Cardiovascular Medications in Pregnancy a Primer

Cardiovascular Medications in Pregnancy A Primer

Karen L. Florio, DOa,b,*, Christopher DeZorzi, MDb,c, Emily Williams, MDb, Kathleen Swearingen, MSN, APRN, FNP-Ca, Anthony Magalski, MD, FHFSAb,c

KEYWORDS Cardio-obstetrics Cardiac medications Pregnancy Medication safety Heart disease in pregnancy

KEY POINTS Pregnancy induces dramatic physiologic and anatomic changes in the cardiovascular system beginning in the first trimester and continuing through the postpartum period. Maternal cardiac arrhythmias during pregnancy are a common occurrence and treatment should be considered from both obstetric and electrophysiologic standpoints. Anticoagulation and antiplatelet medications are prescribed commonly in both cardiology and obstetrics for various reasons.

INTRODUCTION such, clinicians need to have a breadth of funda- mental knowledge regarding the safety profiles of Cardiovascular disease and its related disorders medication use during pregnancy. Many different are the leading causes of maternal morbidity and 1,2 factors need to be balanced when deciding on mortality in the United States. The increasing medications during pregnancy, including gesta- age at first pregnancy coupled with the rising rates tional age, reported teratogenicity, placental trans- of obesity likely contribute to this trend. More port, altered pharmacokinetics, route of women are desiring delayed fertility, which results administration, and dosing. Safety profiles are in higher rates of hypertensive disorders during 3 limited because reports of teratogenic effects are gestation. Increases in women with repaired from observational trials or registries due to the congenital cardiovascular disease becoming ethical dilemma of research on this vulnerable pregnant also add to this patient population. As a population.4 The purpose of this review is to guide result, the use of cardiovascular medications dur- clinical decisions for both obstetricians and cardi- ing pregnancy also is increasing. It has been re- ologists when confronted with a pregnant woman ported that up to 94% of women take at least 1 affected by cardiovascular disease requiring treat- medication while pregnant and approximately ment. This is not meant to be an all-encompassing 70% are taking medication during fetal organo- 4 review of every medication utilized during preg- genesis. The ROPAC trial reported as many as nancy but rather an overview of the more 28% of women with underlying cardiovascular commonly used cardiovascular medications (Ta- conditions were taking medication, a number ble 1) from preconception through postpartum that is likely higher in the United States because and lactation. the burden of disease is significantly greater.5 As

a Heart Disease in Pregnancy Program, Saint Luke’s Hospital of Kansas City, 4401 Wornall Road PEET Center, Kansas City, MO 64111, USA; b University of Missouri-Kansas City School of Medicine, 4401 Wornall Road PEET Center, Kansas City, MO 64111, USA; c Saint Luke’s Mid America Heart Institute, Kansas City, MO, USA * Corresponding author. Heart Disease in Pregnancy Program, Saint Luke’s Hospital of Kansas City, 4401 Wor- nall Road PEET Center, Kansas City, MO 64111. E-mail address: [email protected]

Cardiol Clin 39 (2021) 33–54 https://doi.org/10.1016/j.ccl.2020.09.011

0733-8651/21/Ó 2020 Elsevier Inc. All rights reserved. cardiology.theclinics.com Descargado para Irene Ramírez ([email protected]) en National Library of Health and Social Security de ClinicalKey.es por Elsevier en enero 08, 2021. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. 34 Descargado para IreneRamírez ([email protected]) enNational Libraryof Healthand Social Securityde ClinicalKey.es por Elsevieren enero08, 2021. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. lroe al et Florio Table 1 Classification of cardiac medications used during pregnancy

Onset of Lactation/ Drug Mechanism of Action Action Metabolism Side Effects Teratogenicity Breastfeeding Abciximab Monoclonal antibody, Half-life: Opsonization by way of Bleeding, chest pain, No mutagenicity in No reports of use in binds to glycoprotein 30 min reticuloendothelial hypotension, nausea, animal models; literature; unlikely IIb/IIIa, inhibits Onset: system (when bound vomiting, abdominal limited human data crosses into breast platelet aggregation 10 min to platelets) pain, without evidence of milk (large molecule) thrombocytopenia, teratogenicity; anaphylaxis crosses placenta

Acebutolol Cardioselective b1- Half- Extensive first-pass Bronchospasm, No increased AAP recommends blockade life: metabolism bradycardia, heart teratogenicity, some giving “with 3–4 h block, fatigue, reports of neonatal caution.” plasma dizziness, diarrhea, hypotension ratio in milk higher nausea, vomiting than other b-blockers Adenosine Slows AV node Half- Phosphorylation Flushing, dyspnea, No reported Paucity of data—likely conduction, life: intracellularly to chest discomfort, teratogenicity (rapid safe due to short half activation of cell- 10 s adenosine headaches, nausea degradation by life surface A1 and A2 monophosphate placenta); no effect adenosine receptors on fetal heart rate Alteplase Binds to fibrin and Half-life: Hepatic metabolism Hemorrhage, No mutagenicity in No data available converts initial angioedema, animal models plasminogen to 5 min anaphylaxis, fever (minimal placental plasmin with passage) terminal half- life of 72 min Amiloride Potassium-sparing Half- Excreted unchanged in Headache, weakness, No mutagenicity in No data available diuretic, inhibits life: kidneys nausea, vomiting, animal models. sodium absorption in 6–9 h muscle cramps, Limited human data the renal tubules hyperkalemia, (1 case report with aplastic anemia, skeletal anomalies) neutropenia Descargado para IreneRamírez ([email protected]) enNational Libraryof Healthand Social Securityde ClinicalKey.es por Elsevieren enero08, 2021. Amiod- Benzofuran derivative; Half-life: CYP34 A and CYP2C8 in Nausea, vomiting, Fetal goiter, fetal Avoid use during

Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. arone relaxes vascular depends liver visual disturbances, thyroid dysfunction, breastfeeding smooth muscle; acts on hypothyroidism, skin possible association as an antiarrhythmic patient discoloration, AV with IUGR, (prolongs QRS and but block, QT congenital heart QT intervals) varies prolongation defects, from neurodevelopmental 15–142 d delay; crosses term (active placenta in higher metabolite concentration than 14–75 d) maternal serum Plasma half-life 3.2– 79.7 h. Amlod- Calcium channel Half-life: 90% metabolized in Peripheral edema, No mutagenicity in Limited data—probably ipine blocker: blocks 30–50 h liver, 10% excreted fatigue, palpitations, animal models; compatible calcium entry into unchanged in urine flushing, nausea, limited human data cells causing smooth hypotension but small case series muscle relaxation with increased fetal loss and limb defects Argat- Inhibits thrombin- 39–51 min Hydroxylation and Chest pain, Minimal animal data No data available Pregnancy in Medications Cardiovascular roban catalyzed or induced aromatization in the hypotension, cough, (no teratogenic reactions; activates liver hypersensitivity effects at dose 0.3 factors V, VIII, and reaction, fever, human doses); XIII; enhances ventricular minimal human data platelet aggregation arrhythmias, available (likely bleeding, maternal benefit bradycardia outweighs fetal toxicity) Aspirin Blocks prostaglandin 13–19 min Hydrolyzed in plasma Bleeding, dyspepsia, At large doses, WHO Working Group synthesis to salicylic acid, vomiting, teratogenic to animal on Human Lactation (nonselective COX-1 metabolized in liver thrombocytopenia, models; no increased classified as unsafe and COX-2 inhibitor) nausea risk of human teratogenesis with normal dosing (continued on next page) 35 36 Descargado para IreneRamírez ([email protected]) enNational Libraryof Healthand Social Securityde ClinicalKey.es por Elsevieren enero08, 2021. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. lroe al et Florio

Table 1 (continued)

Onset of Lactation/ Drug Mechanism of Action Action Metabolism Side Effects Teratogenicity Breastfeeding

Atenolol Cardioselective b1- 6–7 h Minimal metabolism in Bradycardia, Decreased fetal weight Excreted in breast milk blockade liver, most is excreted hypotension, in animal models; in higher amounts unchanged in the bronchospasm, crosses placenta, not than maternal urine diarrhea, fatigue, associated with birth plasma, WHO nausea, SLE-like defects but with FGR recommends caution reaction with breastfeeding

Carvedilol Combined ⍺1/b- 7–10 h Hydroxylated by CYP Bradycardia, Animal models with Limited human data— adrenergic blocker system in liver; also hyperglycemia, decreased fetal probably compatible undergoes nausea, headache, weight and glucuronidation; BUN elevation, AST/ pregnancy loss; no 98% protein bound ALT elevation, increased pulmonary edema teratogenicity but increase neonatal hypoglycemia Cholesty- Forms resin that acts as 6 min No modification or Constipation, No mutagenicity in Limited human data— ramine a bile acid absorption in gut, flatulence, nausea, animal models; no probably compatible sequestrant and excreted bound to vomiting, fetal teratogenicity limits absorption of bile acids steatorrhea but some cases of bile abnormal fetal heart tracings and meconium

Clonidine ⍺2-Adrenergic agonist 6–23 h Hydroxylation by CYP Somnolence, No mutagenicity in Excreted in breast milk enzymes in liver (but headaches, therapeutic doses in in higher is poorly understood) nightmares, animal models, concentrations than emotional lability, increased fetal loss in maternal plasma; hypotension, reflex higher doses in neonatal HTN with withdrawal animal models; some hypotension. Likely case reports of compatible teratogenicity with first trimester use Descargado para IreneRamírez ([email protected]) enNational Libraryof Healthand Social Securityde ClinicalKey.es por Elsevieren enero08, 2021. Clopidogrel Platelet inhibitor that 6h; 85%–90% metabolized Bleeding, pruritis, No mutagenicity in Limited data but likely

Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. binds to P2Y12 ADP active by liver by CYP system agranulocytosis, animal models; compatible receptors on platelets metabolite pancytopenia limited human data preventing is 30 min with 1 report of PFO aggregation (likely compatible) Dalteparin Potentiates activity of IV: Liver and Bleeding, No mutagenicity in Not transferred in ATIII, inhibiting half- reticuloendothelial thrombocytopenia, animal models; no breast milk; factor Xa and life 2 h system hematuria, ALT/AST increased compatible thrombin Subcu- biotransformation elevation, rash, teratogenicity in taneous: (disulphation and pruritis human fetuses 3–5 h depolymerization) Diltiazem Calcium channel Immediate Extensive first-pass Headaches, dizziness, Increase in limb and tail Limited human data— blocker: blocks release: metabolism in hypotension, malformations in likely compatible calcium entry into 3–4.5 h CYP3A4 system bradycardia, first- animal models; small cells causing smooth Delayed- degree AV block, increase in fetal loss muscle relaxation release: AST/ALT elevations, in first trimester in 6–9 h syncope humans, no increase in birth defects Digoxin Hemodynamic, 1.5–2 d Only approximately Dizziness, headaches, No mutagenicity in AAP classifies as electrophysiologic 13% is metabolized nausea, vomiting, animal models; no compatible with

and neurohormonal (skeletal muscle), anorexia, increased risk of birth breastfeeding Pregnancy in Medications Cardiovascular effects; stimulates 25% protein bound bradycardia, defects when used in parasympathetic palpitations, first trimester nervous system via gynecomastia, (utilized in vagus nerve, depression, AV block, pregnancy for fetal reversibly inhibits delirium SVT) sodium-potassium ATPase enzyme Enoxaparin Inhibition of factor Xa, 4.5 h Desulphation and Hemorrhage, fever, No mutagenicity in Compatible binds to and polymerization in ALT/AST elevations, animal models; does accelerates ATIII liver; 80% protein nausea, not cross human bound thrombocytopenia, placenta, no osteoporosis (long- increased fetal risks term use) (continued on next page) 37 38 Descargado para IreneRamírez ([email protected]) enNational Libraryof Healthand Social Securityde ClinicalKey.es por Elsevieren enero08, 2021. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. Table 1

(continued) al et Florio

Onset of Lactation/ Drug Mechanism of Action Action Metabolism Side Effects Teratogenicity Breastfeeding Enalapril RAAS activated 11–14 h Hydrolyzed by de- Dizziness, hypotension, No mutagenicity in Compatible angiotensin II esterification by fatigue, cough, animal models with enzyme inhibitor hepatic enzymes; hyperkalemia, Cr doses much higher <50% protein bound elevations, than used in humans, photosensitivity, some studies with angioedema, fetal wastage and neutropenia nephrotoxicity; human data suggests outcomes similar to lisinopril

