Lactation safety of cardiovascular medications

Abstract

Breastfeeding is the gold standard for infant feeding with well-established maternal, neonatal, and pediatric benefits. Patients with preexisting cardiovascular disease have lower breastfeeding rates than the general population. While little evidence exists regarding specific barriers to lactation in patients with preexisting cardiovascular disease, concerns regarding lactation safety and medication exposure in mothers with cardiovascular disease may be a cause for early breastfeeding cessation despite known health benefits. This literature review highlights the lactation safety of common cardiac medications. While some common cardiac medications may have limited safety data available, general pharmacokinetic principles of drug secretion in lactation can help to guide shared decision making in discussion with the patient. Enhancing provider knowledge regarding cardiac medication safety during breastfeeding may improve lactation outcomes in this population.

1. Introduction

Breastfeeding has long been the gold standard for infant feeding. The World Health Organization and American Academy of Pediatrics recommend exclusive breastfeeding for at least six months with continued breastfeeding for two years or as mutually desired by the infant and lactating individual [1,2]. Breastfeeding has been demonstrated to reduce the risk of many acute and chronic pediatric conditions with more recent evidence suggesting an association with reductions in obesity and type 2 diabetes among children and adolescents [1,3]. Lactation also leads to lower lifetime rates of maternal cardiovascular disease, coronary heart disease, stroke, and fatal cardiovascular disease [4]. Despite the robust evidence supporting both pediatric and maternal health benefits, breastfeeding rates in the United States remain low with only one in four infants exclusively breastfeeding at six months of age [5]. Patients with preexisting cardiovascular disease, who may benefit most from lactation, have lower breastfeeding rates than the general population. A 2020 population based Canadian study demonstrated that patients with chronic diseases, including hypertension and heart disease, have twice the odds of early cessation of exclusive breastfeeding [6]. In patients with congenital heart defects, lower rates of breastfeeding have been reported in patients with high risk lesions [7]. Additionally, patients with preexisting cardiovascular disease have increased rates of preterm delivery and complications related to prematurity which may also exacerbate poor lactation practices in this population [8,9].

Little evidence exists regarding specific barriers to lactation in patients with preexisting cardiovascular disease. Concerns regarding lactation safety and medication exposure in mothers with cardiovascular disease may be a cause for early breastfeeding cessation [10]. This review addresses lactation physiology, pharmacokinetics, and lactation safety of common cardiac medications.

2. Physiology

Lactogenesis, the onset of milk secretion, occurs in two separate stages. Secretory initiation, previously known as Lactogenesis Stage I, begins at approximately 16 weeks of gestation. This stage is marked by mammary epithelial cell differentiation to secrete colostrum in response to high circulating levels of placental progesterone. After parturition, secretory activation, also known as Lactogenesis Stage II, leads to the onset of copious milk secretion due to a rapid withdrawal in circulating levels of progesterone while levels of prolactin, insulin, and cortisol remain elevated [11,12].

The initial endocrine control of milk production is mediated primarily by the hormones prolactin and oxytocin [12,13]. Prolactin is produced by lactotrophic cells of the anterior pituitary in response to nipple stimulation and stimulates milk production by mammary epithelial cells. Tactile stimulation of the breast also stimulates hypothalamic release of oxytocin, which is primarily responsible for contraction of the myoepithelial cells surrounding the alveoli resulting in the milk ejection reflex [12,13]. After the milk supply is established at approximately 14 days postpartum, continuing milk synthesis, or galactopoiesis, becomes primarily autocrine controlled with milk removal serving as the primary regulating mechanism for continued production. Involution occurs 40 days after the final breastfeed [12].

Oxytocin has been linked to the protective effects between lactation and cardiovascular risk due to its impact on decreasing blood pressure, its antidiabetic effect, and inhibition of inflammation [4]. In contrast, conflicting literature exists regarding the role of prolactin on cardiovascular risk [4,14]. Lactation has also been proposed to reset negative changes to maternal metabolism during pregnancy including accumulation of visceral fat, insulin resistance, and a rise in lipids and triglycerides. This correction of metabolic disturbance thus offers a long term protective effect against future cardiovascular disease [15].

