Fernanda M. de Oliveira¹, Maria Theresa Fraife¹, Giovanna Ianini F. Barbosa^2,3, Thaissa S. Monteiro², Cristiane C. Lamas^2,4

¹Universidade do Grande Rio (UNIGRANRIO), Rio de Janeiro, Brazil

²Instituto Nacional de Cardiologia, Rio de Janeiro, Brazil

³Universidade do Estado do Rio de Janeiro (UERJ), Brazil

⁴Instituto Nacional de Infectologia Evandro Chagas, Fiocruz, Rio de Janeiro, Brazil

Abstract

Objective: Pregnancy and postpartum infective endocarditis (PPIE), although uncommon, is a very serious condition. To describe cases of infectious endocarditis (IE) in in a cohort of adults with IE in a Brazilian center and to review data from the recent literature on the subject.

Methods: Cases of definite IE by the modified Duke criteria in adults were retrieved in a contemporary cohort of adults with IE from January 2006 to December 2020.  Literature review on the topic was carried out and case reports on PPIE from 2014 to 2020 were compiled.

Results: Two cases of PPIE were found in 401 adult patients with IE, with a prevalence of 0.5% in the cohort, of 2/139 (1.4%) among women and 2/83 (2.4%) of women of reproductive age (18 -49 years) in this same cohort. The search for published case reports from 2014 to 2020 resulted in 61 episodes of PPIE; in these, 7 pregnant women (11.4%), 10 fetuses (16.4%) and 1 premature newborn (1.6%) died. There was a previous valve predisposition in 12 (19.7%) cases and intravenous drug use in 14(23%). Left-sided valves were the most frequently affected in 41 (67.2%) of the cases. The most common isolated infectious agent was methicillin sensitive Staphylococcus aureus in 18/61 (29.5%) patients, although as a group, oral viridans streptococci accounted for 16/61 (26.2%). Valve surgery was done for 70% of patients.

Conclusions: Intravenous drug use remained to be the main risk factor for IE. Mortality remained high for mothers and their children, despite the fact surgery was done more frequently in the recent cases. In the case of fever without an obvious focus in pregnant or post-partum women, the diagnosis of IE must be readily considered, especially in those with prosthesis and/or intravenous drug use.

Key words: infective endocarditis, pregnancy, postpartum

Introduction

Cardiac disorders are the main cause of non- obstetric maternal death and approximately 1% to 4% pregnant women suffer from it, especially mitral valve disease (1-3). The majority are only diagnosed during the third trimester, with the worsening of symptoms (1-3). The incidence of infective endocarditis (IE) during pregnancy is 0.006% or 1 in 8.000 childbirths. Although rare, its occurrence is of concern, due to associated maternal and fetal death (4).

Endocarditis must be considered as a differential diagnosis each time there are signs of cardiovascular symptoms without a clear etiology in a patient, considering the urgent care required for its treatment (5). The predisposing factors leading to IE involve congenital bicuspid aortic valve, rheumatic heart disease (RHD), intravenous drug abuse (IVDU), presence of prosthetic valves, previous IE and congenital heart disease (CHD), frequently associated with odontogenic disease responsible for triggering bacteremia (5-9).

The clinical diagnostic triad of IE is fever, heart murmurs and embolic phenomena (4, 7) . However, pregnancy itself can provoke cardiac strain due to hemodynamic changes, including increase in blood volume (this may increase by 50% in normal pregnancy), in heart rate and in cardiac output. These changes are maximal between the second and third trimester, with an additional climb in the immediate postpartum period.

Poor oral health or dental procedures may lead to bacteremia and IE, as may diagnostic or therapeutic procedures of the genitourinary and gastrointestinal tracts. Childbirth is also associated with situations that favor bacteremia, such as: membrane rupture for more than 6 hours, manual removal of the placenta, prolonged labor, and low socioeconomic status. Prophylactic measures are important in vaginal delivery and Cesarean section in order to reduce morbidity and mortality rates. Adequate antisepsis and asepsis, use of sterile instruments and correct techniques, in addition to antibiotic prophylaxis are required (10).