Esmolol Cardioselective b1- 2 min Rapid hydrolysis of Hypotension, nausea, No mutagenicity in Limited human data— blockade ester linkage in RBCs; dizziness, animal models; no probably compatible 55% protein bound somnolence, increased risk of agitation, headaches, human birth defects bradycardia but neonatal effects include apnea and hypoglycemia Ezetimibe Selectively inhibits 22 h Rapidly and extensively Upper respiratory No mutagenicity at No human data— absorption of metabolized by infections, diarrhea, therapeutic dosing animal models cholesterol and phase II myalgias, fatigue, (associated with suggest risk phytosterol (targets glucuronidation in back pain, skeletal changes at Niemann-Pick C1-like liver hypersensitivity, doses 10 human protein) hepatitis dose) in animal models; no human data Flecainide Blocks fast inward 13 h Metabolized by Dizziness, headaches, In high-dose models, Limited human data— sodium channels, CYP2D6 and CYP1A2 fatigue, palpitations, increased clubbed probably compatible shortens action in liver chest pain, tremors, feet and skeletal potential of Purkinje abdominal pain, defects; no increased fibers dyspnea, heart block, teratogenicity in QT prolongation humans but in neonates, increased bilirubin and abnormal EKGs Descargado para IreneRamírez ([email protected]) enNational Libraryof Healthand Social Securityde ClinicalKey.es por Elsevieren enero08, 2021. Fondaparinux ATIII-mediated selective 17–21 h Not metabolized, 94% Bleeding, AST/ALT No mutagenicity in No human data—

Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. inhibition of factor protein bound elevations, anemia animal models; does probably compatible Xa not cross placenta (1 case report documenting neonatal exposure), no teratogenicity Furosemide Blocks tubular 4–4.5 h Kidneys clear 85%, 40% Hypokalemia, AST/ALT Skeletal anomalies in Limited human data— absorption of sodium biotransformation in elevation, animal models in probably compatible and chloride in the liver hyperuricemia, high doses; can cross proximal and distal hyperglycemia, the human placenta tubules hypotension, muscle and increase fetal cramps, weakness, urine production, metabolic acidosis, possible increase in ototoxicity PDA, neonatal sensorineural hearing loss Gemfibrozil Activates peroxisome 1.5 h Hydroxylation at the Dyspepsia, abdominal No mutagenicity in No human data— proliferator- 50methyl and 40 pain, diarrhea, animal models; potential toxicity activated receptors, positions in the nausea, vomiting, limited human data, which alter lipid CYP2C8 enzymatic AST/ALT elevations some case reports of metabolism system brain and facial Pregnancy in Medications Cardiovascular defects Heparin Inhibition of factor Xa 1.5 h Biotransformation in Bleeding, No mutagenicity in Compatible the liver and thrombocytopenia, animal models; does reticuloendothelial prolonged clotting not cross human system time, fever, AST/ALT placenta elevations, HIT Hydrochlo- Inhibits sodium and 5.6–14.8 h Not metabolized Electrolyte imbalances, No mutagenicity in Compatible (may rothiazide chloride in proximal hypercalcemia, animal models; no decrease milk renal tubules and dizziness, anorexia, increase production in first reduces absorption muscle cramps teratogenicity but month) of water associated with neonatal thrombocytopenia, bleeding, electrolyte imbalances (continued on next page) 39 40 Descargado para IreneRamírez ([email protected]) enNational Libraryof Healthand Social Securityde ClinicalKey.es por Elsevieren enero08, 2021. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. lroe al et Florio Table 1 (continued)

Onset of Lactation/ Drug Mechanism of Action Action Metabolism Side Effects Teratogenicity Breastfeeding Hydralazine Interferes with calcium 2.2–7.8 h Hydroxylation and Headache, Abnormal embryo Limited human data— transport, also glucuronidation in hypotension, development in probably compatible competes with liver palpitations, nausea, animal models likely protocollagen prolyl vomiting, diarrhea, due to hydroxylase neutropenia, lupus- uteroplacental (preventing like reaction hypoperfusion; no degradation of HIF- reports of ⍺1) teratogenicity in limited human data Labetalol Nonselectively 1.7–.1 h Metabolized to Hypotension, dizziness, No mutagenicity in Limited human data— antagonizes b1/b2- glucuronide headaches, fatigue, animal models but probably compatible receptors, a1-agonist metabolites in liver edema, BUN/Cr decreased birth elevation, weights; some bronchospasm, reports associated Raynaud disease, with hypospadias, bradycardia, syncope low birth weight Lisinopril Angiotensin II enzyme 12.6 h Excreted unchanged in Dizziness, hypotension, Abnormal/birth defects Not compatible inhibitor the urine; no protein Cr elevations, cough, in animal models; binding fatigue, human data in first photosensitivity, trimester limited to angioedema, conclude neutropenia teratogenicity but does increased risk of malformations and death in second/third trimester Methy- Stimulates central 105 min Extensively Sedation, angina, No mutagenicity in Compatible ldopa inhibitory metabolized in the weakness, animal models; single ⍺-adrenergic liver bradycardia, study in humans receptors diarrhea, vomiting, showing myocarditis, malformations hypotension Descargado para IreneRamírez ([email protected]) enNational Libraryof Healthand Social Securityde ClinicalKey.es por Elsevieren enero08, 2021.

Metoprolol b1-adrenergic receptor 3–7 h Extensive first pass Bradycardia, influenza- No mutagenicity in Compatible

Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. inhibitor metabolism through like symptoms, animal models; some CYP2D6 enzymatic fatigue, headache, small case studies system rash, hyperuricemia, with fetal sleep disturbances, malformations, heart block associated with low birth weight Milrinone Inhibits erythrocyte 2.3 h O-glucuronidation in Ventricular No mutagenicity in No human data— phosphodiesterase in liver, 80% protein arrhythmias, ectopy, animal studies; no probably compatible myocardium and bound tachycardia, teratogenicity in vascular smooth hypotension, human studies muscle, leading to headache, increased cAMP in anaphylaxis red cells Nadolol Nonselective b- 20–24 h Excreted unchanged in Bradycardia, fatigue, No mutagenicity in Compatible adrenergic blocker the kidney dizziness, nausea, animal studies; no vomiting, increased risk of constipation, teratogenicity but is Raynaud disease, associated with low bronchospasm birth weight

