Pericarditis Management in Individuals Contemplating Pregnancy, Currently Pregnant, or Breastfeeding

Abstract

Purpose of Review

Pericarditis complicates pregnancy planning, pregnancy, or the postpartum period, and the management approach requires special considerations. Here, we aim to summarize the latest research, diagnostic, and treatment strategies.

Recent Findings

Physiologic cardiovascular (CV) adaptations occurring during pregnancy complicate diagnosis, but for most patients, an electrocardiogram (ECG) and transthoracic echocardiogram (TTE) are sufficient to diagnosis pericarditis in the appropriate clinical context. Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) can be used until 20 weeks gestation as needed. The use of colchicine is encouraged at any time point to reduce the risk of recurrence. Glucocorticoids may be used at the lowest possible dose for the least amount of time throughout pregnancy and breastfeeding. For incessant, recurrent, or refractory pericarditis, or when the above therapies are contraindicated, there may be a consideration of the use of IL-1 inhibition during pregnancy, recognizing the limited data in pregnant patients. Finally, we encourage the use of a multidisciplinary team approach including OB-GYN, cardiology, and rheumatology when available.

Summary

The diagnosis and treatment of pericarditis in female patients of reproductive age require special considerations. Although highly effective treatment options are available, there is a need for greater data and larger international registries to improve treatment recommendations.

Clinical Vignette

Thirty-two-year-old G3P2 patient presented at 17 weeks gestation to the local emergency department reporting 1.5 weeks of chest pain followed by progressive dyspnea. Inflammatory markers were elevated, and a transthoracic echocardiogram demonstrated a small pericardial effusion, dilated inferior vena cava (IVC), and early diastolic flattening of the right ventricle (Fig. 1). Together, these findings supported a diagnosis of acute pericarditis. Laboratory data revealed a positive ANA (1:2560, speckled pattern), anti-Ro, and La antibodies, and she was diagnosed with systemic lupus erythematosus. She was treated with colchicine 0.6 mg BID with initial improvement; however, chest pain recurred, ultimately improving after the addition of hydroxychloroquine and subsequently azathioprine.

Fig. 1.

Idiopathic pericarditis in a 32 y/o female G3P2 at 17 weeks gestational age. Top panel (left) demonstrates a small pericardial effusion (yellow arrow), and (right) brief early diastolic inversion of the right ventricle on M-mode (red arrow). Bottom panel left demonstrates a dilated IVC which was non-collapsible (2.5 cm) and right panel demonstrates the absence of significant respiration variation (maximal calculated change of 13%) in the intracardiac Doppler flow velocities across the mitral valve. Together, these findings represent some features of increased intrapericardial pressure but without significant echocardiographic tamponade physiology and support the clinical diagnosis of acute pericarditis

Introduction

Pericarditis is an important medical problem with an incidence of 27.7 cases per 100,000 people per year. Although male individuals have increased susceptibility to pericarditis, this disease nevertheless affects female individuals of reproductive age, including those who are pregnant or breastfeeding [1]. The incidence of pericarditis in pregnancy is not clearly characterized, but data from case series suggest similar frequency as age-matched controls [2, 3]. Although most pericardial effusions in pregnancy are asymptomatic, pericarditis is the leading cause of pericardial disease requiring medical intervention among these patients [4]. Most cases appear to be idiopathic; others are likely secondary to viral infections, autoinflammatory conditions, and connective tissue diseases [1].

Pericarditis is classified based on a spectrum of chronicity. Acute pericarditis is defined as a first episode and new-onset presentation, but if symptoms persist for more than 4–6 weeks, pericarditis is then considered incessant. If symptoms continue for more than 3 months, pericarditis is described as chronic. Recurrent pericarditis occurs when symptoms resolve for a window of typically 4–6 weeks then return [1]. Recurrent pericarditis may complicate 15–30% of all cases of pericarditis, and unfortunately, one recurrence greatly increases the risk of subsequent recurrence [1, 2]. Females are at higher risk of recurrence, possibly due to the higher prevalence of autoimmune diseases in this population and the greater risk of recurrence in pericarditis of autoimmune etiology [5, 6].

