Transient episodes of bradycardia are a common occurrence in the developing foetus and they are usually benign.1 However, sustained foetal bradycardia unrelated to labour is a rare but potentially serious entity. The condition may be due to sinus bradycardia (SB), blocked premature atrial contractions (BPACs), or high degree atrioventricular block (AVB).2 The latest pathology is very important due to its high mortality (17–43%)3–5 and morbidity,3 and to the international controversy surrounding its management.6 In most cases, in the absence of congenital heart disease (CHD), conduction defects are due to the transplacental passage of maternal antibodies that attack the conductive tissue with subsequent fibrosis,7 while in a smaller number of foetuses no cause is found for the block (non-immune or “idiopathic” AVB). In immune-mediated cases, the involved antibodies (anti-Ro/SSA) are necessary but not sufficient to cause disease,8 which affects only 1–2% of children of mothers with these antibodies (the risk is tenfold if the mother has a previous child with the condition).4 In addition to damaging the conductive tissue antibodies can cause diffuse cardiac damage in the form of endocardial fibroelastosis and dilated cardiomyopathy,9 which result in considerably worse outcomes. Different treatment approaches have been used in immune-mediated AVB, including fluorinated steroids, beta-agonists, and plasmapheresis, aiming to prevent myocardial inflammation, increase the foetal heart rate, and reverse heart failure,10–13 but their efficacy is controversial.6,14,15 The lack of consensus on the best strategy to manage these patients accounts for the heterogeneous, even divergent therapeutic approaches of different hospitals.15 This study describes the diagnosis and clinical approach to the management of foetal bradycardia in 9 Spanish hospitals, and aims for starting point for a future prospective multicentre study with a broader, nationwide scope.

In 2008, the Foetal Cardiology group of the Sociedad Española de Cardiología Pediátrica y Cardiopatías Congénitas (Spanish Society of Paediatric Cardiology and Congenital Cardiopathies [SECPCC]) decided to conduct a retrospective study to describe the diagnosis, current management, and outcome of foetal bradycardias.

We conducted a retrospective, descriptive, cross-sectional, multicentre study to analyse the characteristics, treatment, and outcome of all foetuses diagnosed with bradycardia in 9 Spanish hospitals from January 2008 to September 2010 (20 months). To evaluate heart rhythm and the haemodynamic effects of bradycardia, we used M-mode echocardiography, pulsed wave Doppler, and tissue Doppler imaging of mitral inflow/aortic outflow, pulmonary vein/pulmonary artery, or superior vena cava/ascending aorta. Foetal bradycardia was defined as a sustained heart rate below 110beats per minute.16 It was defined as sinus bradycardia when the ratio of atrial to ventricular contractions was 1:1 (A:V=1:1) (Fig. 1), compared to bradycardia due to blocked premature atrial contractions (Fig. 2) with a bigeminal pattern, or to high-degree AVB (Fig. 3), in which the frequency of atrial contractions is greater than that of ventricular contractions (A:V>1). Blocked atrial bigeminy was defined as BPACs with an A:V ratio of 2:1 and varying time intervals between every 2 atrial contractions: one shorter than the interval characteristic of normal sinus beats, and one longer. The strategy, followed by participating centres in pregnant women who had anti-Ro and anti-La antibodies and whose foetuses were at high risk of developing AVB, was to perform an echocardiogram weekly from week 16 to week 28 to analyse the interval of time between atrial and ventricular contractions and detect any prolongation of this interval (suspected first-degree AVB).17 After week 28 through the end of the pregnancy, controls were performed every 4 weeks. Second-degree AVB was defined as having a constant interval between atrial contractions, conducted or not conducted to the ventricles intermittently or with a fixed A:V ratio (example 2:1 or greater). Third-degree AVB was defined as the complete dissociation of atrial and ventricular contractions, with constant intervals between atrial contractions. We recorded information on the diagnosis and therapeutic approach for each case: watchful waiting, intrauterine treatment, or delivery. The primary outcomes were the survival of the foetus and the efficacy of the treatment given (assessing reduction of the degree of AVB or haemodynamic improvement). We collected data on the antibody status of the mother, the association with structural cardiopathies, and the detection of signs of hydrops or ventricular dysfunction (VD). We documented the outcomes of the foetuses and the need for pacemakers in postnatal life. In the statistical analysis, we used Student's t test to compare means, and Fisher's exact test to analyse categorical variables. The level of statistical significance was set at P<.05.

Figure 1.

Simultaneous Doppler recording of superior vena cava and aorta: sinus bradycardia in which each ventricular contraction (V: antegrade aortic flow) is preceded by retrograde flow in the superior vena cava caused by the atrial contraction (A).

(0.09MB).

Figure 2.

Simultaneous Doppler recording of superior vena cava and aorta: blocked premature atrial contractions (A′). It can be observed that A′ happen prematurely compared to atrial contractions during normal sinus rhythm (A) and are not followed by a ventricular contraction (V).

(0.09MB).

Figure 3.

Simultaneous Doppler recording of superior vena cava and aorta: third degree atrioventricular block in which atrial contractions (A) and ventricular contractions (V) are independent.

(0.11MB).

A total of 37 patients were included: 15 foetuses with bradycardia due to BPACs, 3 with SB, and 19 with high-degree AVB.

