Antiarrhythmic therapy of the pregnant woman and of the fetus

The two different situations, therapy of the pregnant woman and of the fetus, should be distinguished. If the pregnant woman needs an antiarrhythmic therapy, a drug is recommended which passes via the placenta in low amounts. On the other hand, if the fetus is the patient, sufficient placental transfer is desirable in order to treat the fetus via the mother. Supraventricular extrasystoles and premature ventricular beats are not harmful, and neither the mother nor the fetus needs medical treatment.

Antiarrhythmic therapy of the pregnant woman

New onset of tachycardia in otherwise healthy women is seldom seen in pregnancy. If supraventricular tachycardia, atrial flutter, atrial fibrillation or ventricular tachycardia has led to an unstable hemo-dynamical situation, electrocardioversion is recommended as in ventricular flutter or fibrillation. This treatment does not affect the fetus, because the electrical threshold of fetal heart is high and the fetus is located outside of the stress field power flow. In the case of a stable heinodynamical situation, a drug-monitored cardioversion should be tried. Another indication for an antiarrhythmic therapy in pregnant women is to prevent a relapse. Bombelli (2003) reported on three cases of successful radiofrcqucncy catheter ablation in drug-refractory maternal supraventricular tachycardia in late pregnancy. Nevertheless, the risk of X-ray exposure time should be taken into account. If treatment of bradycardia is necessary, a pregnant woman should also be fitted with a pacemaker.

Antiarrhythmic therapy of the fetus

In a small percentage of all pregnancies (0.4-0.6 percent), fetal tachycardia, mainly supraventricular, can be found. Fetal tachycardia is defined as more than 180 beats per minute, and mostly occurs in late pregnancy. A majority of affected fetuses do not have a visible heart malformation. If symptoms are persistent, cardiac failure or cardiomyopathy with pleural or pericardial effusion and/or ascites can result and edema. Fetal hydrops is defined as fluid retention in two or more compartments, and can precede intrauterine death. The drug of first choice is digitalis, but in case of hydrops, fetal serum concentration of digitalis might not reach therapeutic levels. This could be the reason why, in cases of fetal hydrops caused by tachycardia, digitalis therapy is often not successful (Oudijk 2002). The drugs of second choice, in combination with or without digitalis, are sotalol and/or flecainide (Doherty 2003, Oudijk 2002). It takes at least 72 hours, sometimes up to 14 days, before flecainide can succeed in converting the rhythm to sinus rhythm (Krapp 2002). Athanssiadis (2004) advocates that verapamil is the drug of second choice, whereas others think that it is contraindicated (Oudijk

2002). Another possibility is to inject adenosine directly into the umbilical vein. If cardioversion has succeeded, hydrops fetalis can regress slowly (d'Souza 2002), which can take from 8 days (Porat

2003) to 4-6 weeks. There is a case report of a fetus treated via the mother with flecainide, where the fetal heart rate decreased without converting to sinus rhythm. Nevertheless, hydrops regressed (Krapp 2002). If there is no success prematurely, labor might be induced in order to try electrocardioversion of the newborn. In general, a healthy pregnant woman seldom suffers from adverse effects of the antiarrhythmic therapy of the fetus. Bradycardia as fetal side effect can occur, which is more likely after injection of adenosine into the umbilical vein than after other treatment. All antiarrhythmics can produce arrhythmias, at worst ventricular fibrillation of the fetus, which can lead to intrauterine death.

A fetal bradycardia can be at first compensated by an increase in cardiac output. However, a fetal heart rate below 55bpm is insufficient, and heart failure with the consequence of fetal hydrops can result (Eronen 2001). The underlying fetal congenital atrioventricular block may have been caused by a congenital heart defect, or by placental passage of maternal autoantibodies (Maeno 2005). In the latter case, halogenated steroids can be tried unless heart block is not complete. Sometimes, sympathomimetics have been given. Induction of labor can be discussed to implant a pacemaker postnatally.