3. Pharmacokinetics

Medication use during lactation often causes concerns regarding possible adverse effects on the infant. Multiple factors influence the safety of drug use during lactation including the amount of drug excreted into human milk, extent of oral absorption by the infant, and potential adverse effects on the infant [16]. During the initial postpartum period, gaps in the alveolar membrane allow for paracellular transport of drugs into breast milk and result in a relatively higher concentration of the drug in the early postpartum period [12,16]. After the first few days postpartum, tight junctions between the alveolar cells close, resulting in drug transfer through the transcellular pathway. Due to the regulatory mechanisms of the transcellular pathways, drugs with high maternal serum protein binding, less lipid solubility, higher acidity, and high molecular weight are less likely to be transferred into breast milk [12,16,17]. Additional pharmacokinetic properties of different medications may also impact drug accumulation into breast milk. For example, drugs with longer half-lives are more likely to accumulate in breast milk [16]. A common way to express the distribution of a drug from serum into breast milk is through milk:plasma ratios (M:P). These ratios express the relative distribution of a drug in breast milk when compared to the concentration in the mother's plasma.

If exposed to a medication during lactation, additional factors may impact the risk of exposure to the infant. Poor oral bioavailability of drugs results in lower infant plasma concentrations despite exposure in breast milk [18]. Infant factors such as prematurity or chronic medical conditions may also impact an infant's ability to metabolize drugs in breast milk and can increase potential risk of toxicity [16,18]. The relative infant dose (RID) can be used to estimate infant drug exposure. It represents the dose received via breast milk compared to the dose the mother received. It is expressed as a percentage; RID levels of <10 % are generally considered safe [17,18] (Fig. 1).

Figure 1.

Pharmacokinetics of medications in lactation.

4. Hypertension

Hypertensive disorders of pregnancy are a common cause of maternal morbidity and mortality and may persist or worsen in the postpartum period. Postpartum hypertension can also be the result of de novo disease following a normotensive pregnancy. Management of postpartum hypertension is targeted at the treatment of the underlying etiology but often includes utilization of antihypertensives, diuretics, and possibly magnesium [19,20]. The lactation safety profiles of these medications can help to guide management decisions for hypertension in the postpartum period (Table 1).

Table 1.

Safety of cardiovascular medications during pregnancy and lactation.

