Introduction

Infective endocarditis (IE) is a serious and potentially fatal infection caused by various types of microorganisms. IE primarily affects the cardiac endothelium and cardiac valves [1, 2]. Although rare, there has been a notable rise in the incidence of IE by twofold from 478,000 cases in 1990 to 1,090,530 cases in 2019, resulting in greater morbidity and mortality [3]. In industrialized countries, infective endocarditis has an estimated annual incidence of three to nine cases per 100,000 persons [4]. This rise in incidence has been linked to epidemiological changes in the industrialized world, a rise in opioid addiction, and a greater proportion of cardiac devices and prosthetic valves [5]. Notably, the cost of IE hospitalizations was estimated to have risen to $2.34 billion in 2016 [6]. It is crucial to remain aware of the occurrence of IE in special population groups, such as pregnant women, in this constantly changing world, and most importantly the need of a comprehensive multidisciplinary approach to care.

In the current literature, there is a significant lack of comprehensive understanding of IE in the antepartum and postpartum periods in pregnant patients, including management of feto-maternal complications. This is largely due to the limited data available because of the low reported incidence and lack of randomized controlled trials. Despite its low incidence (estimated at 0.006%), IE in pregnancy has associated with significant maternal mortality of up to 33% and fetal mortality of 14% [7,8,9]. Prematurity is a major concern of pregnancies complicated by IE, with over half of deliveries occurring prior to term (averaging at 32 weeks of gestation) [10]. This can lead to significant perinatal morbidity and mortality. This review aims to provide a comprehensive overview of research on IE in pregnancy and associated complications. Our analysis covers the physiological changes that occur in pregnancy, key risk factors, potential preventative strategies, fetal and maternal outcomes, management in this group, and future research directions. By understanding the complex relationship between the pregnant body and its response to infections, we hope to guide and inform clinical practice. Our ultimate goal is to contribute to early diagnosis, improved patient care strategies, and better outcomes for this highly vulnerable patient population.

Methodology

A comprehensive search of the PubMed databases was performed from inception to December 2023 to identify relevant articles. Different medical subject headings (MeSH) terms were used, including “Infective Endocarditis,” “Bacterial Endocarditis,” “Endocarditis,” “Pregnancy,” “Post-Partum,” “Peri-partum,” “Pregnant,” and “Heart Failure” were used to generate the search strategy.

Inclusion Criteria

Studies were included in this review if they met the following criteria:

  1. 1.

    Conducted in pregnant patients

  2. 2.

    Focused on IE

  3. 3.

    Included information on presentation of IE

  4. 4.

    Discussed different fetal and maternal outcomes

  5. 5.

    Published in the English language

Exclusion Criteria

Studies were excluded in this review if they met the following criteria:

  1. 1.

    Studies that were not conducted on human subjects.

  2. 2.

    Case reports and papers not published in the English language.

Data Extraction and Analysis

Two reviewers screened the titles and abstracts of all identified studies to determine eligibility for inclusion. The full-text articles of potentially eligible studies were then obtained and reviewed in detail by the same reviewers. Any discrepancies between the two reviewers were resolved through discussion and consensus. The extracted data included study design, patient characteristics, interventions, outcomes, and adverse events. The data was summarized qualitatively due to the heterogeneity of the included studies.

Physiologic Changes of Pregnancy

It is essential to understand that several inherent physiological changes occur to the human body during pregnancy. These changes can affect the clinical presentation and possibly delay diagnosis of endocarditis in pregnancy. For instance, there is an overall increase in cardiac strain. Typical cardiac changes include an increase in preload by almost 50%, elevation of the heart rate, and an increase in cardiac output [11, 12]. Simultaneously, there is a significant decrease in peripheral vascular resistance, resulting in an overall decrease in afterload and systemic blood pressure [13]. These hemodynamic alterations are observed later in pregnancy, particularly during the second and third trimester, as well as in the postpartum period [13, 14]. Various changes to cardiac valves can cause the presence of murmurs during physical examination, which can be difficult to interpret and may be misleading. According to literature, pregnant patients often show enlarged mitral and tricuspid rings and some degree of valvular insufficiency with the highest incidence in right heart valves, estimated at > 90% in tricuspid and pulmonary valves [13,14,15]. In addition, the myocardium of pregnant patients adapts to this physiological state of volume overload, leading to benign left ventricular hypertrophy as well as a short-term systolic and diastolic dysfunction [16].