Pharmacology and toxicology

Antiarrhythmics are divided into different classes (IA, IB, IC, II, III and IV) which arc used for the different forms of arrhythmias.

■ Class IA - quinidine, ajmaline, detajmium, disopyramide, procainamide, and prajmalium

■ Class IB - lidocaine (lignocaine), aprindine, mexiletine, phenytoin, and tocainide

• Class IC - flecainide, propafenone, encainide, and lorcainide a Class II - includes 3-receptor blockers

■ Class III - amiodarone and the fi-blocker sotalol; also bretylium, ibutilide, almokalant, and dofetilide

■ Class IV - the calcium blockers verapamil, gatlopamil, and diltiazem.

Adenosine does not belong to any of the classical categories. Class IA

Quinidine is almost completely absorbed when given orally, and reaches its maximum serum concentration within 1-4 hours. About 20 percent is excreted by the kidneys and 80 percent via the liver. As a vagal antagonist, it can increase the heart rate slightly despite its depressive effect on the pacemaker cells. Quinidine is one of the oldest antiarrhythmics, and is apparently without any noteworthy teratogenic potential. It passes the placenta and reaches similar concentrations in the fetus as in the mother. Successful treatment of mother and of the fetus has been described.

Disopyramide is also thought to have a contraction-promoting effect (Tadmor 1990). There have been no published case reports of malformations after exposure to disopyramide or procainamide. Both cross the placenta. Procainamide has been used for cardioversion in eases of fetal supraventricular tachycardia. There is insufficient experience in pregnancy with prenatal tolerance for ajmaline, detajmium, and prajmalium.

Class IB

Lidocaine (lignocaine) has been used widely as an anesthetic drug during pregnancy (see Chapter 2.16). Since only about 30 percent is utilized after oral administration, due to metabolism in the liver, parenteral administration is necessary in cases of arrhythmia. There was one published case report describing successful therapy with lidocaine in a fetus with QT prolongation in the ECG (Cuneo 2003), which suffered from ventricular tachycardia and incomplete atrioventricular heart block. There is no recognizable teratogenic effect in human pregnancies. Lidocaine crosses placenta in considerable amounts, and can lead to a depressed newborn if the serum concentration is high. A study from France reported about 50 pregnancies where lidocaine was injected into the umbilical vein in order to induce fetocide of malformed fetuses during gestational weeks 20-36. First sufentanil (5/ig) was injected, followed by 7-30 ml lidocaine (1%), which led to cardial asystolia (Senat 2003). Phenytoin is a teratogenic anticonvulsant drug (see Chapter 2.10). Mexiletine crosses the placcnta. There have been a few case reports that have not revealed a teratogenic risk. There is insufficient experience regarding prenatal tolerance for aprindine and tocainide.

Class IC

Many case reports document the efficacy of flecainidc in treating fetal arrhythmias (Krapp 2002). in particular with fetuses that already suffer from hydrops, flecainide is superior to digitalis. In order to minimize fetal adverse effects, close monitoring of the mother's scrum concentration is recommended (Rasheed 2003). In one case report, hyperbilirubinemia of a newborn has been described as an adverse effect of flecainide therapy during pregnancy (Athanassiadis 2004), In contrast to animal data, there is, as yet, no recognizable teratogenic or fetotoxic effect in human pregnancy, but experience of first-trimester exposure is rare. With propafenone, there have not as yet been any indications of teratogenic potential from the 30 cases collected by the manufacturer.

