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Practical practice points
1. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II inhibitors are contraindicated in pregnancy. Although it is unlikely that they are teratogenic, they interfere with fetal renal function in the second and third trimesters.
2. ACE inhibitors can be given to mothers who are breastfeeding, but there are few data regarding the safety of angiotensin II inhibitors and they should probably be avoided.
3. Warfarin (unlike heparin) crosses the placenta and is teratogenic in the first trimester and can cause intracranial hemorrhage, fetal death, and long-term handicap when given in the second and third trimesters. It is, however, not contraindicated in mothers who are breastfeeding.
General considerations
Many women will be on drug therapy for their cardiac condition before they become pregnant, whereas others may need to start medication for the first time during pregnancy. It is therefore vital to consider how the effects of such drugs vary during pregnancy, and whether they have any effect on the fetus.
Pharmacokinetics in pregnancy
Physiological changes occurring in pregnancy may affect the blood concentration of drugs. Gastrointestinal motility and absorption are reduced while lung function is increased. Plasma volume and total body water increase markedly, which has the dilutional effect of reducing the concentration of some drugs. On the other hand, plasma proteins, to which many drugs bind, have reduced levels and this may increase the concentration of the free (active) drug. The glomerular filtration rate rises by almost half, so that drugs that are primarily excreted unchanged by the kidneys are usually excreted more rapidly. The rate of liver metabolism also increases.
A few drugs that have a high molecular weight, such as heparin, do not cross the placenta. However, the placenta is effectively a lipid barrier separating the maternal and fetal circulations and, given time, most drugs of low molecular weight will cross the placenta so that maternal and fetal levels equilibrate.
Effects on the fetus
Only 4% of developmental disorders are caused by chemical and physical agents, and only a small proportion of these are due to medicinal products.[1] However, the list of known embryotoxic/fetotoxic drugs includes several used in women with cardiac disease, including angiotensin-converting enzyme (ACE) inhibitors, phenytoin, and warfarin. New drugs undergo extensive premarket testing but the teratogenic effect of some drugs (e.g. thalidomide) is seen only in humans or other specific species. Some of the effects may therefore not be evident until the drug is in general use. Such effects are then often brought to light by case reports or subsequent epidemiological investigations.
Potential adverse effects of drugs
The developmental toxicity of an individual drug depends on the period of pregnancy during which it is taken. If fetal exposure occurs in the first week after conception, i.e. preimplantation, and the drug has an adverse effect, it may well result in early embryonic loss. The critical time for fetal organogenesis extends from 3 to 10 weeks of gestation, i.e. from 1 to 8 weeks after conception. Exposure during this phase of development to toxic drugs that do not cause miscarriage may result in a structural abnormality. Exposure later in pregnancy can have a range of effects, including fetal growth restriction, functional impairment of a particular organ or system, preterm birth, or fetal death. Susceptibility to adverse effects may also extend into neonatal life.
Balancing of risks
The risks of embryotoxicity or fetotoxicity depend on both the duration and dose of exposure.[2–5] Prepregnancy and early pregnancy counseling needs to consider the risk vs the benefit of prolonged exposure (which can occur throughout the pregnancy). Often, either stopping or changing the drug may be advisable. However, postexposure counseling (usually after a relatively short exposure in early pregnancy before pregnancy is diagnosed) will require a different approach. In this situation, the short duration of exposure is often associated with a very low risk, so that termination or even additional invasive diagnostic procedures are usually not justified.[2,3,5] It should also be remembered that, in some cardiac conditions, the risk to the mother and/or fetus from the underlying disease is greater than the risk associated with taking the appropriate medication. When prescribing any new drug, particularly long-term medication, to a woman of reproductive age who has cardiac disease, the possibility of pregnancy should always be considered. By the time pregnancy is diagnosed, organogenesis is usually well under way. The woman should be asked whether she might be, or is planning to become, pregnant. If there is a risk of unplanned pregnancy, maximally effective safe contraception should be prescribed (see Chapter 2). If pregnancy is planned or possible, medication should be chosen that is safe in pregnancy. In general, monotherapy is preferable and the lowest effective dose should be prescribed.
