Navigating heart failure medications in obstetric practice

Abstract

Heart failure (HF) during pregnancy presents unique challenges due to the complex interplay between physiological changes and underlying cardiac conditions. Pregnancy-induced increases in blood volume, cardiac output, and heart rate can exacerbate pre-existing heart diseases or trigger new-onset HF, such as peripartum cardiomyopathy and preeclampsia-related HF. With pregnancy-related physiological changes altering pharmacokinetics, dosage adjustment becomes crucial, making its application limited to carefully selected cases where benefits outweigh the risks. Medication management for these patients requires a meticulous approach. Beta-blockers like metoprolol and bisoprolol are preferred despite limited evidence, and carvedilol may be cautiously used per clinical experience; atenolol is contraindicated for low-birth-weight risk. Diuretics (furosemide, bumetanide) are safe for congestion relief but warrant judicious dosing. Digoxin is generally safe but requires dose adjustment and regular monitoring due to pregnancy-induced pharmacokinetic alterations. Among positive inotropes, dobutamine exhibits favorable safety in pregnancy, whereas milrinone should be used cautiously for hypotension risk. Renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists and sodium-glucose cotransporter 2 inhibitors are all contraindicated owing to risks of fetal malformations, male fetal feminization, and insufficient safety evidence, respectively.

Key Words: Obstetric practice; Pregnancy heart failure; Peripartum cardiomyopathy; Preeclampsia; Drug management; Physiological changes during pregnancy; Pregnancy pharmacokinetics

Core Tip: Heart failure (HF) in pregnancy poses significant maternal and fetal risks, exacerbated by physiological adaptations and underlying cardiac conditions. This mini-review delineates the pathophysiology, pharmacokinetics, and pharmacological management of pregnancy-related HF, emphasizing the safety and efficacy of medications like beta-blockers, diuretics, and digoxin. Concurrently, it categorically outlines contraindicated medications, including renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers), angiotensin receptor-neprilysin inhibitors, and mineralocorticoid receptor antagonists due to their potential teratogenic effects. It highlights multidisciplinary care models and the need for further research to optimize therapeutic strategies and improve maternal-fetal outcomes.

INTRODUCTION

Among the causes of non-obstetric deaths in pregnant and postpartum women, cardiovascular disease-related deaths rank first. Notably, heart failure (HF) during pregnancy represents a critical challenge to maternal and fetal safety in obstetric practice, with its high prevalence and mortality attracting global concern. A large-scale study indicated that, over a decade-long period, within the Nationwide Inpatient Sample of the United States, the overall incidence of HF among pregnancy-related hospitalizations is approximately 112 cases per 100000 admissions, with a rising trend observed over recent years[1]. Among the diverse array of cardiovascular-related complications that arise during pregnancy, hypertension assumes a notably prominent and antecedent role. Globally, hypertensive disorders of pregnancy – particularly preeclampsia and eclampsia – serve as major precursors of HF, with reported incidence rates ranging from 2% to 8%[2] and accounting for approximately 14% of global maternal mortality[3]. Notably, this risk is likely exacerbated in low-income and middle-income countries due to limited healthcare resources, delayed diagnosis, and suboptimal management of comorbidities. Drawing on four years of frontline clinical experience at Jiangsu Provincial Hospital of Traditional Chinese Medicine, including specialized training in reproductive medicine and gynecological cardiology, the authors have systematically observed the complex interplay between pregnancy-induced hemodynamic changes and underlying cardiac conditions. Pregnancy-specific hemodynamic changes and cardiac structural adaptations place women at particularly high risk of HF between 32 weeks and 34 weeks of gestation. Without timely intervention, HF can lead to severe complications such as pulmonary edema, renal failure, stroke, and disseminated intravascular coagulation, prolonging hospitalization and increasing maternal mortality substantially, by up to 32-fold compared to the general pregnant population (during delivery)[1]. Accordingly, optimizing pharmacologic management strategies for HF in pregnancy – balancing maternal therapeutic efficacy with fetal safety – has emerged as a critical and urgent priority for obstetric and cardiovascular care worldwide. To provide a visual summary of how pregnancy-induced physiological changes affect HF pharmacotherapy, we include a graphic abstract (Figure 1). It outlines key alterations in drug pharmacokinetics (PK) during pregnancy and important considerations for drug management. Readers are encouraged to refer to Figure 1 for a concise overview.

