan A, Benson DW Jr. Clinical and elec-trophysiologic features of fetal and neonatal paroxysmal atrial tachycardia resulting in congestive heart failure. Am J Cardiol 1988;62(4):225–8.12. Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial in-47Gynaecol Perinatol 2011;20(1):44–47 Sokol V. et al. Digoxin and amiodaron in fetal sustained supraventricular tachycardia and nonimmune hydropsfarction and in congestive heart failure: meta-analysis of indi-vidual data from 6500 patients in randomised trials. Lancet 1997; 350(9089):1417–24.13. Graves SW, Valdes R Jr, Brown BA, Knight AB, Craig HR. Endogenous digoxin-immunoreactive substance in human pregnancies. J Clin Endocrinol Metab 1984;58(4):748–51.14. Maxwell DJ, Crawford DC, Curry PV, Tynan MJ, Allan LD. Obstetric importance, diagnosis, and management of fetal tachycardias. Br Med J 1988;297(6641):107–10.15. Rogers MC, Willerson JT, Goldblatt A, Smith WT. Serum digoxin concentrations in the human fetus, neonate and infant. N Engl J Med 1972;287(20):1010–3.16. Van Engelen AD, Weijtens O, Brenner JI, Kleinman CS, Copel JA, Stoutenbeek P, Meijboom EJ. Management outcome and follow-up of fetal tachycardia. J Am Coll Cardiol 1994; 24(5):1371–5.17. Oudijk MA, Ruskamp JM, Ambachtsheer BE, Ververs TF, Stoutenbeek P, Visser GH, Meijboom EJ. Drug treatment of fetal tachycardias. Paediatr Drugs 2002;4(1):49–63.18. Strasburger JF, Cuneo BF, Michon MM, et al. Amioda-rone therapy for drug-refractory fetal tachycardia. Circulation 2004;109(3):375–9.19. Hauptman PJ, Kelly RA. Digitalis. Circulation 1999;99 (9):1265–70.Paper received: 16. 02. 2011; accepted: 02. 03. 2011. Address for correspondence: Dr. Vesna Sokol, Department Obstet. & Gynecol. Univ. Medical School of Zagreb, Petrova 13, 10000 Zagreb, CroatiaU ^ASOPISU »GYNAECOLOGIA ET PERINATOLOGIA«OBJAVLJENE PREPORUKE (SMJERNICE)HRVATSKOG DRU[TVA ZA PERINATALNU MEDICINU HLZ-a 1) Novoro|en~e s mekonijskom plodovom vodom (str. 181/2008). 2) Primjena prostaglandina u novoro|en~adi sa sr~anom gre{kom (str. 182/2008). 3) Smjernice za prerano prijevremeno prsnu}e vodenjaka (str. 132/2009). 4) Europske smjernice za lije~enje neonatalnog sindroma respiratornog distresa (str. 140/2009). 5) Novoro|ena~ki RDS (str. 160/2009). 6) Antibiotska profi laksa rane neonatalne sepse uzrokovane beta hemoliti~kim streptokom grupe B (str. 119/2010). 7) Prijete}i prijevremeni porod (str. 121/2010). 8) Trudno}a/porod nakon ranijega carskog reza (str. 123/2010). 9) Prenatalni probir i dijagnostika kromosomopatija (str. 125/2010).10) Antenatalni »in utero« transport djeteta (str. 54/2011).

DIGOXIN I AMIODARON KOD TRAJNE FETALNE SUPRAVENTRIKULARNE TAHIKARDIJE I NEIMUNOLOŠKOG FETALNOG HIDROPSA

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