Evaluation and Diagnosis

The diagnostic approach in a pregnant patient with suspected pericarditis is similar to that of a non-pregnant patient. The most commonly reported symptom is pleuritic chest pain, worsened with inspiration and relieved by leaning forward. Some patients may endorse dyspnea when supine, which is also a common symptom experienced during pregnancy. Patients may also exhibit systemic symptoms, including fever and malaise. Physical exam findings may demonstrate the presence of a pericardial friction rub in up to one-third of patients [7]. All patients should have an electrocardiogram (ECG), and characteristic findings of widespread ST-segment elevations and PR depression can be seen in both pregnant and non-pregnant individuals. Progressive ECG changes seen in pericarditis, including T-wave inversions, should be interpreted with caution as healthy patients in their second and third trimesters of pregnancy may have inverted T-waves, particularly in leads III, and V1–V3 [8]. Although elevations in ESR and high-sensitivity CRP (hsCRP) are often used to support the diagnosis, such findings should also be interpreted with caution in a pregnant patient as ESR and hsCRP levels often rise progressively in pregnancy (Fig. 2) [9, 10].

Fig. 2.

Challenges of pericarditis diagnosis in pregnancy

Concomitant inflammation of the myocardium (i.e., myopericarditis) is substantially less common in pregnancy but may occur, particularly in the context of viral infection or autoimmune disease [11, 12]. Evidence of myocardial inflammation, although not part of the diagnostic criteria for pericarditis, is considered a supportive finding and suggests perimyocarditis [1]. If there is clinical concern for myopericarditis, testing for high-sensitivity cardiac troponin should be performed. While some studies suggest both gestational hypertension and preeclampsia are associated with elevated markers of cardiac injury, these findings have been inconsistent and serum biomarkers should be viewed in light of the clinical context [13, 14]. Imaging is an important component of the evaluation in suspected pericardial/myopericardial disease, and a transthoracic echocardiogram is the first line given its easy accessibility and lack of associated radiation. Although the subcostal view can be limited in later pregnancy, echocardiography provides valuable hemodynamic information that can inform diagnosis and management [15]. Echocardiography may show an effusion ~ 60–80% of the time [1], though asymptomatic small pericardial effusions are reported in up to 15% of healthy pregnant patients, particularly in the third trimester [16]. Physiologic cardiovascular adaptations that take place in pregnancy, including an increase in blood volume, result in better tolerance of even larger effusions compared to the non-pregnant state. Cardiac magnetic resonance (CMR) may be performed. However, gadolinium contrast is not typically administered during pregnancy owing to data suggesting an association with fetal renal injury and skin toxicity [17].

Management

The treatment of pericarditis in pregnant or breastfeeding patients requires a thoughtful approach that includes consideration of the risk and benefit profile of the various therapeutic choices. Beyond prompt recognition, individualized guideline-based management with a multidisciplinary team-based approach should be incorporated including OB-GYN, cardiology, and rheumatology. The expanding field of cardio-obstetrics specialists has grown, and consultation should be sought if locally available [18]. As Table 1 demonstrates, treatment recommendations may change at different stages of pregnancy, and the overall limited amount of data on many therapeutics in the setting of pregnancy makes management challenging [19]. The most recent European Society of Cardiology (ESC) guidelines for the management of pericardial diseases do not include recommendations during pregnancy [12]. Given the lack of formal pericardial guidelines, it is important to understand the safety profile of each medication used in pregnancy for other clinical indications and formal recommendations for these medications by society guidelines when available [20••].

Table 1.