Figure 1 Graphical Abstract. It summarizes the complex interplay between profound physiological changes during pregnancy, their impact on pharmacokinetics (PK), subsequent medication safety classifications, and the pathophysiology of peripartum heart failure (HF). Key maternal adaptations include altered gastric absorption, significantly increased renal elimination, and modulated hepatic enzyme activity. The underlying pathophysiology for HF during pregnancy involves physiological anemia, decreased cardiac reserve function, and peripheral vasodilation, which collectively increase cardiovascular strain. These shifts necessitate a stringent drug classification system: "Forbidden" denotes agents with high fetal risk, while "Caution" requires vigilant monitoring. Understanding this triad – physiology, PK, and risk categorization – is essential for safe pharmacotherapy in pregnant patients, particularly those with or at risk of cardiac dysfunction. MRAs: Mineralocorticoid receptor antagonists; RASIs: Renin-angiotensin system inhibitors; SGLT2: Sodium-glucose cotransporter 2.

LITERATURE REVIEWS

Study design

This mini-review aimed to comprehensively evaluate the safety and efficacy of pharmacotherapies for HF during pregnancy. The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to ensure methodological rigor.

Search strategy

A comprehensive literature search was conducted across multiple databases, including PubMed, Web of Science, Cochrane Library, Scopus, and EMBASE, from January 1983 to August 2025. The search strategy utilized a combination of Medical Subject Headings and free-text terms to capture relevant studies. Key search terms were categorized into HF-related terms and drug intervention terms, with specific attention to including terms relevant to pregnant women with pre-existing cardiac conditions or HF complications. HF-related terms, including "heart failure in pregnancy", "peripartum cardiomyopathy", "preeclampsia-associated cardiac dysfunction". Drug intervention terms, including "beta-blockers AND pregnancy", "diuretics AND obstetrics", "inotropes AND maternal outcomes", "safety of HF medications in pregnancy". Population-specific terms, including "pregnant women with heart disease", "pregnant women with cardiomyopathy", "high-risk pregnancy and heart failure". Filters, including "English language", "randomized controlled trials/systematic reviews/meta-analyses/case-control studies/case series/case reports/pharmacokinetics (PK) studies/clinical practice guidelines/animal studies/review”. Subsequently, we reviewed the identified studies and examined their references to identify further potential articles.

Study selection

Inclusion criteria: Studies involving pregnant or postpartum women diagnosed with HF (any etiology). Interventions include β-blockers (e.g., metoprolol, bisoprolol), diuretics (e.g., furosemide), positive inotropes (e.g., dobutamine), or other medications. Reporting of maternal safety outcomes (e.g., hypotension, renal dysfunction) or fetal outcomes (e.g., birth weight, congenital anomalies). This mini-review integrated evidence from guidelines, registries, PK studies, and clinical reports. Safety classifications were based on consensus from European Society of Cardiology (ESC)/American Heart Association guidelines and human data where available. Animal studies were included if they addressed mechanisms of drug effects in pregnancy (e.g., placental transfer, fetal organ toxicity); human data were absent or insufficient (e.g., for newly approved drugs). Their findings were biologically plausible and consistent with clinical observations.

Exclusion criteria: (1) Non-English articles; (2) Case reports (n < 5); and (3) Studies lacking quantitative safety data.

Data extraction

Two independent investigators extracted data using a standardized form, including: (1) Study characteristics (author, year, study design, sample size); (2) Patient demographics (age, parity, pre-existing cardiac conditions); (3) Drug regimens (type, dosage, duration of treatment); and (4) Maternal and fetal outcomes. In cases of disagreement between the two investigators, discrepancies were resolved through discussion or, if necessary, by consulting a third investigator for arbitration.

Quality assessment

Systematic reviews/meta-analyses: A Measurement Tool to Assess Systematic Reviews 2 tool was applied to assess methodological quality, with emphasis on domains critical to obstetric pharmacotherapy: (1) Clarity of pregnancy-related research questions (e.g., peripartum cardiomyopathy management); (2) Inclusion of gestational age-stratified data; and (3) Explicit reporting of maternal and fetal safety outcomes (e.g., congenital anomalies).