	Pregnancy⁎	Lactation
Adenosine	Safe	Safe
Angiotensin-converting enzyme (ACE)-inhibitors	Contraindicated ADE: oligohydramnios, FGR, skeletal malformations	Benazepril, captopril, and enalapril are considered safe
Angiotensin receptor blocker (ARB)	Contraindicated ADE: oligohydramnios, FGR, skeletal malformations	Limited safety data on ARB. ACEi are preferred agent. ADE: monitor for fetal hypotension, lethargy, hyperkalemia and/or renal function abnormalities.
Angiotensin receptor-neprilysin inhibitor (ARNI)	Contraindicated	No safety data
Amiodarone	Contraindicated ADE: Infant hypothyroidism, bradycardia, QT prolongation	Contraindicated-prolonged half life
Aspirin	Safe Avoid doses above 325 mg daily
Bempedoic acid	No safety data	No safety data
Beta Blockers
Atenolol	Contraindicated ADE: fetal bradycardia, hypoglycemia, FGR	Contraindicated ADE: neonatal hypotension, tachypnea, cyanosis, and hypothermia
Bisoprolol	Limited safety data	Limited safety data
Carvedilol	No safety data	No safety data
Labetalol	Safe	Safe
Metoprolol	Safe	Safe
Nadolol	Use with caution-small risk of apnea, FGR, hypoglycemia	Avoid if possible ADE: low serum protein binding leads to high breastmilk concentrations
Propranolol	Safe	Safe
Bile acid sequestrants Cholestyramine Colesevelam Colestipol	Safe	Safe
Calcium channel blockers (CCB) Amlodipine Nifedipine Diltiazem Verapamil	Safe ADE: Possible FGR, fetal bradycardia with some CCB Risk of teratogenicity not expected based on limited human data	Safe Limited safety data for verapamil and diltiazem
Clopidogrel	Use with caution-limited safety data. Animal studies do not show adverse effects.	Risk vs benefit discussion, limited data
Class 1C Antiarrhythmics
Flecainide	Safe ADE: maternal visual disturbance, maternal acute interstitial nephritis, fetal bradycardia	Safe
Propafenone	Limited safety data	Limited safety data
Digoxin	Safe	Safe
Direct Oral Anticoagulant (DOAC) Apixaban Dabigatran Rivaroxaban	Contraindicated- Limited safety data	Limited safety data Avoid apixaban
Ezetimibe	Contraindicated- limited safety data, associated with adverse fetal effects in animal studies	Limited safety data
Heparin Unfractionated heparin Low-molecular weight heparin	Safe	Safe
Hydralazine	Safe	Safe
Hydrochlorothiazide	Safe	Safe ADE: May decrease milk production
Isosorbide di/mononitrate	Limited safety data	Limited safety data
Ivabradine	Contraindicated ADE: Teratogenic effect in animal studies	No safety data
Loop diuretics	Safe	Safe ADE: May decrease milk production
Mineralocorticoid receptor antagonist (MRA)	Contraindicated ADE: antiandrogenic effect during first trimester	Spironolactone may be used
PCSK9-i Alirocumab Evolocumab	No safety data	No safety data
Sodium-Glucose cotransporter 2 inhibitor (SGLT2-i)	Contraindicated	Contraindicated ADE: animal studies suggest it may affect neonatal growth
Sotalol	Safe ADE: no teratogenic potential, small risk of fetal bradycardia, hypoglycemia	Risks vs benefits discussion, use with caution as excreted in high amounts in breastmilk
Statins	Risks vs benefits discussion-limited human data	Risks vs benefits discussion Consider using rosuvastatin or pravastatin
Vitamin K antagonist	Avoid first trimester (especially doses >5 mg) ADE: fetal embryopathy, CNS abnormalities	Safe

ADE = adverse drug effects, CNS = central nervous system, FGR = fetal growth restriction, PCSK9-I = proprotein convertase subtilisin/kexin type 9 inhibitor.

^⁎The safety profiles of cardiac medications during pregnancy are provided as reference.

Calcium channel blockers are a diverse group of medications that reduce peripheral vascular resistance through vasodilation and may variably decrease cardiac contractility [21]. Calcium channel blockers are often a first line therapy in the treatment of postpartum hypertension with an overall high safety profile in lactation [20,22]. Nifedipine is a commonly used medication in the postpartum period with extensive safety information and no reports of adverse reactions in infants exposed through breast milk. Nifedipine also has no known effects on milk supply and can be utilized in the treatment of Raynaud phenomenon of the nipple [22,23]. Other studied calcium channel blockers include amlodipine, diltiazem, nicardipine, nimodipine, and verapamil and also have a high safety profile with low drug levels found in breast milk [22]. In general, calcium channel blockers are considered compatible with breastfeeding.

Beta blockers (BB) can also be used in the management of postpartum hypertension and have a wide range of clinical effects due to variations in affinity for the β1 receptor [24]. These drugs are weak bases and therefore excreted into breast milk as a result of ionization [25]. However, the remaining pharmacokinetic properties of BB vary significantly within the class, which leads to diversity in lactation safety profiles. For example, atenolol is poorly protein bound resulting in high excretion into breast milk and high risk of accumulation in infants [22,26]. Cases of adverse infant events including bradycardia, hypotension, tachypnea, cyanosis, and hypothermia have been reported with the use of atenolol during lactation [22,26]. As a result, other beta blockers are preferred over atenolol during lactation. Conversely, labetalol is a nonselective beta blocker commonly used in both pregnancy and the postpartum period with a more favorable lactation safety profile [22,27]. Compared to atenolol, labetalol has moderate protein binding, lower bioavailability, and less risk of accumulation in the infant [22,28]. While some studies have shown no adverse effects with labetalol use during lactation, a case report highlighting bradycardia in a premature infant exposed to labetalol in breast milk demonstrates the potential increased risks for toxicities in preterm infants exposed to drugs in breast milk [22,28]. In the term infant, labetalol, propranolol and metoprolol are considered safe given their overall low excretion into breast milk [29].