Considerations for pharmacologic management of pericarditis before, during, and after pregnancy

	Preconception/Periconception	1st and 2nd Trimesters	3rd Trimester	Breastfeeding
NSAIDs	Avoid if feasible, may affect ovulation	Use (Ibuprofen preferred)	Avoid (except low dose Aspirin)	Use
Colchicine	Use	Use	Use	Use
Corticosteroids	Use	Use (Prednisone or Prednisolone preferred, dose <20mg/day)	Use (Nonfluorinated preferred, dose equivalent of <20mg/day Prednisone)	Use (Nonfluorinated preferred, dose equivalent of <20mg/day Prednisone)
IL-1Ra	Selective use*	Selective use*	Selective use*	Use (limited data, presumed safe)
Azathioprine	Use	Use	Use	Use
IVIG	Use	Use	Use	Use
Methotrexate	Avoid, discontinue 1–3 months prior	Avoid	Avoid	Avoid
Mycophenolate Mofetil	Avoid, discontinue 6 weeks prior	Avoid	Avoid	Consider alternative but reasonable with counseling

Adapted from the 2020 American College of Rheumatology Guidelines for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases [20••] and the American College of Cardiology Expert Analysis on Pericarditis Management in Pregnancy [19].

^*There should be shared decision making with the patient by a multidisciplinary care team (e.g. obstetrics, rheumatology, cardiology) of IL-1 inhibition use in pregnancy recognizing that there are no formal society guidelines that recommend the use of IL-1 inhibition in pregnancy [20••]

Individuals with a prior episode of idiopathic or recurrent pericarditis should ideally achieve disease control for 6 months prior to conception. Although modest absolute numbers of cases of pericarditis in pregnancy limit the conclusions that can be drawn specifically about pericarditis, it is well established that active inflammatory disease, such as rheumatic disease, during pregnancy is associated with adverse pregnancy outcomes, including fetal loss, growth restriction, preeclampsia, gestational hypertension, and preterm delivery [21, 22]. The recommendation to delay pregnancy pending quiescent pericardial disease is extrapolated from these data and the 2020 American College of Rheumatology reproductive health guidelines [20••]. A multidisciplinary approach with specialists in obstetrics and gynecology, including maternal–fetal medicine, is strongly encouraged [20••].

In addition to pharmacologic therapy, all patients should be encouraged to limit strenuous physical activity, as this may potentially decrease the risk of recurrence or the development of complications [23]. Pregnant patients can return to full activity on the same timeline as non-pregnant patients, which is typically encouraged once there is no evidence of disease activity. This includes resolution of chest pain and systemic symptoms, and ideally with normalization of inflammatory biomarkers and absence of a pericardial effusion [23, 24]. However, mild elevations of hsCRP or asymptomatic, small pericardial effusions may occur in otherwise uncomplicated pregnancies; therefore, these findings should be interpreted on a case-by-case basis.

Most pharmacologic management recommendations are informed by case reports and case series. The largest study was a case series of 21 pregnancies in 14 women, with 8 pregnancies analyzed retrospectively (from 2002 to 2010) and 13 prospectively followed (from 2011 to 2017). In the prospective cohort, a pericarditis treatment algorithm was employed. Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) were permitted until 20 weeks gestation as needed. Colchicine, acetaminophen, and prednisone (2.5–10 mg, at lowest effective dose) were allowed throughout pregnancy. After delivery and during breastfeeding, all these medications were permitted with a preference to avoid aspirin if possible. In the retrospective cohort, prednisone was used in 7/8 pregnancies (87.5%) with a median dose of 10 mg (IQR 20.0, 5.0–25.0). In the prospective cohort, prednisone was used in 6/13 pregnancies (46.2%) with a median dose of 2.5 mg (IQR 7.38, 2.0–15.0). Lower dose prednisone in the prospective cohort was associated with a trend towards a higher rate of relapse (53.8% vs 12.5%), p = 0.085, in addition to 5 recurrences within 1 year of delivery in the prospective cohort vs the retrospective cohort, p = 0.111. The only statistically significant birth outcome between these cohorts was a higher birth weight seen in the prospective cohort (mean 3320 g) than in the retrospective cohort (mean 2806.2 g), p = 0.017. Otherwise, rates of fetal loss, cesarean delivery, and prematurity were comparable to those seen in the general population and in rheumatic disease with low disease activity [21].

