Fetal total atrioventricular block in transgender man with systemic lupus erythematosus –  literature review and establishment of a protocol with management and treatment with terbutaline

Summary

This case report describes a case of total atrioventricular block (TAVB) with positive anti-Ro/SSA antibodies in a transgender man who began follow-up at 31 weeks and 3 days of gestation. Despite many disagreements regarding treatment, corticosteroids were recommended for this patient. The fetal ventricular rate at the second weekly visit was 50 bpm and terbulin was started to increase heart rate. Hospitalization and intravenous terbutaline for 3 days was chosen to better control maternal symptoms and monitor fetal vital signs, as well as daily monitoring of the ventricular rate. There was an increase in baseline ventricular rate of approximately 15%. After discharge from the hospital, weekly control fetal echocardiography was performed in addition to the indices proposed by Huhta for echocardiographic assessment of fetal cardiac function. Fetal ventricular rate in ambulatory controls did not fall below 55 bpm. Cesarean section was indicated at 35 weeks and 4 days of gestation due to premature rupture of ovular membranes. A male newborn was delivered weighing 2,250 grams with Apgar scores of 8 and 9 at the 1^st and 5^th minute, respectively. After 88 days of life, the infant was weighing 4,580 grams and a definitive bicameral epicardial pacemaker was implanted without complications. Even if there is a transient increase in fetal ventricular rate with the use of terbutaline, a pacemaker is indicated. Delivery should be at term to allow the fetus to achieve adequate weight and pulmonary maturity for definitive pacemaker implantation.

Keywords:

corticosteroids – management – fetal atrioventricular block – maternal systemic lupus erythematosus – β-sympathomimetics

Introduction

Total atrioventricular block (TAVB) is caused by an electrical disturbance leading to electromechanical dissociation, with interruption of electrical impulses from the atria to the ventricles. Fetal congenital TAVB is an autoimmune disease, acquired passively by the transplacental passage of anti-Ro/SSA antibodies into susceptible fetuses. This type of block occurs more commonly in structurally normal hearts [1], with an incidence of 2% to 6% in pregnant women with systemic lupus erythematosus, and can have different outcomes, depending on how these pregnancies are monitored and managed [2,3]. It is known that around 50% of pregnant women with anti-Ro (SSA) have no symptoms at the time of delivery or at the time of diagnosis [1].

Studies are controversial regarding the use of corticosteroids and b-sympathomimetics in cases of fetal congenital TAVB [4]. With this case report, we sought to carry out a literature review and apply a protocol to help guide treatment in a satisfactory manner, as well as measures for monitoring pregnancy using the cardiovascular profile (Huhta score) and assessment of ventricular function by shortening the fraction (∆D%).

Case report

A 24-year-old transexual male in a stable relationship with a cisgender female. Onset of symptoms with polyarthritis of small and large joints at age 11. Erythema on the face (malar rash) and upper limbs/neck, which worsened by exposure to sunlight. He was diagnosed with systemic lupus erythematosus at the age of 12. He had positive anti-Ro/SSA and anti-La/SSB tests and used prednisone from age 12 to 20. Started hydroxychloroquine at the age of 20 and he is still taking it. Took over-the-counter hormone therapy for 1 year and stopped 5 years ago. During prenatal care, gestational age at 20 weeks and 1 day, the 2^nd trimester scan showed fetal arrhythmia compatible with extrasystole. At 26 weeks and 4 days, fetal echocardiogram was compatible with congenital TAVB. At 31 weeks and 3 days, he was referred to our service and the fetal echocardiogram showed: persistence of the left superior vena cava and TAVB with a ventricular rate of 50 bpm and a Huhta score of 10/10. Following our protocol established after reviewing the literature, the patient was admitted to the hospital and received intravenous terbutaline using a continuous infusion pump at a dose of 2.5 mcg/min with a gradual increase to a maximum dose of 5 mcg/min on the 3^rd day of infusion. On the 2^nd day of infusion, the patient complained of precordial pain, which was discontinued pending evaluation and resumed after troponin dosage and electrocardiogram showed no evidence of ischemia. On the 3^rd day, with the maximum dose initiated, the fetal ventricular rate reached 66 bpm, and according to our protocol, the infusion was stopped and fetal heart rate was monitored at 24 hours. He was discharged from the hospital with a ventricular rate of 56 bpm and a Huhta score of 10/10. Based on the advice of the rheumatology team, prednisone 15 mg/d was started after hospital discharge.

