Cardiac Drugs in Pregnancy (Current Cardiovascular Therapy), 2014th Ed.

General Principles and Guidelines

John Anthony 

(1)

Department of Obstetrics and Gynaecology, Groote Schuur Hospital, Observatory, Cape Town, 7925, South Africa

John Anthony

Email: john.anthony@uct.ac.za

Abstract

Drugs are commonly taken during pregnancy, both by prescription and as over the counter medication. Drugs used during pregnancy may show an altered pharmacodynamic profile when compared to their use in the non-pregnant population. In addition, they may cross the placenta and result in adverse effects on the fetus. There are relatively few data outlining the pharmacodynamic changes characteristic of pregnancy and new drugs are seldom tested in pregnancy when clinical trials are instituted. Prescribing drugs in pregnancy necessarily requires some knowledge of how the pregnancy may alter the pharmacodynamic profile of individual agents and a consideration of any potential adverse effects on the fetus. The use of prescription drugs can only be justified when the anticipated benefits outweigh any known risk. Prescription drugs will be needed in the management of cardiac disease and an understanding of pregnancy physiology will assist in assessing the likely efficacy and risks of these drugs.

Drugs are commonly taken during pregnancy, both by prescription and as over the counter medication. Drugs used during pregnancy may show an altered pharmacodynamic profile when compared to their use in the non-pregnant population. In addition, they may cross the placenta and result in adverse effects on the fetus. There are relatively few data outlining the pharmacodynamic changes characteristic of pregnancy and new drugs are seldom tested in pregnancy when clinical trials are instituted. Prescribing drugs in pregnancy necessarily requires some knowledge of how the pregnancy may alter the pharmacodynamic profile of individual agents and a consideration of any potential adverse effects on the fetus. The use of prescription drugs can only be justified when the anticipated benefits outweigh any known risk. Prescription drugs will be needed in the management of cardiac disease and an understanding of pregnancy physiology will assist in assessing the likely efficacy and risks of these drugs.

Pregnancy Physiology and Pharmacodynamics

The physiological adaptation to pregnancy can affect the absorption, distribution, metabolism and excretion of drugs resulting in sub-therapeutic treatment in some circumstances. The physiological adaptation to pregnancy cannot be simply summated when trying to anticipate the extent to which the non-pregnant pharmacodynamic and pharmacotherapeutic profiles shift during pregnancy. Complex changes may be found in enzyme induction and metabolism, protein binding and excretory function (Isoherranen and Thummel 2013; Anderson 2005). The pregnancy physiology may be transformed by co-morbidity due to illness, the effects of which have been even less studied than pregnancy itself. Finally, the potential exposure of the fetus to drugs may lead to teratogenic as well as other adverse consequences in the neonatal period.

Notwithstanding the deficit in our understanding regarding pharmacodynamic and therapeutic changes of pregnancy, some knowledge about the physiological changes of pregnancy may alert the clinician to potential problems when prescribing drugs during pregnancy.

Physiological Adaptation to Pregnancy and the Cardiovascular System

Increased Plasma Volume

During pregnancy the plasma volume increases by up to 45 % above non-pregnant values, with a net increase of about 1.2 l reached at 30–34 weeks (Sibai and Frangieh 1995). This increase is attained by means of physiological hyperaldosteronism, stimulating renal retention of sodium and water. The retention of water by pregnant women is not confined to the intravascular compartment with dependent interstitial oedema developing towards the end of pregnancy. These increases in intra and extravascular volume have adaptive importance related, firstly, to the necessary increase in cardiac output which ensures an increased rate of delivery of oxygenated blood to the peripheral tissues including the uterus. Fetal oxygenation is thus dependent on volume expansion and increased cardiac output. The increased extravascular volume allows physiological protection against haemorrhage during childbirth by creating an extravascular reservoir of fluid that can be redistributed into the intravascular compartment should haemorrhage develop following delivery. This increase in intra and extravascular volume creates a larger volume of distribution for drugs administered during pregnancy and non-pregnancy dosing regimens may thus give rise to sub-therapeutic serum concentrations.