In the UK, expert advice can be sought from the medicines information services—contact details can be found in the British National Formulary.[4]
Adverse incident reporting
If any adverse fetal or maternal effect occurs in a woman taking cardiac drugs in pregnancy, it should be reported using the yellow label reporting system (in the UK), whether or not this adverse effect is thought to be caused by the drug. Similar reporting systems are in place in other countries, and it is the supervising clinician’s responsibility to report any adverse effects that may be drug related.
Breastfeeding
The benefits of breastfeeding are well established and few drugs are absolutely (or even relatively) contraindicated during lactation (or require that breastfeeding should be avoided or stopped).[6] The concentrations reached by most drugs in the newborn are usually well below therapeutic levels. However, prolonged exposure can lead to accumulation because of the longer half-life in the neonate. The supervising clinician needs to be aware of this possibility so that monitoring for adverse effects can be carried out (for example, some beta-blockers given to the mother in high dosage can cause bradycardia in the baby). If such effects occur, the drug may need to be reduced in dosage or even discontinued. On the positive side, some drugs such as methyldopa have an anti-dopamine effect and may therefore lead to an increase in breast milk production.
Diuretics
In pregnancy, the diuretics of choice are the thiazides and furosemide (frusemide).
Thiazide diuretics
Thiazide diuretics include hydrochlorothiazide, chlorothiazide, indapamide, and chlorthalidone. These drugs are benzothiazide derivatives that inhibit absorption of sodium and chloride in the distal renal tubule and lead to loss of potassium. They may be used in women with cardiac failure and pulmonary edema (they are no longer used in preeclampsia).
They do not appear to be teratogenic. One study (The Collaborative Perinatal Project) followed 233 women exposed to thiazide diuretics in the first trimester and found a slightly increased risk of malformations.[7] However, all of these mothers had cardiac disease themselves, so the significance of these findings is unclear and further studies would be helpful. Another study found no increase in birth defects in 567 pregnant women exposed to hydrochlorothiazide in the first trimester.[6]
The thiazides cause a reduction in intravascular volume; there is thus a theoretical risk of reduced uteroplacental perfusion leading to fetal growth restriction (FGR). When used long-term in pregnancy (usually for women with heart failure), the mother’s electrolytes should be checked regularly. Regular ultrasound scanning is indicated to monitor for FGR and oligohydramnios.
The neonate is also at risk of electrolyte imbalance (hyponatremia, hypocalcemia) if the mother had been given thiazide diuretics toward the end of pregnancy. The neonate may also suffer hypoglycemia because of the diabetogenic effect of thiazides on the mother. Neonatal thrombocytopenia has also been reported. There have been some case reports indicating that these drugs can inhibit uterine contractions and prolong labor,[6] but this is unlikely to be of clinical significance.
Furosemide
Furosemide is a potent loop diuretic whose action wears off in 2–4 h. Its only indications in pregnancy are cardiovascular disorders such as pulmonary edema or heart failure; it should not be used for preeclampsia as it significantly reduces intravascular volume. If used long-term, the decrease in plasma volume may lead to growth restriction in the fetus, although it does not seem to significantly reduce amniotic fluid volume.[8] Furosemide does not appear to be teratogenic. In contrast to the thiazide diuretics, neonatal thrombocytopenia has not been reported with furosemide.
Spironolactone
Spironolactone is an aldosterone antagonist that leads to potassium retention. It does not appear to be teratogenic [6]; however, experience is limited and it is thus relatively contraindicated in pregnancy. Spironolactone is known to have antiandrogenic effects and could theoretically cause feminization of a male fetus, although this has not been reported in practice.