Nicardipine Calcium channel 8.6 h Metabolized Headache, dizziness, May interfere with Probably compatible Pregnancy in Medications Cardiovascular blocker: blocks extensively in liver; hypotension, nausea, embryo development calcium entry into 95% protein bound vomiting, in small animal cells causing smooth tachycardia, studies; no increased muscle relaxation palpitations teratogenicity in small studies Nifedipine Inhibits L-type voltage- 2 h Metabolized by Headaches, fatigue, May interfere with Compatible gated calcium CYP3A4 enzymatic flushing, nausea, embryo development channels system in liver; 92%– vomiting, in small animal 98% protein bound palpitations, studies; no increased hypotension, teratogenicity in bradycardia small studies (continued on next page) 41 42 Descargado para IreneRamírez ([email protected]) enNational Libraryof Healthand Social Securityde ClinicalKey.es por Elsevieren enero08, 2021. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. Table 1

(continued) al et Florio

Onset of Lactation/ Drug Mechanism of Action Action Metabolism Side Effects Teratogenicity Breastfeeding Propafenone Class 1C antiarrhythmic 2–10 h Extensively Dizziness, nausea, Embryotoxic in animals Limited human data— (reduction in metabolized in liver; edema, taste at doses 3–6 probably compatible upstroke of action 97% protein bound changes, vomiting, maximum human potential); reduces blurred vision, dose; limited human fast inward sodium ecchymosis, data but appears to ions ventricular have no increased arrhythmias, QT teratogenicity, is prolongation associated in small case series with fetal loss Propranolol Nonselective b- 8 h Side chain oxidation (to Fatigue, dizziness, No mutagenicity in Compatible adrenergic metabolites) or bradycardia, animal models; no antagonist glucuronidation in hypotension, nausea, increased liver; 85%–96% vomiting, purpura, teratogenicity but is protein bound disorientation, associated with depression, heart decreased birth block weights Rivaroxaban Inhibits factor Xa 5–9 h Metabolized by CYP Bleeding, back pain, No mutagenicity in Limited human data— enzymatic system in pruritis, dizziness, animal models; caution liver; 92%–95% thrombocytopenia, minimal human data recommended protein bound agranulocytosis with only 1 case report of teratogenicity, does cross placenta and cause neonatal bleeding risk Spirono- Inhibits aldosterone- 1.4 h Deacetylation and Electrolyte imbalances, Antiandrogenic effect Compatible lactone dependent sodium excretion in the nausea, vomiting, in animal data with exchange channels in urine; >90% protein dizziness, lethargy, adverse effects on distal convoluted bound menstrual male genitalia, this tubules irregularities, GI was not seen in bleeding, gastritis, human data, some gynecomastia case reports with ambiguous genitalia Descargado para IreneRamírez ([email protected]) enNational Libraryof Healthand Social Securityde ClinicalKey.es por Elsevieren enero08, 2021.

Sotalol b1-adrenergic 10–20 h Not metabolized and Fatigue, dizziness, No mutagenicity in Considered unsafe

Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. antagonist, rapid not protein bound bradycardia, animal models but 1 (excreted in breast potassium channel palpitations, case of fetal death milk in large inhibitor headaches, insomnia, secondary to quantities) heart block, QT arrhythmia; no prolongation teratogenicity

Timolol b1/b2-adrenergic 2.9 h Metabolized by P450 Bradycardia, fatigue, No mutagenicity in Compatible antagonist 2D6 system in liver; dizziness, animal models; no 10% protein bound nightmares, teratogenicity but is headaches, heart associated with low block, ocular birth weight irritation Verapamil Calcium channel 2.8–7.4 h Extensively Dizziness, nausea, Possible cardiac and Compatible blocker: blocks metabolized by P450 hypotension, CNS malformations in calcium entry into system in liver headaches, fatigue, animal models; some cells causing smooth hypotension, case reports of muscle relaxation bradycardia, teratogenicity and is hepatotoxicity associated with low birth weight Warfarin VKA 37–89 h Oxidation in liver by Bleeding, ecchymosis, Mutagenicity in animal Compatible

CYP system, limited abdominal pain, models; associated Pregnancy in Medications Cardiovascular conjugation lethargy, taste with structural changes, paresthesia, malformations in skin necrosis, dose-dependent calciphylaxis manner in human data, neonatal bleeding

Abbreviations: AAP, American Academy of Pediatrics; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATIII, antithrombin III deficiency; AV, atrioventricular; BUN, blood urea nitrogen; cAMP, cyclic adenosine monophosphate; CNS, central nervous system; COX, cyclo-oxygenase; CR, creatinine; CYP, cytochrome P450; GI, gastrointestinal; HIF, hypoxia-inducible factor; HIT, heparin-induced thrombocytopenia; HTN, hypertension; IUGR, intrauterine growth restriction; PDA, patent ductus arteriosus; P2Y12ADP, chemo receptor for adenine diphosphate; PFO, patent foramen ovale; RAAS, renin angiotensin system; RBC, red blood cell; SLE, systemic lupus; WHO, World Health Organization. 43 44 Florio et al