Diuretics may also be incorporated into the management of postpartum hypertension and are generally considered safe in lactation. Thiazide diuretics, including hydrochlorothiazide and chlorothiazide, and potassium sparing diuretics, including spironolactone, have minimal excretion into breast milk with no reported infant side effects [22,25,[30], [31], [32]]. However, higher dose diuretics, such as hydrochlorothiazide 100–150 mg/day or more potent diuretics such as furosemide may suppress lactation in the initial postpartum period [22,25,33]. Conversely, more recent data has shown that furosemide used in the initial postpartum period for treatment of gestational hypertension and preeclampsia found no difference in patient-reported breastfeeding difficulties between groups [34]. Milk supply should be carefully monitored when using diuretics during lactation. No data exists on the impact of diuretics on established milk supply after transition to autocrine control [33].

Renin-angiotensin system inhibitors are not used in antenatal hypertensive disorders of pregnancy due to teratogenicity but can be implemented in the management of postpartum hypertension [22,29]. Angiotensin converting enzyme inhibitors (ACE-Is), such as benazepril, captopril, and enalapril, have low excretion into breast milk with no adverse infant events reported [22,29,[35], [36], [37]]. Given this safety information, these medications are generally preferred over other agents, such as lisinopril which has limited safety data [27,38,39]. Small studies suggest angiotensin receptor blockers (ARBs) are minimally excreted in breastmilk [22,27,40,41]. Despite limited safety information, the pharmacokinetic properties of ARBs, including high protein binding and incomplete oral absorption, are favorable in lactation and thus may be unlikely to affect exposed infants [22]. Until further studies are available, ACE-Is are favored over ARBs during breastfeeding.

5. Heart failure

Heart failure in the postpartum period may occur secondary to preexisting heart disease or peripartum cardiomyopathy (PPCM). PPCM is an idiopathic cardiomyopathy presenting with left ventricular systolic dysfunction towards the end of pregnancy or the postpartum period [42]. In the United States, PPCM occurs in about 1 in 4000 live births and accounts for most cases of cardiogenic shock in pregnancy [42,43]. The etiology of PPCM is poorly understood, but proposed causes include inflammatory, hormonal, and genetic mechanisms. It has been hypothesized that in genetically susceptible individuals, extracellular cleavage of prolactin results in a vasculotoxic peptide that may contribute to cardiomyopathy [43,44]. As a result, studies have investigated the role of suppressing prolactin either via lactation cessation or dopamine agonists to directly suppress pituitary release of prolactin [43]. Results have been conflicting with some studies suggesting that breastfeeding may have no impact on recovery rates, including the U.S based Investigations of Pregnancy-Associated Cardiomyopathy (IPAC) study [45]. However, other global studies have suggested higher rates of improvement in left ventricular ejection fraction in patients with PPCM receiving bromocriptine therapy, but no studies currently exist evaluating bromocriptine in a United States cohort [42]. As a result, the REBIRTH trial (NCT05180773, clinicaltrials.gov) is assessing the impact of bromocriptine therapy on myocardial recovery in patients with newly diagnosed peripartum cardiomyopathy in the United States. Patients with PPCM who desire to breastfeed will also be followed in an observational cohort to provide additional data for guidelines on the role of lactation and associated clinical outcomes. The American College of Obstetrics and Gynecology recommends against discouraging breastfeeding in this patient population given limited data, but ongoing studies are needed for further clinical guidance [46].