Although rare during pregnancy, IE can have devastating consequences for mothers and/or fetuses (4, 11). In this article, we describe cases from a Brazilian cardiology center and provide an update in the topic by doing a literature review of pregnancy and postpartum related IE.

Methods

Cases of PPIE were described retrospectively in a prospective cohort of consecutive adults with definite IE according to the modified Duke criteria (12) included in the years 2006 to 2020. Patients signed an informed consent form for inclusion in the cohort, which was approved by the Ethics Committee of Instituto Nacional de Cardiologia, under number 0171/2007. Variables included were those from the case report forms of the International Collaboration in Endocarditis (ICE) initiative (13). These cases were compared to those obtained from reports in the literature. A literature search for clinical cases of PPIE was carried out for the period from January 2014 to June 2020. Two cases were excluded because the patients did not fit the studied profile of pregnant or postpartum women. The data were organized in tables; to complement the systematic literature review published previously (11). The Scientific Electronic Library Online (SCIELO) and National Library of Medicine (PUBMED) databases were searched. The following keywords were used: Endocarditis, Infectious endocarditis; Bacterial endocarditis; Pregnancy; Bacterial endocarditis AND pregnant women; Infectious endocarditis AND pregnancy; Clinical endocarditis; Endocarditis etiology; Endocarditis etiology AND pregnancy; Streptococcus; Streptococcus AND infection; Endocarditis diagnosis; Endocarditis treatment; Antibiotic therapy; Antibiotic therapy AND pregnant women; Heart surgery; Heart surgery AND endocarditis. Inclusion criteria were original studies describing cases or small series of cases of definite infective endocarditis according to the modified Duke criteria (12) in pregnancy or postpartum.

Women 15 to 49 years of age were considered as of reproductive age, according to the World Health Organization definition (14).

Results

Two cases of IE associated with pregnancy or puerperium were found in 401 adult patients with definite IE in the study period at our institution, with a prevalence of 0.5% of the cohort, and 2/139 among women (1.4%). Considering adult women of reproductive age (18 to 49 years old) in the cohort, the prevalence of IE associated with pregnancy or puerperium was 2/83 (2.4%).

Clinical case 1

A 19-year-old black female farmer, with previous RHD, underwent a Cesarean section and presented two weeks later with fever, malaise, and pain in the left lower limb. She lived in Rio de Janeiro and denied intravenous drug use, HIV, other comorbidities, or a previous episode of IE. On the same day of symptom presentation, she sought the emergency department of a local hospital, a heart murmur was heard, and three blood culture sets were collected, which grew Streptococcus anginosus in all samples.

Computed tomography (CT) scans of the abdomen showed splenomegaly, and embolisms to the spleen and right kidney. She developed heart failure with NYHA III class and acute renal failure (creatinine  1.71 mg/dL), and was referred to our cardiac surgery hospital. A transesophageal echocardiography (TEE) was done, and it showed an aortic valve vegetation of 13x7 mm in size, prolapsing to the left ventricular  outflow tract, on the non-coronary leaflet, which was ruptured; there was severe aortic insufficiency, and the mitral valve was thickened and with moderate regurgitation. She needed inotropic support before surgery, which was performed on an urgent basis, with concomitant aortic and mitral valve replacement. In the intraoperative period, a vegetation was also found on the mitral valve. She bled in the intraoperative period, and this persisted in the postoperative period. The patient also evolved with acute renal failure and had to go on hemodialysis. She died 48 hours postoperatively due to hemorrhagic shock, having undergone a total of nine days of antibiotic therapy. There was no bacterial growth of the aortic and mitral valves, but Gram-positive cocci were seen in histopathology. IE was considered hospital-acquired since the patient had undergone a Cesarean section 2 weeks before the onset of fever.