Case series/case reports: The Joanna Briggs Institute checklist was adapted to prioritize: (1) Representativeness of pregnant populations; (2) Documentation of medication dosing adjustments, and (3) Long-term fetal and maternal follow-up.

Observational studies: The Newcastle-Ottawa Scale was modified to score: (1) Trimester-specific enrollment; (2) Adjustment for confounders (e.g., preeclampsia, maternal age); and (3) Outcome validation (e.g., echocardiography for HF diagnosis).

Mechanistic/PK studies: Appraisal of Guidelines for Research and Evaluation II guidelines were supplemented with criteria for pregnancy-specific physiologically based pharmacokinetic (PBPK) model validation, including: (1) Incorporation of gestational physiological changes; and (2) Correlation of simulated drug levels with observed maternal/fetal concentrations.

Data synthesis

Observational and mechanistic studies were summarized narratively to identify evidence gaps, consensus patterns, and to provide a comprehensive overview of the safety and efficacy of pharmacotherapies for HF during pregnancy. Quantitative data were pooled where appropriate, and meta-analyses were conducted to estimate pooled effect sizes for key outcomes.

PHYSIOPATHOLOGICAL CHANGES OF HF DURING PREGNANCY

To meet the dramatically increased demands for oxygen and nutrients by the uterus, placenta, and maternal organs, pregnancy induces a coordinated series of adaptive changes centered on blood volume expansion, cardiac remodeling, and hemodynamic alterations[4]. Beginning as early as 6-8 weeks of gestation, plasma volume rises in a stepwise fashion via activation of the renin-angiotensin-aldosterone system[5], peaking at 32-34 weeks with an overall increase of 40%-50% relative to pre-pregnancy levels[6]. In contrast, erythropoiesis increases by only 20%-30%[7], leading to a relative decline in hemoglobin concentration below 110 g/L (in view of the relative plasma expansion being particularly marked in the second trimester, the hemoglobin value drops below 105 g/L at this stage) – a physiological anemia[8]. While this hemodilution reduces blood viscosity and favors placental perfusion, it compromises oxygen-carrying capacity, necessitating compensatory cardiac adaptations: (1) Increased stroke volume in early pregnancy; and (2) Elevated heart rate in later stages[9]. These mechanisms together raise cardiac output progressively to a peak at 32-34 weeks. Concurrently, the heart undergoes physiological remodeling[10], with increases in left ventricular (LV) end-diastolic volume to enhance contractility, and a 45%-50% rise in LV myocardial mass[11]. Chamber dilation also causes the apex beat to shift leftward by 1 cm and 2 cm. Such volume and hemodynamic changes heighten the risk of HF in women with underlying cardiac disease. Peripheral vascular resistance experiences a reduction of roughly 25%-30%[12], leading directly to a decline in afterload. With cardiac function still intact, this enables the heart to augment cardiac output, thereby establishing a circulatory state characterized by high output and low resistance. While this state alleviates the heart's workload, it has the potential to obscure early signs of HF, like diminished exercise tolerance. Additionally, gravid uterine compression of the inferior vena cava elevates venous pressure, potentially precipitating right HF via mechanisms such as pulmonary embolism.

During labor, uterine contractions[13] and the closure of placental sinusoids after delivery cause a sudden surge in venous return and cardiac output. This represents the second high-risk period for HF, particularly in women with mitral stenosis, where elevated left atrial pressure induces pulmonary capillary hydrostatic pressure exceeding colloid osmotic pressure. Compounded by physiological increases in blood volume and heart rate during pregnancy, along with amplified hemodynamic stress, these patients are prone to developing pulmonary edema[14]. The third critical period is the early puerperium, characterized by a dual-volume challenge: Interstitial fluid accumulated during pregnancy returns to the circulation at a rate of 0.5-1 L per day, driven by decreased natriuretic peptide levels and reactivated renin-angiotensin-aldosterone system; simultaneously, uterine involution releases substantial blood volume back into systemic circulation. These combined effects markedly increase preload, especially within the first three postpartum days, posing a significant risk for HF in women with pre-existing heart disease.