PHYSIOLOGIC CHANGES IN PREGNANCY the continued increase in plasma volume, resulting Cardiovascular Changes in trivial regurgitation in the mitral, tricuspid, and pulmonary valves.28 Cardiac myocyte hypertrophy Pregnancy induces dramatic physiologic and coupled with increased myocyte stretch leads to anatomic changes in the cardiovascular system higher contractility without an increase in left ven- beginning in the first trimester and continuing tricular strain or a change in overall ejection frac- through the postpartum period. These coordi- tion.8,13 There is a sharp increase in cardiac nated changes function to supply the growing output in the first trimester and again in the third fetus with oxygen and nutrients throughout preg- trimester, driven by the drop in SVR and increased nancy. Prior to conception, only approximately maternal blood volume.6 By 24 weeks, there is a 2% to 3% of total cardiac output flows through 45% increase in cardiac output over baseline, the uterine arteries compared with 25% at and this rises to between 60% and 80% within term.6,7 This shift in cardiac output begins very the hour after delivery secondary to increased early on, peaking at term, and returning to normal venous return and maternal autotransfusion. Car- at 3 months to 6 months.6 diac output does not drop to normal prepregnancy The heart undergoes progressive adaptive values until 3 months to 6 months postde- remodeling and structural alterations, including livery.11,26,29 Increased sympathetic tone in- displacement into the thoracic cavity that is upward creases maternal heart rate by 10 beats per and forward.8 This creates a barrel shape to the minute (bpm) to 20 bpm, but stroke volume is the maternal chest, giving the appearance of cardiome- driving force behind the rise in cardiac output.30–32 galy on chest imaging and left axis deviation on elec- 9,10 trocardiogram (EKG) recordings. Left ventricular Respiratory Changes wall mass and right ventricular wall mass increase, by 52% and 40%, respectively.11–14 This likely is Much like the cardiovascular system, the respira- due to a combination of increased blood volume tory system undergoes dramatic changes in order and signaling from progesterone and vascular endo- to efficiently transport oxygen to and offload car- thelial growth factors, leading to hypertrophy of the bon dioxide from the fetal-placental unit. Fetal off- cardiac myocytes and increased angiogenesis.15,16 loading of carbon dioxide is dependent on a Placental lactogen enhances erythropoietin produc- diffusion differential from the fetal umbilical ar- tion, leading to an increase in red blood cell mass by teries to the maternal venous system. In order for 30%.17,18 Total body water and plasma volume in- this to be accomplished, the respiratory physi- crease by a larger proportion, creating a physiologic ology alters to create a state of alkalosis mediated 19,20 anemia. Increased estrogen activates the renin- by a drop in arterial PCO2 and by compensatory angiotensin-aldosterone system, increasing sodium excretion of bicarbonate by the kidneys.33,34 There resorption and thereby water uptake. Estrogen also is an approximate 20% increase in oxygen con- mediates the release of vasopressin from the hypo- sumption, which is accomplished by increasing thalamus, lowering the maternal osmostat and both tidal volume and resting minute volume.35 decreasing the thirst threshold. This leads to a The functional residual capacity decreases by decrease in colloid osmotic pressure, which contrib- 20% due to a decrease in both expiratory reserve utes to dependent edema and an increased risk for and residual volume, which puts pregnant women pulmonary edema.21 This physiologic dependent at risk for hypoxia due to lower oxygen re- edema can be difficult to discern from edema sec- serves.6,36 Perceived hyperventilation is driven ondary to cardiac failure. by progesterone and can lead to the sensation of To accommodate for the increasing volume, dyspnea in up to 70% of women by 30 weeks’ there is a compensatory increase in venous and gestation.6 Most importantly, from a drug arterial distensibility and a softening of the intimal metabolism standpoint, is the reduced buffering lining of the arterial vessels.14,22,23 Nitric oxide, capacity of the system and the shift in the relaxin, and progesterone mediate smooth muscle oxygen-dissociation curve to the right to ensure relaxation and a drop in systemic vascular resis- offloading to the fetoplacental unit.35,36 tance (SVR).24,25 This drop in SVR is offset by the increase in preload and subsequently cardiac Gastrointestinal and Hepatic Changes output, which leads to minimal change in the From a pharmacologic standpoint, the important mean arterial pressure. This 25% to 30% drop in changes in the gastrointestinal system that poten- blood pressure reaches it’s nadir in mid–second tially could alter absorption, distribution, and trimester and returns to normal prepregnancy excretion include a decrease in serum albumin values by the third trimester.26,27 Dimensions of secondary to hemodilution (and some renal excre- all cardiac chambers increase to compensate for tion), altering drug binding. As each organ system

Descargado para Irene Ramírez ([email protected]) en National Library of Health and Social Security de ClinicalKey.es por Elsevier en enero 08, 2021. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. Cardiovascular Medications in Pregnancy 45

receives an incremental increase in the proportion distribution. For example, prolonged gut transit of cardiac output, so too does the liver, which can decrease the absorption of metoprolol or either can increase or decrease drug clearance verapamil, and drugs that require an acidic envi- depending on the medication involved.37 The cy- ronment may have higher bioavailability leading tochrome P450 enzymes are up-regulated, which to toxicity.48 Pregnant women tend to have more changes the metabolic clearance of many drugs, gastric reflux, which can lead to higher consump- including some cardiovascular medications.37,38 tion of chelators, such as antacids, inadvertently Gastric acidity also is increased due to increased altering cardiac drug metabolism.49 Higher serum placental production of gastrin.6,39 This coupled albumin levels lead to higher levels of bound with decreased sphincter tone leads to increased drugs, decreasing the metabolically active free- rates of reflux. In and of itself this does not interfere form and subsequent decreased mechanism of with drug metabolism and absorption but the action on the target tissue.50 Increased glomerular treatment—antacids—can decrease bioavail- filtration rate (GFR) and renal clearance also can 40 ability of many cardiac medications. Altered a1- lead to lower drug concentrations, as discussed acid glycoprotein along with an increase in fatty previously. The increased blood flow to the liver acids and lipids can displace bound drugs and in- with increased hepatic enzyme activity can alter crease the unbound drug fraction.41 the doses of certain cardiac medications leading to a change in dosing requirements in order to Renal Changes have the desired effects.51,52 The drop in SVR affects the renal vasculature with a concomitant dilatation of the renal arterial sys- PLACENTAL CONTRIBUTION TO tem as the result of rising progesterone levels. Pro- PHARMACOKINETICS gesterone likewise mediates resistance to certain angiogenic factors, such as angiotensin II, The placenta was long held to be a senescent or- ensuring the vasodilatory effects are not miti- gan, functioning as both a barrier to toxic sub- gated.42 Relaxin stimulates formation of endothe- stances and a transport mediator for nutrients to lin, which in turn mediates vasodilation of the the growing fetus. In vivo studies, however, have renal arteries via nitric oxide synthesis.23,43 This found that the placenta is active in both transport hormonally driven drop in blood pressure coupled and metabolism of many xenobiotics in the maternal circulation, and these factors should be with increasing blood volume creates a state of 53 underfilling that is unique to pregnancy, signaling considered when dosing maternal medications. the osmostat to increase water absorption despite Other important considerations include the solubil- a continued rise total body water.44 Decreased ity and lipophilic nature of the drug being given, SVR despite rising plasma volumes is only physio- because many drugs easily cross the placental bar- logically possible because 80% of the volume in- rier by diffusion and become trapped in the fetal 42 compartment as a result of the lower pH in both crease is within the maternal venous system. 37,53,54 With the increasing cardiac output to the renal ar- the amniotic fluid and fetal blood. This leads teries, there is an increase in glomerular filtration to ionization and accumulation of basic drugs within by 50% by the end of the first trimester.45 As a the fetal system and studies of cord blood analysis result, creatinine clearance increases and serum at birth have shown that certain medications creatinine levels fall, both of which can significantly concentrate in the fetal blood stream compared affect the metabolism and clearance of many car- with the maternal system. In general, uncharged, diac medications.44 Drug clearance also can be unionized molecules with high lipid solubility and lower molecular weights readily can cross the affected by the increasing albumin excretion as 53,55 the result of increased glomerular permeability.46 placental barrier. Solute levels also play a key Despite an increase in fractional excretion of albu- role in maternal and fetal concentrations, which min, the normal concentration in the urine should can change dramatically with the previously not exceed 300 mg/d.47 described changes within the maternal cardiovascular system. Active transport is accomplished MATERNAL PHARMACOKINETIC through several different membrane-bound trans- ALTERATIONS DURING PREGNANCY porters and, although they do not play a significant role in the movement of nutrients and wastes, they All of the aforementioned physiologic changes can be targets for transplacental drug transfer. Dur- contribute to altered drug distribution and their ing the first trimester, a member of the adenosine clinical effect during pregnancy. Delayed gastric triphosphate–binding cassette superfamily (ABC) emptying and increased gastrin production can plays a critical role in eliminating medications from lead to altered drug absorption and lowered tissue the fetal compartment, and many cardiac