During pregnancy, the immune system of the mother gets regulated to be able to adjust and maintain the well-being of the mother and the fetus. There is a common misconception that pregnancy is an immunosuppressed state due to complex immune changes. At the materno-fetal interface, the immune system undergoes significant reprograming to accommodate for the developing fetus, which can lead to different responses to different organisms [17]. The overall implicated changes include a decrease in adaptive immunity (specifically B cell cytotoxic function) and an overall increase in innate immunity (coordinated cell migration and pathogen recognition) [17]. This sheds the light on the importance of recognizing distinct physical exam findings of IE during encounters with pregnant women.

Risk Factors

The European Society of Cardiology (ESC) identifies three distinct groups of patients at an increased risk of developing IE: individuals with prosthetic valves, cyanotic congenital heart disease (CHD), and those with a previous history of IE [18]. Patients with prosthetic valves face an increased susceptibility to IE and are more prone to complications compared to those with native valves [19]. Those with untreated CHD or who have undergone surgical interventions such as shunts, conduits, or other prosthesis are also at elevated risk, prompting the task force to recommend prophylaxis for 6 months post-surgery [20]. Similarly, individuals with a history of IE carry a greater risk of recurrence, along with elevated mortality rates and incidence of complications [21].

Despite the lack of differences in the risk factors for IE among pregnant and non-pregnant individuals, there has been an overall change in the prevalence of risk factors in the past couple of decades. Common risk factors for IE include chronic comorbidities (such as diabetes mellitus, hypertension, end-stage renal disease), underlying heart disease, implantable cardiac devices, prosthetic valves, prolonged intravenous access, and intravenous drug use [22, 23]. Episodes of bacteremia significantly contribute to the development of endocarditis. Several procedures are frequently associated with transitory bacteremia such as dental work, genitourinary, and gastrointestinal instrumentation. As microorganisms infiltrate the bloodstream, they have the propensity to adhere to damaged endothelium which facilitates vegetation formation [24, 25]. Additionally, childbirth may introduce another layer of risk, particularly in situations that might favor bacteremia such as membrane ruptures, manual removal of the placenta, prolonged labor, and even low socioeconomic status [26]. In a prospective cohort study done by Sengupta et al., patients with IE in lower to middle income countries were younger than patients with IE in higher income countries at presentation, presented later (52 days since symptom onset in lower income countries compared to 30 days in higher income countries, p < 0.001), had less access to advanced cardiac imaging, underwent surgery less frequently, and had a higher mortality all in all (mortality rate of 23% in lower income countries compared to 15% in higher income countries, p < 0.001) [27]. It is noteworthy that the current literature has yet to investigate whether pregnancy potentiates the risk for IE in individuals with pre-existing cardiac risk factors such as prosthetic valves, CHD, or a history of previous IE.

In the general population nowadays, a prominent contributing risk for bacteremia is intravenous drug use (IVDU), which has been markedly increasing in prevalence, consequently leading to increasing rates of right-sided IE [28]. Different studies have identified IVDU as the predominant extracardiac risk factor for IE during pregnancy, observed in 23% of 61 patients with pregnancy and postpartum IE between 2014 and 2020 [9, 29]. The United States and Eastern Europe have reported higher rates of drug use compared to other counties, potentially predisposing these specific populations. Furthermore, preexisting heart disease remains a significant risk for both the general population and pregnant patients. Despite a notable decrease in the incidence of rheumatic heart disease, there has been a concomitant increase in individuals with congenital cardiac conditions who survive to adulthood and childbearing age [9, 30].