The management of PPCM mirrors standard treatment for other forms of heart failure and focuses on reducing preload, reducing afterload, and increasing cardiac inotropy [47]. The cardiomyopathy management involves using the four pillars of guideline directed medical therapy (GDMT), including beta-blockers, ACE-Is/ARBs/angiotensin receptor neprilysin inhibitors (ARNI), mineralocorticoid receptor antagonist (MRA) and sodium-glucose cotransporter 2- inhibitors (SGLT2-i) (Table 1). The beta blockers that have shown survival benefit in the management of heart failure include metoprolol, bisoprolol and carvedilol, with metoprolol representing the preferred agent with most safety data for its use in lactation. Limited data exists on bisoprolol, although no signal of harm has been observed. No safety data exists on carvedilol in lactation. As discussed previously, ACE inhibitors including benazepril, captopril and enalapril are considered safe to use in lactation, and limited data suggests a favorable safety profile of ARBs [22,40,41]. Newer medications such as ARNIs have no published data regarding safety, but this class of drugs have high plasma protein binding and low oral availability, suggesting they are likely compatible with breastfeeding [40]. Additionally, preliminary reports suggest negligible transfer of ARNIs into human milk, but further safety data is needed [48]. Mineralocorticoid receptor antagonists, like spironolactone, are considered safe in breastfeeding [22,40]. There is no current literature available for SGLT2 inhibitors in humans. Animal studies suggest excretion in breast milk may affect neonatal growth [49]. As a result, SGLT2 inhibitors are not recommended in lactation [49].

Additional medications in the management of heart failure include hydralazine-isosorbide dinitrate, digoxin and ivabradine. Digoxin is considered safe during lactation. In a study of 11 lactating women, the milk:plasma ratio of digoxin was calculated to be 0.62. As a result, the predicted amount of therapeutic drug in the infant would be approximately 3 % [50]. No data exists regarding the safety of ivabradine in lactation [40]. As a result, ivabradine is not recommended in breastfeeding until further safety data is available. In observational studies, hydralazine concentrations have been low in the breastfed infant and no serious adverse effects have been described, hence it is safe to use during lactation [51]. No safety data exists on the use of isosorbide dinitrate.

6. Arrhythmias

Palpitations are among the most common symptoms reported during pregnancy. Physiologic hormonal changes of pregnancy, including higher heart rates and increased blood volume, may contribute to this sensation. In a study performed from 1992 to 2000, the prevalence of admissions secondary to cardiac arrhythmias in all pregnant patients admitted to a Dallas, Texas hospital was 166/100,000 [52]. The most common arrhythmias were sinus arrhythmias (tachycardia and bradycardia), encompassing 60 % of all arrhythmias. The second most common arrhythmia was premature atrial contractions (PAC's) and premature ventricular contractions (PVC's) at 19 %. The most common sustained arrhythmia was supraventricular tachycardias (SVT) at 14 %. Atrial fibrillation, atrial flutter, ventricular fibrillation, and ventricular tachycardia had a prevalence of about 1 % each.

Sinus arrhythmias, such as sinus tachycardia, seldomly require any management. Symptomatic PAC's and PVC's may be managed with beta blockers. Hemodynamically stable SVT may be aborted with attempted vagal maneuvers first. If unable to convert, first line medical treatment includes adenosine, BB, or verapamil as third line therapy [53]. Hemodynamically unstable arrhythmias should follow ACLS protocols including cardioversion or defibrillation if necessary.

The preferred BB is the β1 selective, metoprolol. Alternatives include propranolol or labetalol, consider the latter when there is concomitant hypertension. Nadolol should also be avoided during lactation. It has low protein binding in serum which results in high breast milk concentrations and very high risk of accumulation in infants [54].

Adenosine is endogenous to the human body, as such it is considered safe to use during lactation. Adverse effects observed during treatment include bradycardia, dyspnea, chest pain and flushing [27]. Verapamil is a lipid soluble drug that gets transferred into human breast milk. In two separate studies that looked at the concentration of verapamil in human breast milk and infant's plasma concentration, the levels were undetectable in the infants, hence considered safe to use during lactation [55] [56]. Digoxin is an alternative rate controlling agent which has previously been discussed and is considered safe in breastfeeding.

For rhythm control, sotalol, flecainide and propafenone may be considered during lactation. Flecainide levels in infants are very low and considered safe during lactation. Sotalol is not bound to protein, hence it has a high concentration in breast milk. Prediction models estimate the infant would receive 22 % of the mother's weight adjusted dosage [57] As such, if this medication is used, the infant should be monitored regularly for signs of beta blockade. There is scant research on propafenone to assess the risks of lactation, but in one study the predicted therapeutic levels in the infant were low [58].