Increased Cardiac Output

Cardiac output rises during pregnancy by 30–50 %, beginning from early pregnancy and is maintained throughout pregnancy (Mabie et al. 1994). The early rise in cardiac output is dependent on an increase in pulse rate with the subsequent volume expansion allowing a rise in stroke volume to sustain the increased cardiac output toward the end of the pregnancy. The slight decline in cardiac output sometimes described toward the end of pregnancy has been attributed to the postural effects of caval compression by the gravid uterus. These changes in cardiac output ensure accelerated delivery of oxygenated blood to all peripheral organs, the most significant change amongst which is enhanced uterine perfusion. The consequences of increased cardiac output are manifest when arteriovenous oxygen difference is measured by assessing both peripheral arterial oxygen concentration and mixed venous oxygen concentration (acquired by sampling right atrial blood). This measurement demonstrates a reduction in the difference between arteriovenous oxygen concentration for most of pregnancy despite the extra metabolic demands made by the pregnancy (de Swiet 1980). The arteriovenous gap widens towards non-pregnancy levels as the pregnancy approaches term indicating the increasing metabolic demands of the rapidly growing fetus. It is notable that this measurement is a good indication of how the pregnancy adaptation precedes and exceeds the physiological demands of pregnancy for much of the pregnancy. With regard to vasoactive drug therapy, those agents that limit volume expansion or decrease cardiac output may be expected to have an effect on this mechanism. Having an effect on one aspect of the physiological change of pregnancy may not lead to a measurably adverse outcome because the pregnancy adaptation extends beyond the requirements of normal pregnancy.

Vasodilatation

The increased blood volume and cardiac output of normal pregnancy would lead to severe hypertension were it not accompanied by vasodilatation. The single greatest cardiovascular change in pregnancy is vasodilatation, resulting in a net decrease in systemic blood pressure during the mid-trimester. The mechanism of vasodilatation is disputed but may depend on a variety of endothelial mechanisms including enhanced production of vasodilatory prostanoids, nitric oxide and activation of the endothelium-derived hyperpolarising factor channels (Kenny et al. 2002). Cardiac drugs that intercept or augment any of these mechanisms may have an effect on the vasculature of a pregnant woman. Perfusion of different organs is disproportionately enhanced in pregnancy and drugs that change blood pressure may have disproportionate effects on perfusion in different vascular beds. This may be of direct relevance to uterine and choriodecidual perfusion in the placental bed.

Increased Organ Perfusion

Three vascular beds show evidence of increased blood flow. The uterine perfusion increases tenfold increase by the time term is reached (Assali et al. 1960). The kidney also has a 50 % increase in blood flow while the skin shows evidence of increased perfusion (Davison and Noble 1981). These changes reflect the mechanism of renal adaptation to pregnancy, the process of thermoregulation necessitated by enhanced metabolism as well as the delivery of oxygen and nutrients to the fetus.

Protein Binding

Changes in Serum Protein Concentration

Serum albumin concentrations fall during pregnancy and drugs that bind to serum albumin are present in higher free concentrations. Some of these effects may not be solely related to changes in serum protein concentration but the presence of competitive endogenous inhibitors of drug binding. Albumin binds drugs in two main binding sites with warfarin, digoxin and furosemide being among those bound to subdomain IIa.

Changes in Drug Transporter Proteins

Transporter proteins are expressed on the apical and basal aspects of epithelial cells where they facilitate the movement of endogenous and exogenous substances from the blood into the cells and vice versa (Feghali and Mattison 2011). These proteins may be subject to induction and inhibition by exogenous drugs as well as genetic variation in expression. The placental transporter proteins also show variation in expression with increasing gestational age (Feghali and Mattison 2011).

Metabolic Rate and Metabolism

Cytochrome P450 is the most important system responsible for drug metabolism. While certain of the enzymes associated with this system show increased activity (CYP3A4 and CYP2D6), others have decreased levels of activity (CYP1A2). Hence, nifedipine metabolised by CYP3A4 will have lower trough levels than seen in non-pregnant women given the same dose. The enzyme system involving uridine 5′ -diphosphate glucuronosyltransferase (UGT) is also induced by pregnancy and may accelerate the metabolism of substrate drugs (Feghali and Mattison 2011).

Renal Excretion

Glomerular filtration and effective renal plasma flow increase by 60–80 % during pregnancy. Drugs excreted in the urine may be more rapidly cleared from the plasma. In particular atenolol and digoxin show increased clearance although the changes are not arithmetically predictable due to the confounding effects of glomerular filtration, tubular secretion and reabsorption of individual drugs.

