Cardiovascular Medications in Pregnancy


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Cardiovascular Medications in Pregnancy


 


Alice Chan and Ali N. Zaidi



Key Points


Pharmacokinetics of the cardiovascular medications are affected in pregnancy due to physiologic changes that affect metabolism and efficacy of various drugs


Hydralazine and nitrates can be substituted for ACE inhibitors in treatment of heart failure in pregnancy


Beta-blockers are the most commonly used cardiac medication in pregnancy


Drugs that easily cross the blood–brain barrier usually enter breast milk more readily


Nifedipine and propranolol have similar drug concentrations in the breast milk as in the maternal plasma


 


Introduction


Cardiovascular disease (CVD) is currently one of the leading causes of mortality in pregnant women [14], affecting 1%–2% of pregnancies [5]. Having a good understanding of the use of cardiac medications during this time is important to ensure appropriate management of these patients. However, pharmacological therapy for CVD during pregnancy can be challenging because the effects of the medications often change throughout gestation. The pharmacokinetics of the cardiovascular medications is affected by the physiological changes in pregnant women; the metabolism and the efficacy of the medications are usually altered [4]. Most cardiac conditions require use of medications. According to the Registry of Pregnancy and Cardiac Disease (ROPAC), up to one-third of women with CVD use cardiac medications during pregnancy, and this use was associated with increased fetal risk such as intrauterine fetal growth restriction (IUGR) [6]. The majority of data on the safety of medication use during pregnancy rely on observational studies and expert opinion. It should be kept in mind that drug use in pregnancy affects both the mother and the fetus, and therefore pharmacologic agents are chosen to address those concerns.


 


Drug Risk Categorization


The U.S. Food and Drug Administration (FDA) previously used pregnancy risk categories A, B, C, D, and X, with most cardiovascular drugs categorized as B (no animal studies have shown risk/no controlled studies in humans) or C (animal studies have shown adverse effect/no controlled studies in humans). In 2015, the FDA introduced new risk guidelines for various medications in pregnancy and lactation [7]. This new categorization provides narrative sections for pregnancy and lactation, an overall risk based on known data, and the effects on women and men of reproductive potential. However, implementation of these guidelines will occur in stages over a 5-year period. Even though most providers continue to use the U.S. FDA-approved pregnancy risk categories as outlined above [4], the new system should be followed as much as possible, as it is a more detailed description of effects of drugs on pregnancy and lactation.


 


Pharmacokinetics in Pregnancy


The physiological changes in pregnancy affect many body organs, including the cardiac, hepatic, and renal systems (Table 20.1). Important changes include:


1.Delayed gastric emptying and motility


2.Prolonged small bowel transit time


3.Gastroesophageal reflux


4.Increased plasma volume and fat accumulation


5.Increased volume of distribution


6.Decreased albumin and plasma binding proteins


7.Increased minute ventilation


8.Increased hepatic clearance


9.Increased renal clearance


10.Hypercoagulability



All of these changes may affect drug distribution and clearance [5]. For instance, the glomerular filtration rate (GFR) increases by 25% during pregnancy leading to an increase in the clearance rate on medications that are primarily excreted by the kidneys [5,8]. The increase in the amount of body fat and plasma volume can also affect the medication’s concentrations [4]. These factors are important to keep in mind when prescribing medications to women during their pregnancy. The hormonal influences during pregnancy on the liver increase or decrease metabolism of some drugs without clear patterns. It should also be kept in mind that pregnancy is a hypercoagulable state associated with increased risk of thromboembolism.


The dynamic physiological changes of pregnancy clearly affect the pharmacokinetic processes. Increased activity of liver enzyme systems, GFR, plasma volume, protein binding changes, and decreased serum albumin levels contribute to changes in the pharmacokinetics of many medications [9,10]. The hormonally induced alterations in receptor and transport expression may affect drug activity at receptor sites, and therefore pregnancy introduces unpredictability to the body’s handling of medications.


Absorption


Increased progesterone levels can delay intestinal motility in the small bowel while nausea and emesis can inhibit the absorption of medications. Many changes in medication absorption during pregnancy remain mostly theoretical and not proven.


Volume of Distribution (Vd)


There is an 50% increase in plasma volume and total body water during pregnancy, increasing the Vd of hydrophilic and lipophilic substances. As Vd rises throughout pregnancy, the concentrations of a drug may decrease, requiring an increase in drug dosage. The concentration of drugs during pregnancy depends not only on the Vd but also on the clearance of the drug by the different organ systems (i.e., lungs, kidneys, and liver). Vd is also affected by the amount of drug bound to plasma proteins (e.g., albumin). Therefore, the net exposure of a drug during pregnancy depends on the interplay between Vd, degree of binding to serum proteins, extraction ratio, and clearance [11].