medications, such as verapamil, can inhibit its func- be considered thoughtfully from both obstetric tion.55,56 The placenta possesses metabolizing en- and electrophysiologic standpoints. Ventricular ar- zymes for both phase I (drug oxidation, reduction, rhythmias, although rare, represent an emergency, and hydrolysis) and phase II (conjugation) reactions and unstable patients should be treated immedi- that can substantially alter drug levels and transport ately with electrical cardioversion. Atrial arrhyth- across the placenta.53,56 mias, however, are more common and likely are due to the overall increase in cardiac output and 62 CLASSIFICATION OF CARDIOVASCULAR blood volume. Medications frequently are indi- MEDICATIONS cated in these patients more so for symptom control rather than for an acute emergency. Pregnant Most of the fetal organs fully developed have by the women at risk for arrhythmias include those with end of the first trimester, which is the epoch in preg- prior structural heart disease and those who nancy referred to as organogenesis.57 This is the have had prior cardiac surgery due to congenitally time frame wherein the fetus is most susceptible to corrected lesions. A careful history should be ob- teratogens. Most medications are not teratogenic tained prior to initiating any antiarrhythmic drugs, when used in therapeutic doses, but, again, due to because some medications, such as sotalol or fle- the rapidly changing physiology of pregnancy, cainide, can cause unwanted maternal drug-drug medication levels can inadvertently rise causing un- interactions or side effects. Physicians must wanted side effects. The baseline risk for congenital consider both adverse maternal and fetal side ef- malformations is 1% to 3%.58 Of these, up to 10% fects. Patients with underlying preexcitation on can be attributed to medication use during preg- EKG should avoid the use of verapamil and digoxin nancy.58 The US Food and Drug Administration pre- to avoid promoting conduction down an acces- viously had categorized medication risk in sory pathway. Careful consideration in the preg- pregnancy according to letters (A, B, C, D, and X) nant patient should be taken with digoxin with category A medications posing no substantial because it has reduced drug effect on the mother risk to the fetus and category X medications contra- during pregnancy due to increased drug clearance indicated due to the high risk of teratogenicity.59 Due and increased unbound fraction of digoxin.63,64 to the ambiguity of such classification, however, a Due to a digoxin-like substance reported in the newer risk stratification model was adopted entitled maternal serum, digoxin serum levels are not as the Pregnancy and Lactation Labeling Rule, reliable as in the nonpregnant population.65 In whereby drug applications submitted after June addition, digoxin is cleared renally and, due to 2015 were categorized according to this new the 50% increase in renal blood flow during preg- model.59 The newer labeling removed the dichoto- nancy, may require dosage adjustments. Adeno- mization of the antepartum and labor and delivery sine also may require increased dosages in time frames and has a new subsection for persons pregnancy. of reproductive potential.60 The newer labeling is The fetal effects of antiarrhythmic drugs are meant to provide more general information, important to understand and more frequent moni- including medication (pregnancy) registries, fetal toring may be necessary. Flecainide has an overall risks, and the likelihood of developmental abnormal- good safety profile and is used widely throughout ities. In addition, clinical considerations regarding gestation.66–69 There are some small case reports, timing, dose, and duration of exposure with both an- however, of flecainide associated with neonatal imal and human data are included. It no longer is rec- prolonged QT and heart failure at toxic levels and ommended to use the previous letter classification decreased fetal heart rate variability on external for clinical decision making.61 Use of medications fetal cardiac monitoring.52 Adenosine does not during pregnancy is not without some level of risk, cross the placenta and has a short half-life and, and discussing the potential outcomes should be therefore, is thought to pose minimal risk.52 Signif- part of the counseling of women with cardiovascular icant fetal effects have been reported after the use disease who desire to become or who already are of amiodarone, including hypothyroidism and neu- pregnant. rodevelopmental complications, making it a last The following sections delineate the most resort in the treatment of arrhythmias.61 b- commonly used medications in pregnancy and Blockers are a commonly used medication for their safety profiles. rate control (discussed later). As a class, they usually are considered safe without an increase in ANTIARRHYTHMIC THERAPIES congenital cardiac abnormalities, and first trimester use has not been found to be associated Maternal cardiac arrhythmias during pregnancy with a higher risk of any specific congenital anom- are a common occurrence and treatment should alies.70–73 There are numerous studies looking at