Class II

For ¡-(-receptor blockers, see section 2.8.3. Class III

Amiodarone has a long elimination half-life of 14-58 days. If fetal exposure is to be avoided, medication should have been stopped several months before conception. Amiodarone can cause fetal bradycardia and - because of its high iodine content (39 percent) - congenital hypothyroidism (Lomenick 2004, Grosso 1998). In order to treat fetal hypothyreoidism, injection of thyroxine into the amniotic fluid might be an option, as described in some case reports. Among 27 children who were treated by amiodarone in utero (Pradhan 2006), 5 had hypothyroidism after delivery. A sixth baby with ongoing therapy developed hypothyroidism postnatally at the age of 3 months (Strasburger 2004). Bartelena (2001) analyzed 64 cases that had already been published; there was a maternal indication for antiarrhythmic therapy in 56 cases. A dozen children were diagnosed having transient hypothyroidism; two of them also had congenita! goiter. Some of the hypothyroid and even some of the euthyroid children showed discrete neuropsychological anomalies. Therefore, a direct neurotoxic effect of amiodarone is suggested. Occasionally a QT prolongation in the ECG of newborns was noted. Other children had intrauterine growth restriction, although several causes could account for this: exposure to amiodarone or to the co-medication, mostly i-receptor blockers, or the underlying disease of the mother. To date, most of the exposed children have been healthy - even those who initially suffered from hypothyroidism developed normally (Magee 1999). Experience of first-trimester exposure is limited to approximately 20 pregnancies (Magee 1995), of which 2 resulted in children with congenital anomalies (Ovadia 1994); this might be coincidental.

Sotalol crosses the placenta in considerable amounts; therefore, this is a potent drug for treating fetal arrhythmias. In a case series of 18 fetuses with tachycardia, an accumulation of the drug was found in the amniotic fluid but not in the fetuses themselves. Conversion to sinus rhythm succeeded in 13 of 14 cases with monotherapy, but two fetuses had a relapse. One intrauterine death occurred. Treatment in two of four fetuses that also received digitalis was successful (Oudijk 2003). There is no recognizable teratogenic or fetal effect in human pregnancies to date. A risk of neonatal (i-receptor blockade, e.g. neonatal bradycardia, hypotension, and hypoglycemia, should be taken into account (see Chapter 2.8.3).

Bretylium and ibutilide have to be injected intravenously -bretylium in case of ventricular fibrillation or ventricular tachycardia, ibulilide in case of atrial fibrillation. There is one published case report describing the use of bretylium throughout a whole pregnancy, resulting in an uneventful outcome (Gutgesell 1990). In ani mal studies, ibulitide, almokalant, and dofetitide demonstrated a cluster of malformations similar to phenytoin (Danielsson 2001). Experience during human pregnancies docs not exist.

Class IV

For risk analysis with longer-term use of calcium antagonists such as verapamil and diltiazem, see section 2.8.5. Although animal data indicate teratogenic developmental disturbances of distal phalanges, similar effects have not been observed in human pregnancies.

Adenosine has a very short half-life of less than 2 seconds. It has to be injected intravenously. No specific fetal adverse effects have been described so far, whether the pregnant woman or the fetus is the patient (Hubinot 1998).

The same applies for electrocardioversion, including implanted defibrillators (Joglar 1999) (see above).

Recommendation. Antiarrhythmics themselves can cause arrhythmia, and therefore, provoke a life-threatening situation. For this reason, it is important critically to evaluate the indication, especially during pregnancy. Drugs of choice for the treatment of pregnant women:

■ Class lA-quinidine

■ Class IB-lidocaine

■ Class IC - propafenone and/or, in the second or third trimester, flecainide

If Class III antiarrhythmics are absolutely necessary, sotalol should be chosen. In Class IV, verapamil and diltiazem are acceptable. Because of its proven teratogenicity, phenytoin is contra indicated at least in the first trimester. However, if a pregnant woman has been treated with a drug that is not recommended above, or if such a drug is absolutely necessary for the mother (or fetus), this does not necessitate termination of pregnancy. In cases of first-trimester exposure, especially with phenytoin, a detailed ultrasound diagnosis should be offered; however, this is not necessary if a longer-term use 3-blocker or calciurn-blocker was given. If treatment with amiodarone was administered beyond the twelfth week (when the fetal thyroid begins to function), adverse effects on the fetal thyroid development should be ruled out with an ultrasound scan, and the thyroid status in the newborn monitored.

The drug of first choice for treatment of fetal supraventricular tachycardia is digitalis; the second choice is sotalol or flecainide. Because of its possible adverse effects on the thyroid, amiodarone should be considered as reserve drug.

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