Ethacrynic acid
Ethacrynic acid is another potent diuretic that has an effect similar to that of furosemide. One case report describes ototoxicity in the baby of a woman who took ethacrynic acid and kanamycin in the third trimester.[9] However, experience with this drug in pregnancy is very limited, and for this reason its use is not recommended in pregnancy or breastfeeding.
Amiloride
Amiloride directly influences tubular transport and is a potassium-saving diuretic. It does not appear to be teratogenic.[6] However, data are again lacking and the drug is relatively contraindicated in pregnancy. There are no reports of its use in breastfeeding women.
Mannitol
Mannitol is a potent osmotic diuretic that causes rapid diuresis: interstitial fluid volume falls while intravascular volume increases. Its use in pregnancy or breastfeeding has not been reported (apart from intra-amniotic injection for therapeutic termination of pregnancy [10]).
Antihypertensives
Hydralazine
Hydralazine is a vasodilator and may be used as an antihypertensive or as an afterload-reducing agent. It is well absorbed orally and is also used intravenously. Its half-life is 2–8 h: it crosses the placenta and is metabolized in the liver. In pregnancy, hydralazine is usually given parenterally in the acute management of hypertension. In this situation, it can cause symptoms similar to those of imminent eclampsia, including headache, nausea, vomiting, and flushing. Experience with long-term use of hydralazine in pregnancy is limited. There is one case report of a lupus-like syndrome in the mother that was thought to have resulted from hydralazine sensitivity.[11] Data on first-trimester exposure are sparse, but currently there is no evidence of teratogenesis in humans.
When hydralazine is given intravenously, there is a significant risk of a precipitate fall in blood pressure that may lead to impaired placental perfusion and fetal heart-rate abnormalities. Thus, intravenous administration should always be slow.[12]
Angiotensin-converting enzyme inhibitors
The ACE inhibitor class of drugs includes captopril, enalapril, lisinopril, and ramipril. ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II. Their use in the nonpregnant population has become more widespread in recent years, but most available data on their use in pregnancy relate to captopril and enalapril. However, it is likely that the other drugs in this class have similar fetal and neonatal effects.
In contrast to exposure in the second and third trimesters, it was long believed that ACE inhibitors were not teratogenic in the first trimester.[6,13] However, a report in 2006 found an increased risk of fetal abnormalities, specifically cardiac and neural tube defects, in fetuses exposed to ACE inhibitors (but not other antihypertensives) in the first trimester.[14,15] Physicians had previously felt comfortable prescribing ACE inhibitors to women of childbearing age, believing that the fetal risk was low as long as they changed to a different antihypertensive by the start of the second trimester. After the 2006 report, physicians have tried to avoid prescribing ACE inhibitors to women who might become pregnant.
In 2011, however, a new study of a larger, more diverse population found that while ACE inhibitors were associated with an increased risk of congenital cardiac defects (though not neural tube defects) this risk did not significantly differ from that associated with other antihypertensive drugs.[16] Even more interesting was the finding that the risk of fetal cardiac defects was similar in women with untreated hypertension. The conclusion of these authors and an accompanying editorial is that the underlying hypertensive disease (treated or untreated) is responsible for the increased incidence of fetal cardiac defects, rather than the ACE inhibitor or any other antihypertensive agent.[17]
In contrast, it is now clear that exposure to ACE inhibitors in the second and third trimesters is potentially harmful; it can lead to marked fetal hypotension and decreased (fetal) renal blood flow. This can lead to oligohydramnios and in some cases there is fetal anuria and renal failure in utero. Severe oligohydramnios can result in pulmonary hypoplasia, limb contractures, craniofacial deformities, and patent ductus arteriosus. FGR and preterm delivery have been reported. These adverse effects persist in the neonate, with poor renal perfusion and a reduced glomerular filtration rate; there may be significant hypotension and renal failure severe enough to cause neonatal death.
