Cardiac disease in pregnancy and drug therapy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

ACE inhibitors, Angiotensin receptor blockers (ARBss), aldosterone antagonists and warfarin should be avoided in pregnancy.

• ACE inhibitors can cause morbidity in 30% of fetuses after 14 weeks due to renal tubular dysplasia, neonatal renal failure, oligohydroamnios, reduced cranial oosification and intrauterine growth retardation (IUGR)
• Angiotensin receptor blockers (ARBss). These agents are safe during lactation though.
• Aldosterone antagonists cause antiandrogenic effects in the first trimester and should be avoided.
• HMG-CoA Reductase Inhibitors (Statins) (Risk Category X). These agents may be teratogenic and are not recommended.

• Amiodarone is a pregnancy category D drug. Amiodarone has been associated with fetal hypothyroidism and hyperthyroidism, fetal bradycardia, intrauterine growth retardation. The expert consensus is that amiodarone use should be restricted to the management of refractory maternal or fetal tachyarrhythmias. Given the long half life of amiodarone, if a woman intends to become pregnant, the drug should be discontinued several months before conception. Thyroid function tests in the neonate are recommended if the mother is administered amiodarone.
• Propranolol and atenolol^{[1] [2]}:

• Intrauterine growth restriction
• Hypoglycemia in the newborn

• Carvedilol
• The efficacy and safety of thrombolytics is mostly untested:

• Greatest experience in massive pulmonary embolism
• Streptokinase does not cross placental membrane in animals, but Ab found in neonatal spinal cord fluid
• Urokinase not teratogenic in mice/rats
• Risk for maternal hemorrhage (1 case of placental abruption reported); increased risk when given at time of delivery
• Delivery best delayed at least 2-3 weeks

• Warfarin is teratogenic but is often required in patients with a mechanical heart valve during pregnancy. There is an increased magnitude of anticoagulation in the fetus compared with the mother because the synthesis of vitamin K dependent co-factors is reduced in the fetal liver. The risks of warfarin use should be discussed with the parents and include retroplacental bleeding, intracranial bleeding in the fetus, fetal loss, and premature birth. Warfarin is a better choice for the mother as it reduces the risk of fatal prosthetic valve thrombosis, but is not safe for the fetus for the reasons listed above. The risk of embryopathy (4%-10%) is highest with exposure from weeks 6 to 12, and is increased as the dose of warfarin is increased above 5 mg.

• ASA – low doses should be used. Complications include an increased risk of placental abruption. ASA is used in pregnant women with antiphospholipid syndrome and preeclampsia.
• Beta-1 selective beta-blockers such as lopressor, metoprolol are pregnancy category B drugs and can be used during pregnancy.
• Calcium channel blockers (Nifedipine, Diltiazem, Verapamil) are often administered during the second and third trimesters of pregnancy to manage blood pressure. However, during the first trimester during organogenesis, there may be a risk for teratogenicity based upon frog embryo studies, and CCBs are classified as pregnancy category C.
• Digoxin is a pregnancy category C drug that crosses the placenta and affects the fetus as well. Digoxin is not teratogenic and during the first half of pregnancy, the fetal heart has a reduced ability to bind digoxin. However, during the second half of human gestation, the fetal heart avidly binds and concentrates digoxin. Toxicity in the fetus and neonate is not observed until the serum level reaches 2 to 4 ng/mL, which is greater than adults where toxicity occurs at less than 2 ng/mL. The maternal dig levels should be monitored as the maternal clearance of digoxin is significantly increased.
• Disopyramide is a pregnancy category C drug, and should only be administered when the risks outweigh the benefit as with all pregnancy category C drugs. It is not recommended as a first line agent in the management of ventricular tachycardia.
• Diuretics can reduce placental perfusion and should be used sparingly.
• Eplerenone is a pregnancy category B drug
• Flecaininde is a pregnancy category C drug and affects the fetus as well. Flecainide can be used to manage supraventricular tachycardia (particularly digoxin refractory SVTs) in the mother and the fetus during pregnancy.
• Glycoprotein IIb/IIIa inhibitors: pregnancy category B drugs include eptifibatide and tirofiban; pregnancy category C drugs include abciximab
• Hydralazine is a pregnancy category C drug, and should only be administered when the risks outweigh the benefit as with all pregnancy category C drugs. While hydralazine can be used in pregnancy, it is not a first line agent in the treatment of hypertension during pregnancy in so far as it has been associated with higher rates of placental abruption, and cesarean section.
• IV Adenosine, which has a half life of seconds, can be used to cardiovert patients.
• Lidocaine is a pregnancy category B drug.
• Low Molecular Weight Heparin (LMWH) is a pregnancy category B drug. Studies have found that weight-based low molecular weight heparinoid treatment in pregnancy is inadequate. Use of a low molecular weight heparinoid requires measurement of anti-X a activity to assure adequate anticoagulation. The peak activity four hours after a dose should provide an anti-X a level of approximately one unit per ML. Excessive anticoagulation should be avoided and the anti-X a levels should be kept below 1.5 units per ML.
• Magnesium
• Morphine sulfate is a pregnancy category C drug, and should only be administered when the risks outweigh the benefit as with all pregnancy category C drugs.
• Nitrates should only be administered when the risks outweigh the benefit. A low dose should be administered to prevent fetal distress. Nitrates are secreted in breast milk and can cause fetal methemoglobinemia.Risk Category B: Nitroglycerin; Risk Category C: Isosorbide dinitrate.
• Procainamide is a pregnancy category C drug, and should only be administered when the risks outweigh the benefit as with all pregnancy category C drugs. Procainamide has been used in the third trimester in the management of ventricular tachycardia.
• Propafenone is a pregnancy category C drug, and should only be administered when the risks outweigh the benefit as with all pregnancy category C drugs.
• Quinidine is a pregnancy category C drug, and should only be administered when the risks outweigh the benefit as with all pregnancy category C drugs.
• Sotalol is a pregnancy category C drug and can be used to manage supraventricular tachycardia in the mother and the fetus during pregnancy.
• Thienopyridine derivatives (Risk Category B)
• Unfractionated (UFH) is a pregnancy category C drug, and should only be administered when the risks outweigh the benefit as with all pregnancy category C drugs. Unfractionated heparin has a high molecular weight and does not cross the placenta. The goal is to achieve that PTT 2.5 to 3.5 times the control. Unfractionated heparin is the treatment of choice in late pregnancy and during delivery. Unfortunately there is a sustained increase risk of prosthetic valve thrombosis. There is a consequent increased risk of maternal and fetal mortality. Long-term use of heparin is associated with osteoporosis and 30% of patients develop sterile abscesses, reduced platelet counts and alopecia.

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