EFFECTS OF PHYSIOLOGICAL CHANGES DURING PREGNANCY ON THE PK OF HF DRUGS

Physiological adaptations during pregnancy significantly modify drug PK through alterations in hemodynamics, metabolic function, and renal clearance (CL). These pharmacokinetic alterations predominantly manifest across the four fundamental phases of drug disposition: (1) Absorption; (2) Distribution; (3) Metabolism; and (4) Excretion. This mechanism is further illustrated in Figure 2.

Figure 2 Effect of physiological changes during pregnancy on the pharmacokinetics of heart failure drugs. It summarizes key physiological changes during pregnancy and their impact on drug pharmacokinetics across absorption, distribution, metabolism, and excretion. Major alterations include reduced gastrointestinal motility, increased plasma volume and body fat, modified hepatic enzyme activity (e.g., induction of CYP3A4, inhibition of CYP1A2), and elevated glomerular filtration rate. These changes significantly affect drug levels: Absorption rates decrease, volume of distribution increases for hydrophilic drugs, unbound drug concentration rises, and clearance is enhanced for many agents (e.g., digoxin, atenolol). Understanding these adaptations is crucial for dosing adjustments and therapeutic drug monitoring in pregnant patients. CL: Clearance; DME: Drug metabolising enzyme; GFR: Glomerular filtration rate; Vd: Volume of distribution.

Absorption

Drug absorption, defined as the process by which medications enter systemic circulation, is quantified by bioavailability (F) – the fraction of active drug reaching circulation intact. Pregnancy induces two key alterations. Firstly, pregnancy-associated reductions in gastrointestinal motility can delay gastric emptying and reduce gastric secretions, which can increase gastric pH and alter the drug absorption process[15,16]. For example, increasing the ionisation of weak acids (e.g., aspirin), which reduces absorption, while promoting the non-ionised form of weak bases (e.g., caffeine), which may increase absorption. It is of concern that nausea and vomiting in early pregnancy reduce the availability of the drug, making it necessary to administer the drug during the intervals when symptoms are minimal. However, the above changes are mainly based on theory. In fact, several studies on cardiac drugs (including sotalol and propranolol) have shown that there is no difference in bioavailability compared to non-pregnant states, suggesting that further research is needed[17-19].

Distribution

Distribution refers to the reversible transfer of a drug between different locations in the body after it enters the systemic circulation. Pregnancy-related changes in plasma volume and blood flow, body weight and fat composition, and plasma protein concentrations alter the volume of distribution (Vd) of a drug by affecting tissue perfusion, tissue binding, lipid solubility, and plasma protein binding. Changes in Vd primarily affect the plasma concentration of a drug, which can directly influence its therapeutic efficacy and adverse effects. For example, expansion of extracellular volume and total body water volume increases the Vd of hydrophilic drugs, thereby reducing plasma concentrations. Similarly, the swelling of maternal fat theoretically increases the Vd of lipophilic drugs[20]. The resulting dilemma is that solubility-driven changes in Vd require dosage adjustments, but fetal safety constrains drug selection. In the clinic, this may be resolved by administering dose adjustments and splitting the dose to compensate for concentration fluctuations. Albumin and α1-acid glycoprotein concentrations are significantly reduced compared to non-pregnant individuals, which affects the unbound fraction relative to the total drug concentration[21]. Highly protein-bound drugs are most likely to exhibit changes in the unbound fraction during pregnancy, which may affect maternal efficacy, maternal and fetal toxicity, and dosage requirements[20].

Metabolism

Concerning drug metabolism, changes in hepatic drug metabolism and CL during pregnancy significantly affect drug systemic PK, with three core mechanisms. Firstly, the effect of changes in hepatic blood flow on hepatic CL for drugs with a high hepatic extraction rate, but the relevant data are limited and variable[22]. Notably, during pregnancy, hepatic blood flow remains stable or increases, which may accelerate the metabolism of high-extraction-ratio drugs like propranolol, potentially requiring dose adjustment. Secondly, changes in CL for drugs with a low-to-moderate hepatic extraction ratio in the liver not only relate to hepatic blood flow and plasma protein binding, but also involve significant alterations in endogenous maternal hepatic CL[16,23]. Thirdly, targeted changes in hepatic drug metabolising enzyme activity during pregnancy, such as induction of CYP2C9, CYP2D6, CYP2E1, CYP3A4, and UGT1A1/UGT1A4 activities and inhibition of CYP1A2, which occur via altering first-pass metabolism and elimination half-life, affect systemic drug exposure[15,24]. For example, nifedipine and metoprolol are catalysed by CYP3A and CYP2D6, respectively. Both of these enzymes are induced during pregnancy, resulting in lower drug levels compared to non-pregnant states[25,26]. Additionally, labetalol is an example of a drug that has a shorter half-life during pregnancy due to upregulation of phase II glucuronidation metabolism[27]. It should be noted that enzyme activity is inherently affected by race, gender, age, and non-pregnant disease states, and because enzymes are often multisubstrate (i.e., different drugs may be metabolised by more than one enzyme), metabolic interactions may be triggered when drugs are used in combination. PK studies in pregnancy are challenging, and PBPK modelling is increasingly important to provide a mechanistic basis for dose optimisation. The impact of pregnancy on renal drug clearance is discussed in the following section on excretion.