One day after discharge from the hospital, he returned to the outpatient clinic with a fetal ventricular rate of 55 bpm, ∆D33%, and a Huhta score of 10/10. Patient was scheduled for weekly monitoring, with cardiovascular risk assessed by the Huhta score, ventricular function assessed by ∆D%, and fetal weight estimated to be as close to 2,800 grams at delivery. In subsequent weeks, fetal ventricular rate reached 51 bpm, with ∆D% within normal limits, but the Huhta score dropped to 9/10 (loss of 1 point due to an inverted A wave in the ductus venosus on Doppler) and in the last week before the delivery date to 7/10 (umbilical artery with positive diastole, umbilical vein with pulsation, and ductus venosus on Doppler with an inverted A wave) with an estimated fetal weight of 2,128 grams (Fig. 1).

At 35 weeks and 4 days of gestation, he was admitted to obstetric emergency because of vaginal loss of a large amount of clear fluid, which progressed to moderate intensity contractions and blood pressure of 140 × 100 mmHg, with no other symptoms. Cesarean section was scheduled due to premature rupture of ovular membranes and fetal TAVB, which made it impossible to monitor fetal well-being during labor.

A male newborn was delivered weighing 2,250 g, with Apgar scores of 8 and 9 at the 1^st and 5^th minute, respectively. Postnatal electrocardiogram confirmed the diagnosis of congenital TAVB with a fetal ventricular rate of 56 bpm showing a fossa ovalis-type atrial septal defect measuring 3 mm, and mild dilation of the right and left ventricles with preserved systolic function. Newborn progressed with the need for supplemental inhaled O₂ due to the drop in saturation, and it was decided to start intravenous dobutamine 5 mcg/kg/hours, which he received for about 24 hours. After evaluation by cardiac surgery and clinical cardiology, definitive pacemaker placement was indicated and it was decided to wait until the newborn was an active 3,000 grams if there were signs of heart failure or 4,000 grams if it was asymptomatic. Newborn progressed with hemodynamic stability, with a ventricular rate between 45 and 52 bpm. At 40 days of life, newborn developed a significant systolic murmur, progressive dyspnea, and signs of discomfort. A new echocardiogram showed moderate valvular stenosis, thickened pulmonary valve, mild right ventricular hypertrophy, and minimal tricuspid and mitral regurgitation. Percutaneous pulmonary valvuloplasty was performed with significant improvement (Fig. 2).

Definitive pacemaker implantation was performed at 88 days of age when the infant weighed 4,580 grams. The procedure was performed under general anesthesia with a median sternotomy and pericardial incision for pacemaker implantation. The postoperative heart rate was 100 bpm (pacemaker programming) (Fig. 3). The infant was discharged at 103 days of age, weighing 4,645 grams and in good general condition.

Discussion

Atrioventricular blocks (AVB) are electrical conduction disturbances that occur between atrial depolarization and ventricular depolarization. Bradycardia and electromechanical dissociation cause the fetal heart to accommodate a larger systolic volume to maintain adequate cardiac output. AVB can be classified as 1^st degree – cardiac impulse is conducted from the atrium to the ventricle with a prolongation of the atrioventricular conduction time, characterized by a PR interval > 150 ms, 2^nd degree or incomplete – progressive increase in the PR interval until no atrial electrical impulse is conducted to the ventricle, and 3^rd degree or complete (TAVB) – interruption of electrical impulses from the atria to the ventricles due to an anatomical or functional defect in the conduction system, with uncoordinated contraction between the atria and the ventricles [5,6]. The incidence of AVB is 1 in 15,000–20,000 live births, with 50% to 55% is associated with structural congenital heart disease, 60% of which is associated with left atrial isomerism, and 40% is associated with positive maternal SSA/Ro or SSB/La antibodies [1,6]. A pregnant woman with systemic lupus erythematosus and anti-Ro/SSA antibodies can have congenital AVB in 2% to 6%, with a recurrence rate in subsequent pregnancies of 18% and a mortality rate of approximately 30% [2].