Microorganisms

Streptococcus, Staphylococcus aureus, and Enterococcus are the microorganisms responsible for most cases of IE in both pregnant and non-pregnant patients, with Staphylococcus aureus being the most common causative organism. The American Heart Association (AHA) and American College of Cardiology (ACC) have described a significant rise in overall Staphylococcus aureus endocarditis, attributing it to increased use of cardiac devices, prosthetic valves, and the rise of IVDU alongside industrialization [5].

The impact of Staphylococcus endocarditis extends beyond pregnancy, as multiple studies identify it as the most common causal organism followed by streptococcus species [9]. De Oliviera et al. found that Staphylococcus aureus accounted for approximately 33% of cases, while Streptococcus viridans group constituted 26% [29]. Importantly, there is a significantly lower incidence of beta-hemolytic Streptococcus, attributed to antenatal care and screening for Streptococcus agalactiae [29]. Despite scarcity of literature on perinatal and postnatal IE, certain case reports have shed a light on unusual organisms and on IE in pregnant patients with no common risk factors. A case report from Turkey documented a case of postpartum IE with Enterococcus in a 24-year-old female who underwent a vaginal delivery, with the performance of an episiotomy being identified as a significant risk factor [31]. The awareness of the genitourinary instrumentation during the peripartum period should raise suspicion regarding the potential development of IE postpartum.

Diagnosis of Infective Endocarditis in Pregnancy

The intricate and constantly changing epidemiology poses a persistent diagnostic challenge. Over the years, diagnostic criteria have been established to help in the recognitions of IE. The AHA/ACC and European Society of Cardiology (ESC) have comprehensively reviewed the diagnostic process, with no specific adjustments suggested when diagnosing IE in pregnancy [5, 18]. In 2015, the ESC IE guidelines noted special consideration to the cardiac physiologic changes of pregnancy that may mimic cardiac disease, such as murmurs during physical examination, potentially complicating the clinical picture [18].

The diagnosis of IE primarily relies on the Duke Criteria for IE, which has been revised into the 2023 Duke-ISCVID criteria (International Society for Cardiovascular Infectious Disease Criteria for Infectious Diseases) [32]. Table 1 shows the updated Duke-ISCVID diagnostic criteria with description of the major and minor diagnostic criteria. Duke-ISCVID criteria operate as a point system, facilitating the diagnosis of IE by categorizing cases as definitive, possible, and rejected IE (described in Table 2), based on the presence of major and minor criteria.

Table 1 2023 Duke-ISCVID criteria for diagnosis of infectious endocarditis
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Table 2 Infective endocarditis definition criteria and classification on possible diagnosis
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Validation studies on the 2023 Duke-ISCVID criteria have been conducted, with two noteworthy researches. In Amsterdam, a study involving 595 patients with suspected found that the 2023 Duke-ISCVID Criteria exhibited greater sensitivity in diagnosing IE compared to the modified Duke criteria (2000) and ESC 2015 criteria [33]. Another study performed in France with a patient population of 1194 similarly found a higher sensitivity with 2023 Duke-ISCVID Criteria compared to modified Duke and ESC 2015 criteria [34].

Materno-Fetal Outcomes and Complications

While women with IE face a range of various complications, a notable distinction during pregnancy is the heightened mortality risk, along with fetal complications arising from premature delivery. Similar to the general population, pregnant women with IE may experience adverse outcomes such as heart failure, worsening infection, systemic emboli, aneurysm, and preterm birth. The morbidity rate is significantly increased in pregnant patients and is particularly associated with prolonged hospital stay [35].