Excretion

Renal drug excretion depends on glomerular filtration rate (GFR), tubular secretion, and reabsorption. Although GFR increases uniformly during pregnancy, differences in tubular transport (secretion or reabsorption) can lead to different effects on renal CL of drugs[28]. For example, it has been shown that digoxin, which has a renal CL of 80 per cent, is cleared 20-30 per cent more in late pregnancy compared with the postnatal period[29]; while Atenolol CL during pregnancy is only 12 per cent higher[30]. For drugs that are predominantly excreted by the kidneys (e.g., digoxin, atenolol), the dosage must be adjusted according to the CL pathway of the specific drug (GFR dependence/tubular transport dependence) and the stage of the pregnancy: During mid-to-late gestation, drugs primarily eliminated by glomerular filtration (e.g., digoxin) require incremental dose escalation. In contrast, those influenced by tubular transport (e.g., atenolol) necessitate only minor adjustments. All dosage modifications should be guided and confirmed by therapeutic drug monitoring (TDM) (Figure 2).

CURRENT PHARMACOTHERAPEUTIC APPROACHES: EFFICACY, SAFETY, AND EVIDENCE GAPS

Pharmacotherapy for pregnancy-associated HF is stratified by clinical acuity and delivery status: (1) Acute cardiogenic shock mandates hemodynamic support with inotropes/vasopressors and potentially urgent delivery; (2) Stabilized antepartum management employs hydralazine-nitrates [replacing contraindicated Renin-angiotensin system inhibitors (RASIs)], cautious beta-blockade, and diuretics; and (3) While postpartum care transitions to full guideline-directed therapy including RASIs, mineralocorticoid receptor antagonists (MRAs), and device consideration for severe systolic dysfunction, with bromocriptine reserved for peripartum cardiomyopathy. Particular caution is needed in the treatment of HF in women in labour, where the maternal benefits of medication must be carefully weighed against the potential fetal risks, and it needs to be recognised that discontinuation of essential medicines may exacerbate HF. Even with intensive pharmacological treatment, decompensation may still occur and lead to an increased risk of maternal cardiac complications[31]. Thus, the management of HF in pregnancy is extremely challenging. Table 1 classifies pregnancy-compatible cardiovascular drugs by risk, integrating historical Food and Drug Administration (FDA) categories and contemporary evidence[27,29,31-50].

Table 1 Precautions for medication use in heart failure during pregnancy.