Hepatic Clearance


Hepatic extraction ratio refers to the fraction of drug removed from the circulation by the liver. Some drugs like propranolol, verapamil, and nitroglycerin are rapidly taken up into hepatocytes, and their clearance depends on the rate of blood flow to the liver. In pregnancy, perfusion to the liver stays stable or increases, causing some drugs to be metabolized faster, which in turn may require an increase in drug dosing. Clearance of those drugs that are not affected by hepatic clearance, such as warfarin, depends on the intrinsic hepatic activity as well as on the unbound fraction of the drug in plasma [12].


Renal Clearance


Effective renal plasma flow increases as much as 50%–85% in pregnancy [8]. GFR increases by 45%–50% by the end of the first trimester [8] and continues to rise until term, with a possible downtrend in the last few weeks. The tubular function remains variable [13].


 


Medications in Pregnancy


Some cardiovascular medications may be continued in pregnancy, but others are teratogenic and will need to be changed during pregnancy. Medications such as beta blockers, digoxin, and furosemide are safe in pregnancy [4], whereas angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are contraindicated in pregnancy (Table 20.2). Patients on ACEI or ARB for treatment of heart failure and/or hypertension would need to switch these medications to a safer alternative because of their teratogenic potential once pregnancy is confirmed, or ideally, prior to anticipated pregnancy [1,4]. Table 20.3 lists commonly used cardiovascular medications.












































Table 20.2


Medications Contraindicated in Pregnancy


Medication Classification


FDA Category


Safety in Pregnancy


Safety in Lactation


Aldosterone antagonists


Variable


Contraindicated


Contraindicated


Statin


X


Contraindicated


Contraindicated


DOACs


Variable


Contraindicated


Contraindicated


ERAs


X


Contraindicated


Contraindicated


ACEIa


D


Contraindicated


Use with caution


ARB


D


Contraindicated


Unknown





































































































































































































































































































Table 20.3


Common Cardiac Medications in Pregnancy


Medication


FDA


Teratogenicity


Fetal Effects


Safety in Lactation


Antiarrhythmic


Amiodarone


D


No


Fetal thyroid toxicity


Contraindicated


Procainamide


C


No


Use with caution


Use with caution


Sotalol


B


No


Human data suggests risk


Possibly hazardous


Lidocaine


B


No


Safe


Safe


Flecainide


C


No


Limited human information


Use with caution


Phenytoin


C


No


Hemorrhagic disease of newborn


Safe


Atrioventricular nodal blocking drugs


Adenosine


C


No information


Safe


Use with caution


Digoxin


C


No


Safe


Safe


Beta-blockers


Metoprolol


C


No


Potential growth restriction


Use with caution


Atenolol


D


No


Potential growth restriction


Use with caution


Esmolol



No


Beta blockade in the fetus


Unknown


Labetalol


C


No


Safe


Use with caution


Carvedilol


C


Limited information


Potential growth restriction


Unknown


Propranolol


C


No


Safe


Use with caution


Calcium channel blockers


Nifedipine


C


No


Safe


Safe


Amlodipine


C


No


Use with caution


Use with caution


Diltiazem


C


No


Safe


Use with caution


Verapamil


C


No


Safe


Safe


Inotropic drugs


Dopamine


C


No


Safe


May inhibit prolactin release


Dobutamine


B


No


Safe


Unknown


Norepinephrine


C


No


Safe


Unknown


Vasodilators


Hydralazine


C


No


Safe


Safe


Ephedrine sulfate


C


No


Safe


Caution with chronic use


Nitroglycerin


C


No


Use with caution


Unknown


Isosorbide dinitrate


C


No


Use with caution


Unknown


Nitroprusside


C


No


Potential fetal cyanide toxicity with high doses


Use with caution


Antiplatelet


Aspirin


C


No


Use with caution


Use with caution


Clopidogrel


B


No


Use with caution


Use with caution


Ticagrelor


C


Limited information


Use with caution


Unknown


Anticoagulation


Heparin


C


No


Safe


Safe


Enoxaparin


B


No


Safe


Safe


Warfarin


D


Limb defects, nasal hypoplasia


Fetal hemorrhage


Safe


Argatroban


B


No


Use with caution


Unknown


Direct factor Xa inhibitors


(rivaroxaban or apixaban)



No


Crosses placenta, bleeding risk


No information


Alpha blockers


Alpha-methyldopa


B


No


Safe


Safe


Clonidine


C


No


Use with caution


Unknown


Diuretics


Furosemide


C


No


Safe


Caution


Hydrochlorothiazide


B


No


Use with caution


Safe


Metolazone


B


No


Use with caution


Unknown


Torsemide


B


No


Use with caution


Unknown


Pulmonary hypertension drugs


Sildenafil


B


No


Use with caution


Use with caution


Treprostinil


C


No


Unknown


Unknown


Epoprotenol


B


No


Use with caution


Unknown

Jul 17, 2021 | Posted by in OBSTETRICS | Comments Off on Cardiovascular Medications in Pregnancy
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