Following inadvertent exposure in early pregnancy (usually in a woman who has unexpectedly conceived while still taking the drug), termination of pregnancy or invasive diagnostic procedures are not indicated because the drug does not seem to be teratogenic at this stage of pregnancy. However, these drugs are contraindicated after the first trimester, so the woman should be converted to another medication if possible. Where ACE inhibitors must be continued, the lowest possible dose should be used and amniotic fluid levels and fetal growth should be monitored carefully. Blood pressure and renal function should be monitored closely in the neonate.[18]
Breastfeeding
ACE inhibitors are excreted in breast milk at very low concentrations, with an average milk/plasma ratio of 0.012. No adverse effects have been observed in the neonate and these drugs are generally regarded as safe.[19]
Angiotensin II inhibitors
The angiotensin II inhibitors include losartan and valsartan. These are specific angiotensin II receptor antagonists and so have properties similar to those of ACE inhibitors. They are relatively recent drugs and data are still scanty. However, their mechanism of action is very similar to that of ACE inhibitors. It seems likely that the fetotoxic effects observed with ACE inhibitors in the second and third trimesters may also be associated with angiotensin II inhibitors. A case report published in 2001 described anhydramnios and fetal death, with pulmonary hypoplasia and facial and limb deformities typical of marked oligohydramnios.[20] These changes were attributed to losartan, which the woman had been prescribed for hypertension. There is a similar report of neonatal renal failure in a baby born to a woman who had taken candesartan throughout pregnancy.[21] These drugs are thus not recommended in pregnancy unless all other treatment avenues have been explored and failed.
Antiarrhythmics
Minor maternal arrhythmias do not need treatment, but if the arrhythmias become hemodynamically relevant use of antiarrhythmics will need to be considered. They are arranged in classes according to the effect they have on electrical conduction in the heart and the arrhythmia for which they are used.[22] As discussed below, the classes of antiarrhythmics are 1A, 1B, 1C, 2, 3, and 4.
Class 1A antiarrhythmics
Class 1A antiarrhythmics include disopyramide, quinidine, and procainamide. The last two are used relatively commonly in pregnant women with cardiac disease and do not appear to be teratogenic.[6] In high doses, quinidine has an oxytocic effect and may cause miscarriage,[23] but this has rarely been observed at therapeutic doses and should thus not influence its choice.
Class 1B antiarrhythmics
Class 1B antiarrhythmics include lidocaine (lignocaine) and phenytoin, among others. Lidocaine has no teratogenic effects. However, if maternal lidocaine toxicity occurs, then some of the effects such as hyperthermia may harm the fetus.[24]
The teratogenic effects of phenytoin were first recognized as long ago as 1964.[25] The risk of congenital abnormality associated with its use is 2–3 times greater than the background risk. Typical anomalies observed include craniofacial abnormalities, abnormalities of the distal phalanges, cardiac defects, and FGR. The typical appearance of an affected baby includes a broad nasal bridge, wide fontanelles, low-set hair and ears, a cleft lip and palate, and microcephaly. Neurodevelopmental delay has also been observed. Phenytoin may also lead to early hemolytic disease of the newborn, probably by depleting fetal vitamin K levels. If phenytoin must be used, then maternal blood levels should be monitored and the lowest level compatible with effective treatment maintained. Consideration should be given to folic acid supplementation throughout pregnancy and extra vitamin K in the last trimester. Phenytoin appears to be safe in breastfeeding.
Class 1C antiarrhythmics
Flecainide has been used to treat fetal arrhythmias, but there do not appear to be any teratogenic or fetotoxic effects in humans.[6]
Class 2 antiarrhythmics
Class 2 antiarrhythmics comprise the beta-blockers, which are discussed in a separate section below.