Amiodarone is a long acting antiarrhythmic used for atrial and ventricular arrhythmias outside of the context of pregnancy in which it is contraindicated. It has a long half of 100 days, and contains iodine which transfers into breast milk, along with its active metabolite desthylamiodarone. The measured levels in breast milk have a very wide range which is dose dependent. Infant serum concentrations of the drug and its metabolites can be between 14 and 74 % of maternal levels [[59], [60], [61]]. These compounds contain iodine which can be released during the medication's metabolism potentially leading to infant hypothyroidism. Its use can also cause bradycardia and QT prolongation. For these reasons, amiodarone should be avoided during lactation (Table 1).

7. Hyperlipidemia

Statins are 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA) inhibitors used for reduction of LDL cholesterol. Women of childbearing age are commonly prescribed these medications for familial hypercholesterolemia or, less frequently, for a history of atherosclerotic events like myocardial infarction or stroke. Prior research demonstrates that statins transfer into human breast milk [62]. However, in one study of a woman taking 20 mg of rosuvastatin daily, the RID was found to be 1.5 %, well below the threshold of concern [63]. An additional study assessing milk samples of three breastfeeding patients taking varying doses of atorvastatin showed a low weight-adjusted RID of 0.09 % [64]. No studies have been done to assess the clinical effects of statins in infants. In 2021, the Food and Drug Administration (FDA) removed their strongest warning against using statins in pregnancy. The recommendation remains to consider stopping the medication when breastfeeding. If after a risk versus benefit discussion, the decision is to continue statin therapy, a hydrophilic statin, like rosuvastatin or pravastatin, should be used to reduce the concentrations in milk. Rosuvastatin is the preferred agent due to increased protein binding, higher molecular weight and higher volume of distribution [65]. Bempedoic acid acts on the enzyme upstream from HMG-CoA reductase. There is no evidence of its safety during lactation.

The recommended cholesterol lowering medication during lactation are bile acid sequestrants, cholestyramine, colesevelam, or colestipol. These medications are not absorbed by the intestine; they never reach maternal circulation or the breast milk, resulting in the safest option during lactation.

There is no evidence on the safety of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-i), like alirocumab or evelocumab. Because of their high protein weight, their predicted M/P ratio is relatively low: 0.00351772 and 0.00149997, respectively [66].

Only one study has been published regarding the RID of ezetimibe, a prodrug whose active metabolite inhibits intestinal absorption of cholesterol. They measured the concentration of total ezetimibe plus ezetimibe glucuronide in breast milk of two mothers. Using pediatric physiologically based pharmacokinetic (PBPK) models they predicted the RID to be about 0.16 % and 0.25 %, respectively [67] (Table 1).

8. Anticoagulation and antiplatelets

Heparin products, including low-molecular-weight heparin and unfractionated heparin, in part due to their large molecular size, do not cross the placenta and are considered safe in pregnancy [68]. Low-molecular-weight heparin is preferred for most cases of anticoagulation in pregnancy given its reliability and ease of administration [68]. In lactation, the high molecular weight and highly charged nature of unfractionated heparin theoretically prevents excretion into breast milk, although no published studies exist in the literature assessing measurements in breast milk [69,70]. Low-molecular-weight heparins, such as enoxaparin and dalteparin, are also relatively too large for excretion into breast milk given their molecular weights of >2000 Da respectively [69,71,72]. Dalteparin specifically was undetectable in the breast milk of two patients [73]. In another study of 15 patients using dalteparin, anti-Xa activity was low in breast milk, and given its low oral bioavailability, unlikely to have clinically relevant impacts on the infant [74]. Similarly, anti-Xa activity has also been undetectable in the breast milk of patients using enoxaparin, with no adverse infant outcomes reported [75]. Heparin products are therefore compatible with breastfeeding, and patients using these medications should be reassured [69].