Notably, this case series occurred before the introduction of IL-1 receptor antagonists (IL-1Ra) for the management of recurrent pericarditis. Anakinra (a recombinant human IL-1Ra) and rilonacept (a soluble decoy receptor “trap” that binds both IL-1α and IL-1β) are the two medications in this class, and rilonacept is the first FDA-approved medication to treat recurrent pericarditis. Canakinumab is a human anti-IL-1β monoclonal antibody which has limited use in pericarditis due to both limited data and the recognition of the importance of IL-1α inhibition [25]. In 2016, Brucato et al. published the results of AIRTRIP, a small open-label trial which showed that among 21 patients with colchicine-resistant, steroid-dependent pericarditis (with 3 or more previous recurrences), use of anakinra compared with placebo reduced recurrence risk over 14 months [26]. Subsequently in 2021, Klein et al. published the results of the RHAP-SODY trial, a phase 3 double-blinded placebo-control multicenter randomized clinical trial exploring the efficacy of rilonacept among 86 patients with recurrent pericarditis. In this trial, patients treated with rilonacept experienced rapid resolution of symptoms with a reduced risk of future recurrence (7% compared to 74%, hazard ratio, 0.04; 95% CI, 0.01–0.18; P < 0.001) [27••]. IL-1Ra are well tolerated, with infection-site reactions and mild upper respiratory infection the most common adverse effects.

Regarding their use in pregnancy, in a more recent case series, Lotan et al. report on management and outcomes in 12 patients with 14 pregnancies [28]. In 8 pregnancies, pericarditis was recurrent. Use of corticosteroid of an unspecified dose was more common in patients with recurrent pericarditis (7/8, 87%), compared with use in patients with acute pericarditis (2/6, 33%). Colchicine was used in 13/14 (93% of pregnancies, at an average gestational age of 25 weeks (±15 weeks). One patient without prior treatment response was successfully treated with anakinra. All pregnancies culminated in live birth at a mean gestational age of 37±1.4 weeks. Authors noted that patients with recurrent pericarditis who had been treated with colchicine were less prone to recurrence [28].

There is limited data, largely from isolated case reports, on the management of constrictive pericarditis in pregnancy, including indications for surgical pericardiectomy which would be reserved for extreme circumstances. In general, diuretics are not recommended in pregnancy unless absolutely necessary given the effects on amniotic fluid and fetal growth [29].

Standard Therapies for Pericarditis

Non-steroidal anti-inflammatory drugs (NSAIDs) are an effective and widely used first-line medication for the management of pericarditis in non-pregnant patients [7]; however, careful attention is needed for the use of NSAIDs during pregnancy and recommendations are guided by the gestational age. A multidisciplinary approach is critical to the management and typically involves clinicians with expertise in obstetrics, cardiology, and rheumatology. NSAIDs should only be used through the first and second trimesters as later usage can be associated with premature closure of the fetal ductus arteriosus and oligohydramnios. On the contrary, low-dose aspirin is safe for patients throughout conception, pregnancy, and breastfeeding [30]. Ibuprofen is a preferred NSAID due to reduced cross-placental transfer and shorter half-life [31]. As in non-pregnant patients, a typical duration is a high-dose NSAID for 1–2 weeks for a first occurrence and 2–4 weeks for a recurrence, followed by a taper [7].

Colchicine has been shown in both the Colchicine for Acute Pericarditis (COPE) study and the Investigation on Colchicine for Acute Pericarditis (ICAP) randomized trials to decrease the risk of recurrence when used for 3 months as an adjunct to anti-inflammatory therapy [32, 33]. For this reason, we encourage its use in pregnant patients being treated for a first episode of acute pericarditis. Although it is unclear if the postpartum period is associated with a heightened risk of pericarditis recurrence, it is well established that the postpartum period is associated with an increased risk of disease flare in a range of inflammatory diseases [34, 35]. Historically, colchicine was considered a potential teratogen due to concerns of increased rates of both malformations and miscarriages seen in animal studies [36]. However, doses administered were substantially higher than those typically used in humans. Furthermore, there is growing evidence, largely from studies of Familial Mediterranean Fever (FMF), of the safety of colchicine in pregnancy [36]. In a meta-analysis that reviewed the cumulative literature, there were no significant increases in miscarriage or fetal malformation. Colchicine can be found in breastmilk although the concentrations are low [37]. Thus, the 2020 American College of Rheumatology reproductive guidelines encourage its use at all stages of pregnancy and during breastfeeding [20••, 36].