The Effect of Co-morbidity Arising from Obstetric Disease

Various obstetric and medical disorders may give rise to changes in pregnancy physiology which may in turn affect the use of drugs needed in the treatment of cardiovascular disease. Hence, renal and liver failure may complicate pregnancies affected by pre-eclampsia and fatty liver of pregnancy. Obstetric haemorrhage can result in a coagulopathic state and renal failure. Cardiac disease may arise from pregnancy complications which included pre-eclampsia (both diastolic and systolic dysfunction) while peripartum cardiomyopathy causes impaired systolic function.

Teratogenesis and Fetal Adverse Effects

Teratogenesis arises during embryogenesis. The first 2 weeks after conception are not associated with the risk of teratogenesis possibly because the maternal use of drugs in the pre-implantation phase of pregnancy limits fetal exposure to the drug (Rakusan 2010).

The overall risk of major malformations is cited at 1–3 % of all births with 1 % of these abnormalities being attributable to drugs ingested during pregnancy. Drugs are commonly used during pregnancy but only a relatively small number of the available drugs are known teratogens. The teratogenic effects of drugs are classified by the United States Food and Drug Administration into categories of risk based upon available evidence (see Table 1).

Table 1

United States Food And Drug Administration classification of drug teratogenicity

Category

Definition

A

Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities in any trimester of pregnancy.

B

Animal studies have revealed no evidence of harm to the fetus; however, there have not been any adequate and well-controlled studies performed in pregnant women.

C

Animal studies have shown an adverse effect; however, there have not been any adequate and well-controlled studies in pregnant women, or no animal studies have been conducted and there have not been any adequate and well-controlled studies in pregnant women.

D

Adequate, well-controlled or observational studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective.

X

Adequate, well-controlled or observational studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities or risks. The use of the product is contraindicated in women who are or may become pregnant.

Two drugs used in the management of cardiovascular disease are known to be associated with teratogenic effects. Angiotensin converting enzyme inhibitors may lead to tubular dysgenesis and decreased skull ossification (Koren et al. 1998). This may result in prolonged neonatal renal failure. Angiotensin II receptor blockers and direct renin inhibitors should be considered to have the same risks as the ACE inhibitors. In general, ACE inhibitors are regarded as contraindicated during pregnancy. The evidence of malformation arising from the inadvertent use of these drugs in the first trimester is contradictory and prior exposure to ACE inhibitors is not usually regarded as an indication for termination of pregnancy (Rakusan 2010).

Warfarin is a clearly identified teratogen giving rise to nasal hypoplasia when used in the first trimester. It may also cause calcification of the fetal long-bone epiphysis (chondroplasia punctata) (Rakusan 2010). Warfarin will anticoagulate the fetal circulation and increase the risk of fetal haemorrhage. This can result in intrauterine death or the delivery of a neonate with cerebral haemorrhage.

There is evidence that antihypertensive drugs used in the first trimester are associated with a higher risk of fetal disease including Ebstein malformation, coarctation of the aorta, pulmonary valvular stenosis and atrial septal defects. Nevertheless, antihypertensive drugs are mostly classified as FDA category C agents (Caton et al. 2009). Beta-blockers are generally regarded as safe with the exception of atenolol which has been implicated in the development of intrauterine growth restriction.

Antiarrhythmic drugs have been variably classified by the FDA. Hence, sotalol (potassium blocking agent) is category B while amiodarone, in the same group of antiarrhythmic drugs is associated with fetal hypothyroidism and prematurity. Class IV anti-arrhythmic drugs such as calcium channel blockers are in FDA category C and generally regarded as safe (Rakusan 2010). The same applies to the Class II antiarrhythmic drugs – the beta blockers that also classify into Category C. The exception to this rule is atenolol. Class I anti-arrhythmic drugs (sodium channel blockers) are also classified into Category C. These include quinidine, procainamide and lidocaine (Rakusan 2010).

General Principles of Prescribing in Pregnancy

Only clearly-indicated drugs of proven efficacy and safety should be prescribed in pregnancy. Every effort should be made to avoid the use of drugs during the first trimester and where pregnant women have been exposed to known teratogens the risks of adverse outcome should be disclosed and considered by the physician and his/her client.

The efficacy of drugs used during pregnancy may be altered by pregnancy and attention should be paid to the adjustment of doses and the possible effects of drugs on the fetus once they have crossed the placenta.

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