Class 3 antiarrhythmics
Class 3 antiarrhythmics include amiodarone, bretylium, and the beta-blocker sotalol. Amiodarone has been used to treat both maternal and fetal arrhythmias. However, it contains high levels of iodine and can lead to congenital goiter or hypothyroidism.[26] Nevertheless, most newborns do not seem to suffer any adverse long-term effects from the transient hypothyroidism produced.[6] Ventricular septal defects have been reported,[27] as has FGR. However, these effects may not be due to the amiodarone alone and may be caused, at least in part, by the mother’s disease or other drug therapies such as beta-blockers.
Because data are limited and adverse effects, particularly on the thyroid, are well documented, amiodarone should not be a first-line drug in pregnancy, either for maternal arrhythmia or for uncomplicated cases of fetal supraventricular tachycardia (SVT).
Breastfeeding
Because of its high iodine content, amiodarone could theoretically cause hypothyroidism in the nursing neonate. It is excreted in the breast milk and has a long half-life, so breastfeeding is not recommended if the mother is currently taking amiodarone or has taken it regularly within the past few months.
Sotalol
Sotalol has been used to treat both maternal and fetal arrhythmias. As with other beta-blockers, it has the potential to cause FGR and reduced placental weight. Oudijk et al. evaluated the use of sotalol for fetal tachycardia in 21 pregnancies.[28] They concluded that sotalol is effective for fetal atrial fibrillation, but in fetal SVT the mortality rate was high and the conversion rate low so that the risks outweighed the benefits. For maternal treatment, the risks and benefits must be weighed on an individual basis. If used, serial ultrasound scans for growth are indicated. Sotalol may also cause neonatal bradycardia or hypoglycemia.[29]
Class 4 antiarrhythmics
Class 4 antiarrhythmics include the calcium antagonists, diltiazem and verapamil. If taken in the first trimester of pregnancy, these drugs do not appear to be teratogenic.[30,31] Data dealing with exposure at that stage are limited, however, so these drugs are not considered first-line in early pregnancy. Having said that, exposure during the first trimester is not an indication for termination of pregnancy or invasive diagnostic procedures.
There is more experience with calcium channel blockers in the second half of pregnancy, and they appear to be relatively safe. Two small prospective studies of calcium channel blockers, mainly nifedipine and verapamil, in pregnancy reported two birth defects of the extremities in 100 babies.[30,32] However, the authors point out that the abnormalities may have been due to the maternal disease or other medications. In contrast, several large studies suggest that use of calcium channel blockers in the second and third trimesters has no significant adverse effects.[33,34] These drugs may be considered first-line for the treatment of cardiac arrhythmias in the second and third trimesters in appropriate women.[35]
Nitrates
This group includes glyceryl trinitrate, isosorbide mononitrate, and isosorbide dinitrate. They are used as coronary dilators after myocardial infarction and to treat angina. They have also been used as tocolytics. Data on their use in pregnancy are limited, especially as regards the first trimester (although their use is expected to increase as the average age of women at first pregnancy increases, and as the incidence of ischemic heart disease during pregnancy rises accordingly). However, they appear to be safe; occasional transient hypotension in the mother does not appear severe enough to affect placental perfusion significantly.
Breastfeeding
No data are available for nitrates in breastfeeding but the risks are likely to be low.
Nonpharmacological treatment of arrhythmia: Electrical cardioversion
Direct current cardioversion appears to be safe and effective in pregnancy. Its use has been reported in pregnancy for the treatment of atrial fibrillation, atrial flutter, and atrial tachycardia resistant to drug therapy.[23,36]
Pulmonary hypertension in pregnancy
Pulmonary hypertension (PH) is associated with a high risk of maternal mortality (approximately 30–50%), so pregnancy should be discouraged in this patient group. If pregnancy occurs, patients benefit from expert referral to discuss the available treatment options. Medical therapies include:
Prostacyclin—has been used successfully to treat a woman with Eisenmenger syndrome in pregnancy and is employed by some for the management of other forms of PH in pregnancy.[37]