Clinical case 2

A 39- year- old white housewife, with aortic and mitral mechanical prosthesis and tricuspid valve annuloplasty 7 years before, was admitted to our cardiac hospital with a weight loss of 15 kg, associated with dizziness and worsening heart failure, with a NYHA functional class II-III. Two weeks earlier, she reported night sweats and chills. She also reported the presence of cough with intermittent whitish sputum. Past medical history included three episodes of “pneumonia” in the previous year, the last one of which was 6 months earlier, treated with levofloxacin. She referred a transient ischemic attack 3 years earlier. She had undergone mitral valvuloplasty 9 and 15 years before, due to rheumatic mitral stenosis.  She was an active smoker (total was 14 pack-years). On physical examination, she presented a 4+/6+ systolic murmur in the aortic, mitral, tricuspid and pulmonary areas which radiated to the carotid arteries. Two days after admission, a TEE was performed and showed images suggestive of vegetations on the atrial aspect of the mitral prosthesis, the lateral one measuring 1 cm and the medial one 0.9 x 0.8 cm, with mild mitral regurgitation; there was also significant stenosis of the aortic prosthesis with moderate to severe regurgitation, mild tricuspid regurgitation, with a pulmonary artery systolic pressure of 43 mmHg and the left ventricular ejection fraction was 68.5%. Blood cultures were collected and ampicillin and gentamicin started. Due to amenorrhea, a pregnancy test was requested and resulted positive; a pelvic ultrasound scan confirmed pregnancy, and a fetus estimated to be 7-weeks old was seen.  She had vascular embolic events to the liver and elevated C reactive protein levels. Blood cultures taken on two different days were negative. Serologies for Bartonella henselae and Coxiella burnetii were negative. Surgery for heart failure and aortic prosthesis stenosis and regurgitation was indicated. Cardiac surgery was performed nine days after hospitalization, on an urgent basis, after the patient's consent. Vegetations on the mitral and aortic prosthesis were seen on operation, as well as pannus and thrombi. Postoperatively she developed atrioventricular block and needed a pacemaker implantation. The histopathology of the aortic mechanical prosthesis showed active endocarditis. She had several other events post-operatively: on day 4, a hypertensive acute pulmonary edema, on day 5, absence of fetal cardiac beats was noted on the obstetric ultrasonography, on day 8, a brain CT scan showed an acute right frontal ischemic lesion, on day 9 a definitive pacemaker was inserted, on day 16 uterine evacuation was performed by manual technique due to retained abortion.  On day 29 postoperatively, after a repeat brain CT scan which showed a residual hypodense lesion in the left frontal cortico-subcortical area, she was discharged from hospital, asymptomatic, hemodynamically stable and without motor deficits. She completed 28 days of ceftriaxone 2g daily after surgery.

Analysis of reported cases with PPIE

Table 1 presents data from published case reports, complemented by the described 2 cases from our cohort. Data synthesis is presented on Tables 2 and 3. Overall, 61 cases reports were found on IE associated with pregnancy and puerperium, of which 55 were found related to pregnancy, and 4 to the postpartum period and in 2 cases, this was not informed (15-46).

Regarding responsible etiologic agents isolated in blood cultures, methicilin-sensitive Staphylococcus aureus  was the most frequent pathogen (26%), closely followed by viridans group streptococci (23.2%); however, it is important to highlight that 17% of cases had no microorganisms identified in blood cultures. These results are presented in Table 3.

Discussion

In this present work, we sought to describe cases of pregnancy and puerperium-related IE in a cohort of adult patients with definitive IE in a reference hospital for Brazilian cardiac surgery and to make an updated review of the literature on the subject, synthesizing the most relevant aspects.