Heart failure is a frequent complication of IE, primarily caused by severe valvular regurgitation and cardiac fistula formation and often necessitates surgery [36]. In the context of pregnancy, the acute deterioration in cardiac function may warrant an emergency cardiac surgery, exposing the maternal body to the elevated stressors of such a procedure and the risks of complications. The initiation of antibiotics prior to cardiac surgery is recommended, with one study indicating that pregnant patients typically received an average of 18 days of antibiotic therapy prior to cardiac surgery [1, 37]. Risks are notably elevated when interventions are performed in earlier gestational periods. Some studies suggest deferring cardiac operations until after 28 weeks of gestation due to the increased risk of fetal demise [38]. Intraoperative cardiotocography plays a crucial role in these surgeries, given that cardiopulmonary bypass is associated with acute decompensation of the fetus along with high fetal mortality [39, 40].

Shapero et al. shed the light on the increased rates of complications, with all studied patients experiencing adverse outcomes from IE. Fetal outcomes predominantly involve prematurity, with average birth occurring at 32 gestational weeks, accompanied by the risk of fetal demise [35]. The repercussions of fetal prematurity are numerous, encompassing various complications such as infections, low birthweight, respiratory distress syndrome, and intraventricular hemorrhage. Likewise, fetal complications are linked with neurodevelopmental issues, although long-term pediatric outcomes in these cases have not been thoroughly investigated [41, 42]. In a notable study, it was observed that nearly half of infants born to mother with IE required admission to the neonatal intensive care unit, with an average length of stay of 44 days [35]. Prenatal monitoring and understanding disease progression in the pregnant patient with IE is closely related to postnatal outcomes.

Treatment

Despite the existence of different guidelines providing recommendations for antimicrobial treatment of IE in the general population, there is a notable absence of dedicated recommendations for IE during pregnancy. In general, antibiotic therapy is directed towards the organisms isolated from blood cultures. Due to limited literature and the absence of a major consensus, the initial antimicrobial treatment typically involves the empiric coverage with anti-staphylococcal beta-lactams in pregnancy, considering their established safety in pregnancy [35, 43]. These management measures are implemented based on the assumption that the causal organism will most likely be equivalent to the most common organisms that infect non-pregnant persons. In patients with IE of a native valve, the recommended duration of antibiotic therapy is 4 to 6 weeks. In patients with IE of a prosthetic valve, the recommended duration of antibiotic therapy is 6 weeks. There are special factors that require a prolonged treatment with antibiotics, such as left-sided vegetations, drug-resistant organisms, and the use of slowly bactericidal agents such as vancomycin [5, 31]. Literature dedicated to the pregnant patient population is limited, and more research efforts dedicated to developing guidelines for guidance of treatment of IE in pregnancy are needed.

Prevention and Antimicrobial Prophylaxis

The AHA/ACC has issued guidelines specifying the conditions and procedures that would warrant antibiotic prophylaxis to prevent IE, and the American College of Obstetrics and Gynecology (ACOG) adopted these recommendations for the pregnant patient [44]. Most antibiotic prophylaxis trials utilize bacteremia as an endpoint, aiming to protect the patient during procedures with increased risk for bacteremia [45]. The ESC provides Class I recommendation for the use of antimicrobial prophylaxis in high-risk procedures for patients with any prosthetic cardiac valve and any type of congenital heart disease, with dental procedures being the primary high-risk procedures [46]. AHA/ACOG guidelines do not recommend the use of routine antibiotic prophylaxis during vaginal or cesarean deliveries, as there is insufficient evidence from compelling studies demonstrating an associated increase in bacteremia that would risk the development of IE postnatally.

Conclusion

Infective endocarditis represents a rare yet life-threatening infection during pregnancy and the postpartum period, requiring a high level of suspicion for early diagnosis and prompt initiation of appropriate management. The severity of IE during pregnancy necessitates a comprehensive multidisciplinary approach involving obstetricians, neonatologists, and the endocarditis team. Managing pregnancy and the postpartum period in the context of IE poses a significant challenge, particularly if cardiac surgery becomes a necessary consideration during the course of disease. Effectively navigating the complexities of IE in pregnancy necessitates a collaborative approach. Clinicians and researchers must work together in order to develop evidence-based guidelines accounting for the unique challenges of IE in pregnancy.