Triple threat in pregnancy

Abstract

A woman aged 22 years with a history of lupus presented in the 18th week of pregnancy with hypertensive emergency and flash pulmonary oedema. Bedside echocardiogram revealed severe left ventricular (LV) dysfunction with an ejection fraction (EF) of 25% and pericardial effusion. Laboratories revealed hypocomplementemia, proteinuria, elevated C reactive protein and anti-DS-DNA, raising concern for a lupus flare. Cardiac MRI showed an acute intramyocardial oedematous process, consistent with lupus carditis, and further worsening of LVEF to 13%. Shared-decision-making with the patient included discussion of maternal risks of continuation of pregnancy in the setting of worsening heart function and the fetal risks of definitive treatment with cyclophosphamide for a lupus flare and the patient decided to proceed with medical termination of pregnancy. Treatment with immunosuppressants, including cyclophosphamide, and steroids, was then initiated. 2 months after discharge, cardiac MRI showed marked improvement in LVEF to 50% and the patient remains clinically free of heart failure.

Background

Lupus flares during pregnancy are known to be associated with high maternal and fetal mortality. Lupus myocarditis, in particular, in the setting of pregnancy is hard to treat, since no specific guidelines exist, and most medications known to have some benefit are teratogenic. This case illustrates the need for extra vigilance for early detection of organ involvement in lupus flare whereby institution of appropriate treatment can halt progression, thereby avoiding the need for escalation of therapy with cytotoxics. Moreover, this case proves the importance of adequate prenatal counselling for female lupus patients.

Case presentation

A woman aged 22 years in the 18 weeks of pregnancy, with a recent diagnosis of lupus with rash, arthritis and proteinuria, presented to the hospital with symptoms of crushing chest pain, shortness of breath and pedal oedema. Two weeks prior to this admission, she was admitted for fever and pancytopenia and was diagnosed with a lupus flare. The patient was noted to have evidence of hypocomplementemia, proteinuria (>500 mg/dL), elevated C reactive protein (CRP) (1.5 mg/dL) and elevated ESR (80 mm/hour) with positive serology for SSA, SSB, SM and RNP antibodies. On discharge, she was prescribed hydroxychloroquine 200 mg two times a day, azathioprine 50 mg three times a day and prednisone 40 mg daily. While continuing this medical regimen, the patient developed acute shortness of breath and chest pain. She had an elevated blood pressure of 190/100 mm Hg, and was hypoxic, tachycardic and tachypnoeic with jugular venous distension and bilateral crackles on lung examination, suggesting pulmonary oedema. Laboratories showed leucocytosis with hypocomplementemia, elevated ESR, CRP and proteinuria. An EKG showed sinus tachycardia. Chest X-ray is shown (figure 1). Bedside echocardiogram (ECHO) showed a normal sized left ventricle (LV) with an ejection fraction (EF) of 25%, global hypokinesis and a moderate to large pericardial effusion without tamponade physiology (figure 2 and video 1). The patient was treated with intravenous nitroglycerine and a furosemide drip, which improved her blood pressure and oxygenation. She was maintained on oral carvedilol, isosorbide mononitrate, hydralazine and furosemide. In spite of aggressive treatment for the lupus flare and hypertension, a repeat echocardiogram showed worsening of LVEF to 15%.

Figure 1.

Chest X-ray showing bilateral pleural effusions, pulmonary oedema.

Figure 2.

Echocardiogram showing myocardial edema and pericardial effusion.

Other than the lupus, she had a medical history of polycystic ovarian disease, asthma and had surgery for excision of multiple fibroadenomas. There was no family history of rheumatological diseases. She did not smoke or drink alcohol or use illicit drugs.

Investigations

With worsening LV function by ECHO, a definitive diagnosis was required and therefore, a cardiac MRI was performed. Cardiac MRI with T2 imaging showed markedly abnormal pattern in the apex and septum and an acute intramyocardial oedematous process, consistent with lupus carditis (figure 3). The LVEF was estimated at 13%.

Figure 3.

Cardiac MRI (T2) image showing resolution of myocardial oedema and pericardial effusion.

Differential diagnosis

Since the patient presented with hypertensive emergency, pulmonary oedema and proteinuria, pre-eclampsia was a consideration. However, in pre-eclampsia, proteinuria and hypertension usually manifest after 20 weeks of gestation, whereas this patient was in her 18-week of gestation. Hypertensive cardiomyopathy in the setting of lupus nephritis was considered, although the patient's LV size and wall thickness were normal, suggesting an acute systolic dysfunction versus a slowly progressive hypertensive cardiomyopathy. Viral myocarditis can also present acutely as systolic dysfunction but is usually not associated with hypertension. Owing to the constellation of findings of proteinuria, hypocomplementemia and acute LV systolic dysfunction, lupus myocarditis was high on the differential diagnosis. This was subsequently confirmed by the findings on cardiac MRI.

Treatment

A multidisciplinary team, including cardiology, rheumatology and maternal–fetal medicine, discussed options for further treatment. The major concern was the inability to adequately treat the lupus myocarditis with the most effective agents such as cyclophosphamide due to known teratogenicity. In the absence of such definitive treatment, the maternal risks of continuing pregnancy in the setting of worsening cardiac function were discussed with the patient and family. The only other alternative that could be used in addition to steroids and Imuran was intravenous immunoglobulin which is considered to be relatively safe in pregnancy.¹ However, success with this agent has only rarely been reported with myocarditis.² After evaluating all options presented by the team, the patient decided to proceed with termination of pregnancy. She was continued on prednisone 100 mg daily, carvedilol 12.5 mg twice a day, furosemide 80 mg daily, isosorbide dinitrate 60 mg daily, hydralazine 25 mg three times a day, azathioprine 50 mg three times daily and hydroxychloroquine 200 mg twice a day. Aggressive treatment of myocarditis and nephritis was then initiated with cyclophosphamide infusions 500 mg intravenous given for 6 months. The Euro-lupus nephritis protocol was followed.³