We found that intravenous drug use remains the most frequent predisposing extracardiac risk factor for IE in pregnancy, being present in a quarter of our cases, compared to 14% in a previous literature review. Kebed et al. (11), found 90 cases in their literature review from 1988 to 2012, but only 51(56.7%) involved pregnancy, 14 were post-abortion (15.6%) and 25 (27.8%) puerperium. Although our case series is not directly comparable, we compare some features of both cohorts in Table 4. Rheumatic valve disease had a similar frequency, CHD was less frequent, and implanted prosthesis was more frequent in our series. We suppose less CHD is present in the latter period because these are being corrected at an earlier age in recent years; for this same reason, we may see more prosthesis, which are inserted in congenital and acquired valve disease. More drug use has been reported in the USA and Eastern Europe overall in more recent years, and this may be why we are seeing this predisposition in these pregnant women.

Viridans group streptococci, as well as staphylococci, became more frequent as agents of IE in our cohort, but the frequency of beta-hemolytic streps decreased, which may be due to better antenatal care and screening for S. agalactiae.

Valve replacement surgery in IE has improved the prognosis for patients with left-sided endocarditis, and we found more patients were offered surgery in our review, compared to a previous one (70 vs 53%).  This may reflect the consensus in endocarditis published in 2015 by the American Heart Association and the European Society of Cardiology, in which the role of the Heart Team and of surgery in left sided IE are emphasized. The benefits of surgery in the acute clinical picture should always be balanced with the risk of mortality and the likelihood of the new valve recolonization in the presence of continuous bacteremia (4, 7). In the scenario of intravenous drug use, the role of surgery is even more contentious since the danger of recurrence is high (4). It must be emphasized, however, that when IE involves right-sided valves, as is often the case in intravenous drug use, surgery is most often not necessary, and mortality is lower (47). In pregnant women presenting with acute heart failure secondary to acute valve regurgitation, immediate surgery is indicated. However, there is high fetal mortality risk. During cardiopulmonary bypass, maternal outcomes remain the same as for nonpregnant but fetal mortality is high, ranging from 16% to 33%  (48).  

It is necessary to highlight the need for thorough prenatal monitoring, with the evaluation of the pregnant woman's valves and cardiovascular condition, so that in cases of fever with no obvious source, endocarditis is considered and expeditiously investigated, minimizing complications including maternal and fetal death.

It is also important to refer patients with left sided IE to centers with a Heart Team and have them evaluated early so that surgery may be indicated at the right moment, since heart valve surgery saves lives in left sided IE. The Heart Team in PPIE should obviously include an obstetrician and pediatrician for the best management of these patients.

Study limitations

Limitations of our study are reporting bias, as not all cases of pregnancy and postpartum related IE are published. Strengths are providing available and more recent information on this severe condition, putatively comparing data from a previous review and possibly outlining trends.

Conclusions

Staphylococci accounted for a third of PPIE.

Intravenous drug use remains the most frequent predisposing extracardiac risk factor for IE in pregnancy, being present in a quarter of cases reviewed.

Rheumatic valve disease had a similar frequency, congenital heart disease was less frequent, and heart valve prosthesis was more frequent in this recent literature review series.

Surgery was done for over 2/3 of PPIE, a rate higher than previously reported in the literature.

Maternal and fetal mortality remain high.

Pregnancy and puerperium related to IE is a serious condition, and fever in intravenous drug users, women with previous valvular heart disease or prosthesis should prompt its diagnosis, so as to improve prognosis.

Evaluation by a Heart Team with expertise in endocarditis, plus an obstetrician and pediatrician, is essential, especially in left-sided PPIE, where surgery often saves lives.

Ethics: Written patients consent form was obtained from patients before all procedures and study was approved by Ethics Committee of Instituto Nacional de Cardiologia

Peer-review: Internal and external

Conflict of interest: None to declare

       Authorship: F.M.O., M.T.F., G.I.F.B., T.S.M., C.C.L. equally contributed to the patients management, study and manuscript preparation.

Acknowledgement: We acknowledge all medical and non-medical staff from Instituto Nacional de Cardiologia for their dedication and care to patients

Funding: None to declare