Although the pathophysiology of immune-mediated AVB is not fully understood, in susceptible fetuses, autoantibodies bind to ribonucleotide proteins (antibodies) expressed in cardiomyocytes of the fetal myocardium, specifically 52 kD Ro/SSA (Ro52), 60 kD Ro/SSA (Ro60), and 48 kD La/SSB (La48). These antibodies enter the fetal circulation in the middle of the 2^nd trimester and trigger an immunological process leading to inflammation of the fetal conduction tissues and myocardium, with progressive and irreversible fibrosis being the most likely explanation [1]. Immune-mediated congenital AVB usually presents with a fetal heart without associated structural heart defects, but functional abnormalities may coexist, including cardiomegaly, ventricular hypertrophy, impaired ventricular function, and atrioventricular valve regurgitation, which may contribute to pericardial effusion, and in severe cases, fetal heart failure and hydrops fetalis [1]. In addition, one study described the presence of ventricular fibroelastosis [2].

Because of the unique aspects of the intrauterine environment, fetal heart failure has peculiar characteristics. Some situations may improve spontaneously or respond to treatment in utero or after delivery; others respond poorly or are refractory to therapy and may progress to heart failure with hydrops, multiple organ failure, and fetal death [7]. Indices for echocardiographic assessment of fetal cardiac function is a proposed system for grading and monitoring the severity of fetal heart failure using five echocardiographic parameters:

1. fetal effusions/hydrops;

2. venous Doppler;

3. cardiac size;

4. cardiac function;

5. arterial Doppler.

Assessment and quantification of heart failure are fundamental steps in counseling and decision making for these at-risk pregnancies, both intrauterine and neonatal [7]. There are various parameters used to assess cardiac function, some of which are easily reproducible and some of which are not, depending on the pathology. One of the parameters used in our case report that is easy to apply was the shortening fraction (∆D%) with normal values > 28% and cardiovascular profile (Hutha score):

1. 8–9 = mild;

2. 6–7 = moderate;

3. ≤ 5 = severe heart failure.

Scores < 7 require intervention [8].

Various treatments have been tried for fetal congenital AVB, but no consistent studies have been achieved. Ciardulli et al. [9] proposed a review to evaluate maternal corticosteroid therapy in preventing progression of immune-mediated 2^nd degree congenital AVB. Progression from 2^nd degree to continuous or intermittent 3^rd degree congenital AVB occurred in 52% of treated fetuses and in 73% of untreated fetuses. The results had limited evidence on the role of corticosteroids in the natural history and it was suggested that this treatment improves myocardial performance and prevents progression to TAVB. The opinion of the authors was that once 2^nd degree immune-mediated AVB is diagnosed, the use of corticosteroids should not be discouraged. The aim is to interfere with the inflammatory process in the fetal conducting tissues and to accelerate lung maturation if there is a risk of preterm birth [9]. In cases with positive anti-Ro/SSA and/or anti-La/SSB antibodies and without an installed congenital AVB, it is recommended to monitor the PR interval weekly, especially between 18 and 26 weeks of gestation. If PR interval is < 150 ms, monitor this interval every 4 weeks until delivery. If PR interval is > 150 ms or its progressive increase, consider using dexamethasone and monitor the interval every 2 weeks [10].

Carrilho et al. [5] demonstrated that there is evidence against the use of corticosteroids in cases of established congenital AVB due to adverse effects on the pregnant woman and the presence of irreversible fibrosis in cardiac conduction tissues of the fetus. A multicenter study in 175 patients demonstrated that in fetuses with ventricular rate < 50 bpm or in the presence of hydrops and/or cardiomegaly, there was no benefit to the use of corticosteroids [11]. Yoshida et al. [12] concluded that maternal treatment with corticosteroids in early pregnancy has been used, but it does not appear to be effective in fetuses with established congenital AVB.