Outcome and follow-up

The patient underwent repeat echocardiography and cardiac MRI 2 months after initiation of cyclophosphamide infusion. The MRI showed no evidence of intramyocardial fibrosis, and inflammation, and there was a marked improvement in non-invasive assessment of cardiac index and a significant decrease in the size of the pericardial effusion and improvement in EF to 50% (figure 4). ECHO also showed significant improvement in EF to 50% (figure 5 and video 2). The patient has completed five doses of intravenous cyclophosphamide to date. Doses of blood pressure medications have been significantly reduced and she is no longer on a diuretic or steroids. The patient has had no heart failure exacerbations and is undergoing cardiac rehabilitation.

Figure 4.

Cardiac MRI after treatment. Note the uniform intensity in the septum and lateral wall of left ventricle suggesting resolution of myocardial oedema.

Figure 5.

Echocardiogram after treatment showing resolution of pericardial effusion and improvement in ejection fraction.

Video 1.

Download video file ^{(4.2MB, mp4)}

DOI: 10.1136/bcr-2016-216385.video01

Echocardiogram showing a normal sized left ventricle with an ejection fraction (EF) of 25%, global hypokinesis and a moderate to large pericardial effusion without tamponade physiology.

Video 2.

Download video file ^{(4MB, mp4)}

DOI: 10.1136/bcr-2016-216385.video02

Echocardiogram showing a significant decrease in the size of the pericardial effusion and improvement in ejection fraction to 50%.

Discussion

All of the cardiac structures can be involved in lupus: the pericardium, myocardium, endocardium, coronary arteries and conduction tissue. Although necropsy studies have shown a prevalence of myocarditis in the range of 40–70%, symptomatic myocarditis is reported in only 5–10% of patients with lupus.^4–6 This suggests that subclinical cardiac involvement is a common finding in systemic lupus erythematosus. Limited case reports of lupus myocarditis exist, but only one case report was found pertaining to pregnancy, in which an African-American woman aged 22 years presented with symptoms similar to our patient. Although she responded to steroids, the LV function did not completely normalise and the delivery was premature, with a low birth weight baby. In most of the published cases of lupus myocarditis, patients had pre-existing lupus, were female and presented with symptoms of heart failure. Fever, chest pain, dyspnoea, palpitations, tachycardia out of proportion to body temperature, cardiomegaly and peripheral oedema can be seen. Laboratory findings that support diagnosis include leucocytosis, elevated ESR, elevated CRP and elevated troponins. Global hypokinesis on ECHO in the absence of other causes is quite suggestive of this diagnosis.⁷ Acute lupus myocarditis merits urgent clinical attention because of the likely progression to arrhythmias, conduction disturbances, dilated cardiomyopathy and heart failure.⁶ Immunofluorescence studies demonstrate fine granular immune complexes in the walls and perivascular tissues of myocardial blood vessels, supporting the hypothesis that lupus myocarditis is an immune complex-mediated disease.^4–6 The relative rarity of the condition makes controlled trials on optimal treatment infeasible, and management is based on anecdotal reports. Usual therapy includes high-dose corticosteroids, in addition to standard cardiac medications such as ACE inhibitors, β blockers and diuretics. Although the prognosis of lupus myocarditis is primarily based on case reports and case series, acute presentations usually have a good prognosis with treatment, and recurrences seem to be rare. African-American ethnicity, presence of hypertension and high lupus-related disease activity index at diagnosis are associated with worse outcomes.⁸

Pregnancy in lupus is a high-risk condition and needs multidisciplinary care and preconception counselling. In one study, the rate of lupus flare in pregnancy was 60%.⁹ Untreated lupus flare increases maternal mortality 20-fold and also there is a 20.8% higher risk of preterm labour, 5.6% higher risk of intrauterine growth restriction and 22.5% higher incidence of pre-eclampsia.¹⁰ Pregnancy outcomes are likely to be best when disease activity is lowest.¹¹ Our case was especially challenging since the disease involved the myocardium and there are no clear treatment pathways for lupus myocarditis, which is a life-threatening illness for mother and fetus. In addition, our patient had evidence of hypertension that started before 20 weeks of pregnancy with proteinuria, suggesting lupus nephritis. This combination of acute myocarditis and nephritis in pregnancy is rare, which is the triple threat we refer to in our title.

Cyclophosphamide, the most effective treatment agent for lupus myocarditis, is a known teratogen. It causes skeletal abnormalities, coronary artery agenesis and late-onset tumours in the fetus. In the mother, it is a known cause of premature ovarian failure.¹² Age >31, long-term therapy (>15 cycles) and cumulative doses >10 g are risk factors of future infertility. The overall rate of infertility was 12% in short-term therapy.¹² This is an important consideration when counselling young women who receive cyclophosphamide. These patients should be offered the choice to freeze oocytes for future child bearing. Unfortunately, due to the acute and serious nature of her illness, the option of oocyte freezing was not discussed with our patient.

In conclusion, lupus myocarditis is a life-threatening condition that requires timely treatment. In the setting of pregnancy, management can be challenging, as illustrated by this case.

Learning points.

• Pregnant patients with lupus need adequate prenatal counselling, so that pregnancy can be timed when disease activity is lowest.

• Lupus myocarditis should be in the differential diagnosis for any patient with lupus flare presenting with chest pain, dyspnoea and other symptoms of heart failure.

• Lupus myocarditis should be initially managed with steroids; however, if no clinical improvement occurs, cytotoxic agents may be needed.