fetal growth restriction (FGR) and b-blockers, joint discussion between the patient, the obstetri- including 1 study showing FGR in a group of pa- cian and the cardiologist. The use of low- tients taking propranolol, metoprolol, atenolol, or molecular-weight heparin (LMWH) is associated bisoprolol compared with control.74,75 Atenolol with less risk of valve thrombosis than unfractio- was associated most strongly with FGR and, nated heparin but still higher than with vitamin K therefore, should be avoided in pregnancy.76 antagonists (VKAs).79 The higher risk of valve Use of these medications while breastfeeding is thrombosis with heparin use likely is secondary an important consideration when discussing medi- to its increased excretion in the maternal kidneys cation options in the postpartum period. Some as a result of the higher GFR in pregnancy, medications, although contraindicated during because heparin is known to be excreted renally. pregnancy, can be used safely during breastfeed- Meticulous monitoring of anti-Xa levels (rather ing and lactation. Most antiarrhythmic medica- than partial thromboplastin time) should be tions, including b-blockers, calcium channel employed and followed by an experienced cardiol- blockers, digoxin, flecainide, lidocaine, mexiletine, ogist or maternal-fetal medicine specialist procainamide, propafenone, quinidine, and sota- because these patients are at increased risk for lol, are compatible with breastfeeding because both subtherapeutic and supratherapeutic levels they have little transfer into the breast milk.77 It is due to these physiologic changes. According to unknown if adenosine transfers to the breast the European Society of Cardiology 2018 guide- milk. Amiodarone is a bit more controversial and lines, the use of VKAs throughout pregnancy, un- requires a conversation with the patient prior to der strict international normalized ratio control, is initiation. If a patient is on amiodarone and wishes the safest regimen to prevent valve thrombosis.61 to breastfeed, the infant’s pediatrician should be Concomitant aspirin use for valve thromboprophy- alerted so that neonatal plasma levels can to be laxis is recommended by the American College of monitored because breast milk and infant serum Cardiology (ACC) and the American Heart Associ- levels are somewhat unpredictable, likely due to ation (AHA) and has been shown to be safe for the long half-life.78 both mom and fetus alike.52 It also is used widely in the high-risk obstetrics population to mitigate the risk for preeclampsia.80 Studies have shown ANTICOAGULATION AND ANTIPLATELET there is no evidence that low-dose aspirin alone in- THERAPY creases maternal or fetal bleeding risks, risk of Maternal Issues placental abruption, or complications at the time Anticoagulation and antiplatelet medications are of neuraxial anesthesia during delivery. The risk prescribed commonly in both cardiology and ob- of bleeding, however, when combined with other stetrics for various reasons. An understanding of anticoagulants has led the ESC guidelines, in the hypercoagulable state of pregnancy is para- contrast to the AHA/ACC guidelines, to not recom- mount because it may change the indication, mend use of low-dose aspirin for mechanical dosing, and frequency of certain medications. valves.61,81–83 Although anticoagulation commonly is used in the obstetrics realm for thrombophilia or prophy- Fetal Issues laxis after surgery, a pregnant patient with a mechanical valve is an uncommon situation, which Warfarin embryopathy is a significant morbidity may involve multidisciplinary discussion regarding associated with VKAs.84 First-trimester transpla- use and safety. Due to the thrombogenic propen- cental passage increases the risk for fetal warfarin sity of pregnancy, these people are at increased syndrome or Di Sala syndrome.85 The most com- risk for valve thrombosis.79 As well, the changing mon teratogenic findings include facial dysmor- volume of distribution creates significant chal- phisms, such as nasal hypoplasia, skeletal lenges in regard to therapeutic windows, putting abnormalities (limb hypoplasia and stippled epiph- them at risk for a venous thrombus embolism or yses), central nervous system abnormalities hemorrhage, and these women should be moni- (ventral and dorsal midline dysplasia), and cardiac tored more regularly.61 The risk of valve throm- defects.84–88 In the second and third trimesters, bosis depends on the type and position of the there is a 0.7% to 2% risk of ocular/central ner- mechanical valve with lower pressure positions vous system abnormalities and intracranial hemor- (mitral valve) being at higher risk for thrombosis.79 rhage with VKAs.61 There are higher rates of The risks of fetal teratogenesis with warfarin need miscarriage and stillbirth reported when daily to be weighed against the relatively high risk of doses exceed 5 mg.89 Current guidelines recom- valve thrombosis with the use of first-trimester mend women who are taking this dose or higher heparin, and which modality to use should be a during the first trimester to be transitioned to

LMWH or unfractionated heparin by the end of the is considered safe.77,89 Unfractionated heparin sixth week of gestation to decrease the risk of fetal and enoxaparin largely are considered safe but malformations.83 In women on warfarin who pre- the amount that crosses into breast milk is sent in labor, the recommendation is to consider unknown.77 cesarean delivery to avoid neonatal intracranial 90 hemorrhage. During the last week of gestation, HYPERTENSIVE DISORDERS AND it is not unreasonable to admit patients and have PREECLAMPSIA: RECOMMENDED them on a heparin drip in either anticipation of TREATMENT spontaneous labor or for a planned induction. Heparin and LMWH both are large molecules Hypertensive disorders of pregnancy (HDPs) and do not cross the placenta. Given the changing affect up to 10% of all pregnancies in the United volume of distribution in pregnancy along with in- States and the rates continue to climb.100 Due to crease excretion of these medications through the rising rates of obesity, women entering preg- higher GFR, both peak and trough levels should nancy with comorbid chronic hypertension also be monitored throughout pregnancy. A meta- are on the rise. Chronic hypertension, or elevated analysis of maternal and fetal outcomes in more blood pressure, either prior to pregnancy or as a than 800 women with mechanical heart valves uti- new diagnosis, defined by 2 blood pressures of lizing different anticoagulant strategies found that 140 mm Hg systolic or higher and/or 90 mm Hg VKAs were associated with the lowest risk of diastolic or higher separated by 4 hours prior to adverse maternal outcomes, whereas the use of 20 weeks, complicates 3% of all pregnancies LMWH was associated with the lowest risk of and, therefore, makes up a large portion of the adverse fetal outcomes.79 morbidity associated with adverse pregnancy out- There are minimal human data on the terato- comes.100,101 Definitions are important because genic effects of aspirin use in the first trimester.77 they dictate management, timing of delivery, and Case-control studies of children with congenital treatment recommendations. As well, outcomes heart defects found no association between these for different HDPs are varied, with more severe abnormalities and maternal use of aspirin.91,92 A events occurring in women with higher recorded meta-analysis did not find an increased risk of blood pressures. For instance, women with gesta- congenital defects associated with first trimester tional hypertension (new-onset elevated blood use of aspirin and a prospective study of more pressures as defined by a systolic pressure of than 50,000 pregnancies did not report aspirin- 140 mm Hg or higher and/or a diastolic pressure associated malformations, altered birth weight, of 90 mm Hg or higher on 2 occasions separated or perinatal deaths.93,94 High-dose aspirin and by 4 hours without proteinuria or any other signs near-term use of aspirin and other prostaglandin of end-organ damage) have lower rates of adverse synthase inhibitors may result in closure or outcomes including small for gestational age in- constriction of the fetal ductus arteriosus with fants and maternal stroke as well as lower rates resultant pulmonary hypertension.95 of recurrence of HDPs in any future pregnan- There are several case reports of clopidogrel cies.100,102–104 As well, the American College of used during pregnancy without documented Obstetricians and Gynecologists does not recom- congenital defects although sufficient data to mend that women with gestational hypertension determine absolute safety are lacking.96–98 There receive antihypertensive treatment because are insufficient data to recommend direct oral an- studies have not shown an improvement in out- ticoagulants for women in pregnancy and few data comes with treatment and, because up to 50% in regard to prasugrel, ticagrelor, abciximab, or of women with gestational hypertension progress eptifibatide; therefore, their use is not to preeclampsia, treatment would be masking recommended.52 any worsening disease.104 Severe disease should be treated, however, once a diagnosis has been established. Preeclampsia has been redefined Breastfeeding and Lactation and now women with new-onset elevated blood Although there are variations in the ability of these pressures of 140 mm Hg systolic and/or 90 mm medications to transfer to breast milk, there are Hg on 2 occasions separated by 4 hours after few absolute contraindications to their use. Aspirin 20 weeks’ gestation with proteinuria now are is excreted in the breast milk and likely is safe at a reclassified as preeclamptics without severe fea- lower doses.77 Prasugrel and ticagrelor have been tures.104 Preeclampsia with severe features has shown to transfer in rat studies but, overall, as with numerous laboratory and clinical inclusion criteria. clopidogrel, their effect largely is unknown.99 For the treating cardiologist, the most important Warfarin has only minimal transfer and generally change is that preeclampsia with severe features