Cases of congenital AVB with fetal ventricular rate > 55 bpm have a good prognosis. Fetal ventricular rate < 55 bpm is associated with cardiac decompensation and low cardiac output. Fetuses with ventricular rate < 50 bpm may develop signs of heart failure and hydrops. Immature fetuses with very early hydrops and ventricular rate < 50 bpm have a poorer prognosis and the only possible intervention is premature delivery and implantation of a temporary pacemaker. The use of salbutamol, terbutaline, or isoprenaline is indicated when the ventricular rate is < 55 bpm and/or in the presence of fetal heart failure and hydrops. These drugs are usually well tolerated, but extrasystoles and maternal sinus tachycardia may occur. There is an increase in fetal heart rate of approximately 10–15% of the baseline rate, and although small, may prolong pregnancy to term or near term. There are no studies showing that the use of these medications can alter the survival of these fetuses. Follow-up and management of these cases is not well established. The indication for timing of delivery should be assessed according to the degree of manifestations [10,12].

Studies also differ regarding sympathomimetic treatment. In one study, oral terbutaline was chosen as the b-sympathomimetic drug because of its good transplacental passage [4]. In another study, terbutaline, which stimulates adrenergic receptors in the heart, increased heart rate, but this increase was transient and not very effective in reducing mortality [13]. Yoshida et al. [12] showed a case of b-sympathomimetic administration in successfully treated isolated congenital AVB. They started intravenous terbutaline in the hope of increasing the fetal heart rate and improving cardiac function, and this drug proved to be effective in preventing heart failure, especially in those fetuses not affected by hydrops or structural heart disease. The only contraindication to b-sympathomimetic therapy with high doses of salbutamol is placental insufficiency [14].

So 46 of the 57 cases of isolated congenital AVT (32 with positive and 14 with negative Ro/SSA and La/SSB antibodies) had no treatment with dexamethasone or b-sympathomimetics. The 32 untreated seropositive fetuses had survival rates of 93% and 90% at 1 year. In 5 fetuses, b-sympathomimetics were started without steroids and then continued intravenously or orally because of ventricular rate of 55 bpm and hydrops, with no survivors. One fetus in 5 received oral terbutaline (2.5 to 5.0 mg over 4 hours). These treatments caused a transient increase in fetal ventricular rate (5 to 20 bpm), with a return to baseline after a short period of time despite the medication (1 to 5 days). Untreated patients did not have such an unfavorable outcome, with live birth and 1-year survival rates similar to those in the treated group. The better outcome is explained by the improvement in intensive care facilities and not by the introduction of dexamethasone into the treatment [15].

Follow-up protocols for isolated congenital AVB show that fetal ventricular rate > 55 bpm with normal cardiac function start with dexamethasone alone. The use of dexamethasone therapy is based on the assumption that the cause is inflammatory carditis. If ventricular rate is < 55 bpm, b-sympathomimetics are added to dexamethasone. Follow-up is weekly or bi-weekly. Delivery should be scheduled at a tertiary center and caesarean section or vaginal delivery is indicated up to 37 weeks of gestation if the course is satisfactory. In the event of progression of fetal hydrops, cesarean section and pacemaker placement is indicated immediately after delivery [16].

Some authors recommend the use of intravenous immunoglobulin in cases where the fetus has systolic cardiac dysfunction and/or signs of endocardial fibroelastosis and/or myocarditis, but its efficacy has not been proven. Other authors recommend immunoglobulin at a dose of 1 g/kg, Max. 70 gram dose, every 3–4 weeks in the presence of endocardial fibroelastosis or incomplete AVB [6]. Hydroxychloroquine is not a reversal agent for antibody-mediated atrioventricular block; however, it may reduce the recurrence rate in future pregnancies by > 50 % [6].

In those hydropic and immature fetuses with a very low ventricular rate, intrauterine pacemaker implantation can be considered, which still has technical limitations and is still under experimental study [10].

Conclusion

Treatment with intravenous terbutaline with the pregnant woman hospitalized and fetal ventricular rate is < 50 bpm offers greater safety in terms of controlling any side effects and better control of the heart rate and vitality of the fetus. Furthermore, even if it is transient, the increase in heart rate for the fetus is very important, with a gain of sometimes another week of gestation and consequently an increase in fetal weight, and finally definitive implantation of the pacemaker is not recommended in very low birth weight premature newborns.