In contrast to more frequently utilized heparin products, warfarin is rarely used during pregnancy due to its risk for fetal embryopathy (nasal hypoplasia, stippled epiphyses). These effects appear to be dose-dependent, particularly in the first trimester [68]. However, warfarin may still be indicated in pregnant patients with high risk for thrombosis, such as those with mechanical heart valves [68,76]. Warfarin is unlikely to be excreted into breast milk given its polar ionic structure and was undetectable in the breast milk of 13 patients utilizing the drug [77,78]. No adverse infant effects have been reported in lactating patients using warfarin, hence this drug is considered safe in breastfeeding [[77], [78], [79]].

Although direct oral anticoagulants (DOACs) have become increasingly popular outside of pregnancy, they are currently not recommended in pregnancy given insufficient data regarding their safety profiles [68,80]. Furthermore, there is little to no data guiding their use in breastfeeding [68,69]. Dabigatran, a direct thrombin inhibitor, has been shown to be poorly excreted in the breast milk of two patients and unlikely to have clinically significant effects [81]. However, given limited data, it is not recommended by the manufacturer in lactation. Direct factor Xa inhibitors, such as apixaban and rivaroxaban, have insufficient evidence to support their safe use during lactation. While rivaroxaban levels excreted in breast milk are thought to be low, apixaban levels appear to accumulate in the breast milk [68,69]. In an observational case study, rivaroxaban was found to have a milk to plasma ratio of 0.4 and a RID of 1.3 % [82]. Conversely, the M:P ratio for apixaban was 2.61 and the RID was 12.78 %, above the 10 % safety limit [83]. Increased apixaban concentrations in breastmilk are hypothesized to be secondary to active secretion by the breast cancer resistance protein (BCRP; ABCG2) [84].

During pregnancy, antiplatelet drugs are commonly utilized. Low dose aspirin (81 mg/day) has been used to prevent preeclampsia in high risk patients [85]. In breastfeeding patients on low dose aspirin doses of 75 to 325 mg daily, the aspirin metabolite salicylic acid was present in clinically insignificant amounts in breast milk [86]. However, higher doses of aspirin were associated with adverse events in breastfed infants [69,87,88]. Therefore, low dose aspirin is considered safe in lactation but should be avoided in higher doses [69]. Clopidogrel, a P2Y₁₂ inhibitor, is also considered safe in pregnancy [89]. In lactation, limited data exists regarding the safety of P2Y₁₂ inhibitors such as clopidogrel, although the manufacturer reports no adverse effects in breastfed infants [90]. In a recent observational case series, the M:P ratio was calculated at 4.2, 0.01 and 0.03 in clopidogrel, its inactive metabolite and active metabolite, respectively [91]. The RID was <0.8 % and 0.01 % for clopidogrel and its inactive metabolite. Unreliable maternal plasma sample precluded the RID calculation for the active metabolite of clopidogrel. No adverse events were observed in the breastfed infant (Table 1).

9. Conclusion

Patients with cardiovascular disease and their infants may experience significant long-term health benefits from lactation. However, concerns about preexisting conditions and medication safety often lead to breastfeeding discontinuation in this population [10]. Enhancing provider knowledge may help to mitigate these concerns; however, the literature shows significant gaps in provider breastfeeding understanding [92]. Future research may be directed at increasing provider confidence in managing cardiovascular medications during lactation, as well as developing software applications that are readily accessible for providers to consult. Available resources for lactating patients and their healthcare providers include mothertobaby.org for updated information on safety in lactation. LactMed is a regularly updated web-based platform and repository of medication with information regarding infant exposure. It is essential to adopt a patient-centered approach in which risk and benefit discussions lead to shared clinical decision making. Given the complexity of these patients' needs, a multidisciplinary team including cardiology, obstetrics, maternal fetal medicine, pediatrics, pharmacy, and lactation specialists, are crucial for improved outcomes.

CRediT authorship contribution statement

Cristina Nunez-Pellot: Writing – review & editing, Writing – original draft, Validation, Supervision, Investigation, Conceptualization. Allison Akers: Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Investigation, Conceptualization. Sarah Običan: Writing – review & editing. Mary Ashley Cain: Writing – review & editing. Daniela R. Crousillat: Writing – review & editing, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for this journal and was not involved in the editorial review or the decision to publish this article.