(previously known as severe preeclampsia) can be safety profile to labetalol but a longer onset of ac- defined by blood pressures alone, despite being tion, which is not ideal for acute hypertensive aproteinuric.101,104 Any new-onset severe range emergencies in pregnancy. Women treated for un- blood pressures, defined by systolic of 160 mm derlying chronic hypertension on metoprolol can Hg or greater and/or diastolic readings of continue with their current medication regimen, 110 mm Hg or greater separated within minutes, however, keeping in mind that metoprolol has a can qualify as pr-eclampsia with severe fea- higher clearance rate in the second and third tri- tures.104 Although women with gestational hyper- mesters and may require aggressive adjustments tension or preeclampsia without severe features in dosing/frequency in order to maintain a thera- are managed without antihypertensive therapy on peutic window.112 Both have long-term follow-up an outpatient basis, it is recommended that studies in children exposed in utero with no asso- women with preeclampsia with severe features ciated adverse health outcomes.113,114 remain in the hospital until delivery and receive Hydralazine is a potent arterial vasodilator that is antihypertensive therapy to prevent adverse recommended as a second-line alternative to maternal outcomes, such as worsening hyperten- labetalol for the treatment of acute hypertensive sion and stroke.3,104,105 urgencies during pregnancy.104,105 Hydralazine Usually, a cardiologist is asked to become does, however, have a higher risk for hypotension involved to manage chronic hypertension prior to compared with oral nifedipine or intravenous labe- 20 weeks or during the postpartum period when talol and should be taken into consideration when fluid shifts and autotransfusion after delivery can administering due to the risk for uterine hypoperfu- exacerbate HDPs. It, therefore, is important to sion and subsequent non-reassuring fetal sta- have knowledge regarding the safety profiles of tus.115 There are no associated risks for birth the most commonly used antihypertensives for defects when used in the first trimester and it is both pregnancy and lactation. considered safe for breastfeeding mothers.107,116 Calcium channel blockers are categorized as either dihydropyridines or nondihydropyridines. Treatment of hypertensive Disorders of Nifedipine, a dihydropyridine, is used widely in Pregnancy: Recommended Antihypertensive pregnancy for control of chronic hypertension, Medications acute hypertensive emergencies, and uterine Although b-blockers are considered fourth-line tocolysis.100,104,117 It has been shown more effec- therapy outside of pregnancy, due to their fetal tive at lowering and maintaining blood pressure in and neonatal safety profile, labetalol is the first- an acute hypertensive crisis than hydralazine and line agent recommended for the treatment of its rapid onset of action makes it ideal for women both chronic hypertension and acute hypertensive without intravenous access or with contraindica- emergencies throughout gestation.100,104–106 tions to b-blockade.104,115,118 Nifedipine is consid- Labetalol is a nonselective a1-, b1-, and b2-adren- ered safe during the first trimester and does not ergic blocker, which lowers blood pressure by pe- pose an increase in teratogenic risk.119 ripheral vasodilation and has not been shown to Methyldopa is an a2-receptor agonist with a have teratogenic effects when used in the first long track record of safety in pregnancy. Although trimester despite its ability to cross the previously the first-line agent, its longer onset of placenta.107 It has been associated with maternal action precludes it from being used in hyperten- hypotension, fetal bradycardia, perinatal jaundice, sive urgencies.120 Women with chronic hyperten- and neonatal hypoglycemia.70,108,109 There is the sion who come into pregnancy well-controlled on association of low birth weight with the use of methyldopa may continue using it but again should labetalol; however, this likely is independent of be aware that due to the increased volume of dis- drug use and rather a manifestation of the hyper- tribution may require more frequent and/or tension itself.110 Although it has been found in increased dosing.121 It has not been associated the maternal breast milk, it generally is considered with any fetal, neonatal, or maternal adverse safe for the neonate.111 Labetalol is recommended outcomes.122 as first-line therapy for women with chronic hypertension planning a pregnancy and for the acute Antihypertensive Medications To Be Used treatment of severe hypertension secondary to with Caution either chronic hypertension exacerbation or preeclampsia with severe features (intravenous Amlodipine, another dihydropyridine, has not been dosing only).100,104 Due to the increased volume used widely in pregnancy and, therefore, there are of distribution, labetalol may require 3-times daily minimal safety data reported. There are some case dosing during pregnancy. Metoprolol has a similar series, however, reporting an increase in seizure

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