Glucocorticoids are recommended as a second-line therapy when treatment with NSAIDs and colchicine have not adequately controlled symptoms. Glucocorticoids, though effective, may be associated with a prolonged disease course or higher risk of recurrence, particularly at higher doses [7, 38]. Both the glucocorticoid class and dose require special attention in pregnancy. Non-fluorinated glucocorticoids, such as prednisone and prednisolone, are metabolized more rapidly than fluorinated glucocorticoids which limit fetal exposure. We encourage the preferential use of non-fluorinated glucocorticoids at the lowest possible dose for the least amount of time. In particular, patients should be treated with doses below the equivalent of 20 mg/day of prednisone, but ideally ≤ 10 mg/day. If patients require more than several weeks of treatment, an IL-1 receptor antagonist may be considered based on the severity of pericarditis and the degree of exposure to alternative agents. In the post-pregnancy period, patients treated with glucocorticoid doses higher than the equivalent of 20 mg of prednisone should discard breast milk produced within 4 hours of medication exposure. For lower doses, breastfeeding is safe at all time points [20].

For IL-1 inhibition, in cases of incessant, recurrent, or refractory pericarditis in pregnancy, there may be the consideration of IL-1 inhibition when refractory to more conventional pericarditis therapies. While there are no formal society guidelines recommending the use of IL-1 inhibition in pregnancy, there are a growing number of case reports and retrospective studies, predominantly of patients with cryopyrin-associated period fever syndromes [39, 40•]. A challenge has been determining if adverse outcomes are secondary to maternal disease activity or to IL-1 inhibitors used in pregnancy. There is also inconsistency in dosing and length of antenatal exposure [41]. There is very limited evidence on the use of these agents in pregnancy to treat pericarditis. One recent case report highlights the safe and successful use of Anakinra throughout pregnancy and breastfeeding in a pregnant patient with recurrent pericarditis. In this case, the patient was treated starting 2 months into her pregnancy with 100 mg daily for 1 month, then 100 mg every other day for the subsequent month, followed by 100 mg weekly through the remainder of her pregnancy and breastfeeding. She delivered healthy twins at 36 weeks gestation, who were breastfed on this regimen [42]. Although the data are incomplete, the growing literature supports cautious use of IL-1 inhibition in pregnancy in select patients with persistent disease, and particularly in patients with high-dose glucocorticoid dependence. While data in breastfeeding are also limited, the use of IL-1 inhibitors during breastfeeding is conditionally recommended [20••, 43].

Alternative Treatments

There is incomplete evidence for the use of azathioprine or intravenous immunoglobulin (IVIG) to treat pericarditis, but these agents are safely used in pregnancy and breastfeeding [20••]. By contrast, although methotrexate and mycophenolate mofetil (MMF) are less commonly used to treat recurrent or refractory pericarditis, these agents are contraindicated both in the preconception period and throughout pregnancy. Methotrexate is contraindicated during breastfeeding while there are mixed data regarding the use of MMF in breastfeeding patients [43]. Patients should discontinue methotrexate 1–3 months prior to conception, and MMF at least 6 weeks before conception [20••].

Conclusion

In conclusion, pericarditis in pregnancy is a rare but important diagnosis. Judicious selection of diagnostics that consider normal changes in physiologic and laboratory parameters in pregnancy is essential. Treatment options continue to grow, and there are several effective treatment approaches with excellent maternal benefit and minimal fetal risk, but patient-centered counseling is essential. A multidisciplinary team approach is recommended from the prenatal to postnatal period to optimize maternal–fetal outcomes. There is a need for more data in this area, including the need for larger international registries to improve treatment recommendations.