Drug class	Specific agents	Former Food and Drug Administration Category	Safety	Key considerations	Ref.
Absolute contraindications
Renin-angiotensin system inhibitors	Angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, angiotensin receptor-neprilysin inhibitors	D	Contraindicated	Contraindicated throughout pregnancy: Risks of fetal renal dysplasia, oligohydramnios, craniofacial malformations, intra-uterine growth retardation. Discontinue preconception	Bullo et al[33], Nadeem et al[34], van der Zande et al[35]
Mineralocorticoid receptor antagonists	Spironolactone, eplerenone	D (spironolactone), not applicable (eplerenone)	Contraindicated	Spironolactone: Anti-androgenic effects (male fetal feminization). Eplerenone: Critically lacking human safety data	Struthers et al[36], Pandey et al[37], Dey et al[38], Deng et al[39]
Sodium-glucose cotransporter 2 inhibitors	Sodium-glucose cotransporter 2 inhibitors	Not applicable	Contraindicated	Critical lack of human safety data; adverse pregnancy outcomes in animal studies	DeFilippis et al[32]
Agents requiring cautious use
Beta-blockers	Metoprolol, bisoprolol	C	Preferred	No significant harmful effects in pregnant women with structural heart disease (registry of pregnancy and cardiac disease registry)	Ruys et al[31], Halpern et al[40]
	Labetalol	C	Permitted	Pharmacokinetics change: Shorter half-life (upregulation of phase II glucuronidation). Dosage: Oral 200-1200 mg/day (2 and 3 divided doses); intravenous 20-40 mg every 10-30 minutes (maximum 220 mg)	Rogers et al[27], Brown and Garovic[41]
	Carvedilol	C	Vigilant use	Monitor for neonatal hypoglycemia	Kubota et al[42]
	Atenolol	C/D	Contraindicated	Increased risk of fetal growth restriction and low birth weight	Duan et al[43]
Diuretics	Furosemide, bumetanide	C	Safe	No increased risk of congenital anomalies or small for gestational age infants; monitor maternal hypovolemia, uterine underperfusion, decreased lactation	DeFilippis et al[44], van der Zande et al[45], Bandyopadhyay et al[50]
	Torasemide, metolazone	C	Limited evidence	Comparatively limited pregnancy-specific evidence	DeFilippis et al[44]
	Hydrochlorothiazide	B	Restricted use	Recommended dose for gestational hypertension: 12.5-25 mg/day; monitor maternal hypovolemia	Brown and Garovic[41]
Positive inotropes	Dobutamine	Not applicable	Generally safe	Safe when clinically indicated	Stapel et al[47]
	Milrinone	Not applicable	High caution	Potent vasodilatory effects increase hypotension risk (reduced systemic vascular resistance); stringent hemodynamic monitoring is imperative	Bozkurt et al[48]
	Digoxin	C	Relatively safe	PK adjustment: Increased volume of distribution and renal clearance necessitate higher doses. Monitoring: Therapeutic drug monitoring essential for efficacy/toxicity (safe for fetal tachyarrhythmias)	Hebert et al[29], Purkayastha et al[46]
Special agents
Bromocriptine	Bromocriptine	Not applicable	Investigational	Add-on to standard therapy in acute peripartum cardiomyopathy improved left ventricular ejection fraction and mortality (proof-of-concept pilot study)	Anthony and Sliwa[49]

Effective management hinges on three pillars: (1) Strict avoidance of known teratogens [angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II type 1 receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), MRAs]; (2) Preferential use of agents with established relative safety profiles (e.g., select β-blockers, loop diuretics, digoxin); and (3) Vigilant monitoring for efficacy and adverse effects in both mother and fetus[32]. Treatment regimens need to be highly individualized, with a multidisciplinary team (cardiology, obstetrics, pharmacy, neonatology) making decisions to find the optimal balance between effective control of maternal HF and maximum fetal safety. All medication adjustments should be based on an ongoing assessment of maternal benefit-fetal risk and refer to the latest evidence-based medicine.

Contraindicated medications for HF in pregnancy: Evidence-based safety protocols

RASIs, including ACEIs and ARBs, are contraindicated throughout pregnancy. Robust clinical evidence links their use to severe fetal toxicities, including renal dysplasia, oligohydramnios, craniofacial malformations, and intrauterine growth restriction[33,34]. Therefore, early cessation or early change of medication is recommended, and patients should be followed up before conception[35]. ARNIs share this contraindication based on the 2023 ESC Guidelines and the Former FDA Category. Preconception counseling and medication review are critical for women of childbearing potential requiring renin-angiotensin system inhibition.

MRAs are contraindicated in pregnancy. Spironolactone poses a well-documented risk of anti-androgenic effects, specifically feminization of the male fetus, precluding its use[36,37]. While eplerenone demonstrates greater receptor selectivity and a potentially reduced anti-androgenic risk profile in vitro and in preclinical models, human safety data in pregnancy are critically lacking[38,39]. Consequently, eplerenone is also contraindicated for the treatment of HF in pregnant patients. Rigorous clinical studies are urgently needed to evaluate the safety of any MRA in this population.

Cautious pharmacotherapy for HF in pregnancy: Permitted agents and risk mitigation

There is overall limited data on the efficacy and safety of beta-blockers in pregnancy. Of the cardioselective beta-blockers that are effective in HF, metoprolol and bisoprolol are the preferred agents[40]. Observational data, notably from the large registry of pregnancy and cardiac disease registry, indicate no significant harmful effects associated with beta-blocker use in pregnant women with structural heart disease[31]. In terms of dosage, the recommended dose of labetalol as an oral medication is 200-1200 mg/day, divided into two to three doses, while as an injection, the basic usage is 20-40 mg every 10-30 minutes, with a maximum of 220 mg infusion[41]. However, carvedilol necessitates vigilant monitoring for neonatal hypoglycemia, a potential risk suggested by clinical reports[42]. Atenolol is specifically discouraged due to its established association with increased risk of fetal growth restriction and low birth weight[43].

Loop diuretics are safe and effective for managing congestion in pregnancy-associated HF[40]. Furosemide and bumetanide are preferred based on more extensive safety data supporting their use[44]. Large observational studies confirm that these agents, particularly furosemide, do not increase the risk of congenital anomalies or small-for-gestational-age infants[45]. Torasemide and metolazone should be used more cautiously due to comparatively limited pregnancy-specific evidence[44]. It is worth noting that the recommended dose of hydrochlorothiazide in the recommended management protocol for gestational hypertension is 12.5-25 mg daily[41].

Digoxin is usually considered relatively safe in pregnancy[29]. However, significant pharmacokinetic alterations during pregnancy, including increased Vd and enhanced renal CL, frequently necessitate higher maternal doses to achieve therapeutic levels. TDM is therefore essential to ensure efficacy and avoid toxicity. Its proven safety profile extends to the treatment of fetal tachyarrhythmias, demonstrating adequate placental transfer without compromising fetal safety[46].

Beyond digoxin, the use of adjunctive positive inotropes in pregnancy requires careful agent selection due to differing safety profiles. When clinically indicated, dobutamine is generally considered safe for positive inotropic support in pregnant women; however, it may induce irreversible HF in peripartum cardiomyopathy (PPCM) patients with reduced cardiac STAT3 expression[47]. Milrinone, however, significantly increases the risk of profound hypotension in this population due to its potent vasodilatory effects, particularly given the baseline reduction in systemic vascular resistance during pregnancy. Therefore, if milrinone is necessary, stringent hemodynamic monitoring is imperative[51].

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are contraindicated during pregnancy. This recommendation is based on a critical lack of human safety data and evidence of adverse pregnancy outcomes in animal studies[32].

PHARMACOLOGICAL FEATURES OF HF INDUCED BY PPCM

PPCM is an entity of dilated cardiomyopathy[52]. PPCM accounts for 70% of all HF during pregnancy[1]. The European Society of Cardiology defines PPCM as an idiopathic cardiomyopathy that usually manifests itself as HF with reduced blood counts in the last month of pregnancy or in the months after delivery in women with no other known cause of HF (HFrEF)[10]. Current management of PPCM centres on standard Guideline-Directed Medical Therapy for HF with reduced ejection fraction[48]. Management of PPCM requires stratified decision-making based on gestational status (pregnancy/postpartum), disease stability, and cardiac function grading, with coordinated care by a multidisciplinary pregnancy cardiac team[10,53].

In addition to the general principles and contraindications for guided dosing as described above, the dosing regimen for PPCM varies according to the degree of HF. For patients with mild HF (New York Heart Association class II), standard HF medication titration should be implemented in the general ward or outpatient setting, and regular follow-up should be ensured to optimise outcomes[10]. When patients with moderate to severe respiratory insufficiency are admitted to an intermediate care unit or HF unit, the treatment plan should include intravenous titration of a diuretic (furosemide) until congestion resolves, along with maintenance of SpO₂ > 95% with oxygen therapy[54,55]. It should be particularly emphasised that if pharmacological treatment is ineffective within 72 hours, an mechanical circulatory support device should be implanted as early as possible[54]. Notably, in a small proof-of-concept study of acute PPCM, the addition of bromocriptine to standard HF pharmacological therapy was associated with improvements in LV ejection fraction and mortality[56]. This PPCM treatment strategy integrates three core elements: (1) Severity-based stratification; (2) Evidence-based medicine; and (3) Disease pathophysiology. It embodies precision medicine principles while enabling individualized care.

CHARACTERISTICS OF MEDICATIONS IN HF ASSOCIATED WITH PREECLAMPSIA

Pre-eclampsia is an important risk factor for the development of HF in pregnancy and postpartum, in addition to PPCM[49]. Two different types of HF can develop in pre-eclamptic women. Some patients with pre-eclampsia develop a form of HF characterised by LV systolic dysfunction known as HFrEF, whilst others exhibit varying degrees of LV diastolic dysfunction resulting in HF with preserved ejection fraction[13]. Pathophysiology, cardiovascular mechanics, treatment options, and perinatal management strategies differ for these two forms of HF in preeclamptic women. This requires clinicians to be able to effectively screen for HF, correctly identify subtypes, and risk-stratify pre-eclamptic women with HF so that appropriate targeted interventions can be initiated in the perinatal period. Similar to the approach to PPCM, the consensus on hypertension associated with preeclampsia is to control HF while avoiding adverse effects on the mother and fetus.

In the pharmacological management of preeclampsia in pregnancy and lactation with combined HF, the safety of the drugs needs to be rigorously assessed and particular attention paid to the monitoring of the mother and child during the administration of the drugs: (1) Loop diuretics (e.g., furosemide), although compatible in pregnancy and lactation, need to be monitored for the risk of maternal hypovolemia, uterine underperfusion, and decreased lactation; (2) β-blockers, although safe to use, may cause fetal hypoglycemia and bradycardia, and need to be monitored closely; (3) Nitrate-based drugs (e.g., nitroglycerides), although not banned, need to be monitored for uterine hypoperfusion due to maternal hypotension; (4) Digoxin, although safe overall, may be associated with low birth weight, and the pros and cons need to be weighed; and (5) RASIs and MRAs, as listed above, are prohibited. For anticoagulation, heparin (unfractionated or low molecular weight heparin) is indicated throughout, but the risk of bleeding and the timing of intrathecal anaesthesia should be noted; warfarin should be avoided in pregnancy (risk of teratogenicity, intracranial haemorrhage, and miscarriage) and resumed in breastfeeding. This dosing strategy needs to be individualised based on maternal and infant safety data, taking into account haemodynamic effects and fetal developmental risk, with particular emphasis on the contraindication of ACEIs/ARBs and mineralocorticiod antagonists in pregnancy, whereas the choice of drugs for breastfeeding is relatively lenient, although the potential impact of breast milk exposure on the infant needs to be assessed[50].

CONCLUSION

Throughout pregnancy, physiological changes drive significant modifications in the pharmacokinetic properties and pharmacodynamic profiles of drugs, posing exceedingly formidable challenges for the pharmacological management of HF in this patient population. Clinically, beta-blockers, diuretics, and positive inotropes have demonstrated relatively favorable safety and efficacy profiles, emerging as pivotal options for managing HF during pregnancy. Conversely, RASIs, ARNIs, MRAs, and SGLT2i are strictly contraindicated during pregnancy due to potential fetal risks. Addressing this complex scenario necessitates a multidisciplinary approach, which plays an indispensable role in balancing maternal therapeutic benefits and fetal safety.

Historically, there remains a critical knowledge gap regarding dose adjustment strategies for pregnant women with HF who also present with concurrent morbidities such as renal or hepatic dysfunction, valvular heart disease, or varying types and severities of cardiac impairment. The systematic exclusion of pregnant women from clinical trials has perpetuated this deficit, leaving clinicians without evidence-based guidance for these complex cases. Promisingly, ongoing research, coupled with enhanced insights into pregnancy-induced cardiovascular adaptations, is propelling the establishment and advancement of standardized evidence-based care models. In forthcoming research and clinical initiatives, emphasis ought to be placed on the formulation of sophisticated dosing regimens that duly consider the complexities associated with multi-morbid conditions. Such an approach will facilitate the realization of personalized and secure pharmacotherapeutic interventions. Concurrently, it is imperative to establish a seamless, integrated care framework that extends across the continuum from the preconception phase through to the postpartum period. By implementing these strategies, we can significantly bolster the global dedication to ensuring the protection and well-being of maternal and neonatal health.

ACKNOWLEDGEMENTS

We thank the staff of Nanjing University of Chinese Medicine for technical support.