Sustained foetal bradycardia always requires exhaustive investigation. If the bradycardia is caused by BPACs, the prognosis is good and it usually resolves spontaneously.18 Our series corroborated that foetuses with BPACs may develop sustained supraventricular tachycardia before or after birth, a complication that has been described in up to 13% cases in the literature.19 When it came to sinus bradycardia, which is commonly associated to sinus node dysfunction and a favourable prognosis,20 our series demonstrated that it can be associated to severe pathologies and a poor outcome. This finding is consistent with other studies that have shown an association of SB with intrauterine hypoxia and severe diseases, such as long QT syndrome21,22 and noncompaction cardiomyopathy.23 We want to highlight that anti-Ro and anti-La antibodies were found in a foetus diagnosed prenatally with SB and with sick sinus syndrome after birth, which shows that the range of diseases associated to those antibodies is quite broad.24

Our results corroborated that high-degree AVB is the most frequent cause of sustained foetal bradycardia in utero.2 For the purposes of analysis, this group of foetuses can be divided into 3 subsets according to aetiology: AVB secondary to cardiac malformation, AVB mediated by circulating maternal antibodies, and idiopathic AVB. Our case series confirms that the subset with AVB due to CHD has a very poor prognosis,25,26 and that the diagnosis of complete AVB is made earlier in association with this aetiology than with others (mean of 18 vs 23.8 WGA). In fact, first-trimester foetal bradycardia is considered a possible marker of left isomerism.27

Mortality in the idiopathic AVB subset of our study was 33%. Although prior research has shown that this subset has better outcomes,28 other studies have not confirmed this finding,14,15 and the number of cases in our study is too small to reach a reliable conclusion.

When it came to immune-mediated AVB, our case series was consistent with the time of prenatal diagnosis between 18 and 24 WGA described in the literature.3,4 We also found that mortality was considerable, even if it was lower than in cases associated with CHD. The predictors for poor outcome found in our series were consistent with those described in the literature: hydrops and VD at the time of diagnosis.3–5,15 When we analysed mortality in relation to a heart rate lower than 50–55 beats per minute, another predictor of poor outcome reported in previous case series,5,15 we found that a greater proportion of foetuses in our study died when the ventricular rate was lower than 55 beats per minute. This difference was not statistically significant, probably due to the sample size. Morbidity in cases of AVB diagnosed before birth was also high.3 Most of these patients required a pacemaker in the first 18 months of life, and one of them, who had VD, needed a heart transplant. The therapeutic approach of Spanish hospitals was heterogeneous as it concerned treatment of AVB with steroids, reflecting the current controversy that surrounds the subject. From a pathophysiological standpoint, steroids are administered in immune-mediated AVB to revert or diminish the inflammation that is part of the process leading to fibrosis of the conduction system.29 Many research groups have suggested courses of dexamethasone or betamethasone (fluorinated steroids that are not metabolised in the placenta), but their use is currently under debate.14,15 On one hand there is no strong evidence on the efficacy of this treatment, and a recent European retrospective multicentre study did not find statistically significant differences in foetal or neonatal mortality between treated and untreated foetuses.15 As for third-degree AVB, our series confirms that once the block is complete it is irreversible, a fact that is unquestioned in the scientific community.3,29 There are authors who suggest that the efficacy of steroids in reducing mortality can be demonstrated, particularly in cases with VD and hydrops.3,30,31 Our results did not support this approach. While 2 out of 5 foetuses that met this description showed signs of improvement, the latter was temporary and 1 of the foetuses died in utero. Treatment with steroids in foetuses with incomplete AVB is meant to prevent disease progression,29 and the efficacy of treatment in this set of patients is also subject to debate. It is not known whether first-degree AVB is the precursor of higher degrees of AVB, in which case treating it may be beneficial,32 or whether it results from physiological variations in vagal tone, in which case it would tend to revert spontaneously.33 Our series did not include any cases of suspected first-degree AVB with observation of prolonged atrioventricular conduction, and while there is no consensus on the management of these patients, we believe that steroid therapy should be offered, properly informing the parents about its risks and benefits, as this is the clinical presentation in which steroids are most likely to succeed. Cases of second-degree AVB that have regressed with steroid treatment have been reported,15,34 although frequently the regression was temporary and there was subsequent progression to third degree,15,34,35 as seen in the only case of second-degree AVB in our series; therefore, it is not clear that treatment is beneficial in these patients.14 While the therapeutic efficacy of steroids is still to be demonstrated, their prolonged use has been associated to serious adverse effects,15,36–38 such as intrauterine growth restriction, oligohydramnios (diagnosed in 10% of foetuses treated with steroids in our series), adrenal failure, and abnormal brain development in foetuses; and hypertension and gestational diabetes in pregnant women. In short, our data confirm that despite multiple international studies performed to this day, many doubts remain regarding the potential benefits of steroids in immune-mediated AVB,6,15 and consequently steroids should be used with extreme caution, especially considering their potential side effects.

There are limitations to this study. Although it was a multicentre study, this pathology is rare and the number of documented cases is small. Secondly, we were unable to analyse the relationship between the development of immune-mediated AVB and the amount of circulating antibodies, when previous case series found an association between the risk of foetal arrhythmias and higher levels of circulating antibodies.39 Thirdly, the postnatal follow-up was of short duration. Finally, since the study did not include all the foetal cardiology and prenatal diagnosis facilities in Spain, the results may not be fully representative of how foetal bradycardia is managed in Spain.

Sustained foetal bradycardia always requires an exhaustive investigation, even in cases of sinus bradycardia. Bradycardia due to BPACs usually has a good prognosis, although there is a risk for tachyarrhythmias. Morbidity and mortality are considerable in high-degree AVB diagnosed in utero, especially in cases associated with CHD. Prenatal treatment of immune-mediated AVB remains controversial. Improved knowledge of the natural history of this disease could help develop new, more specific therapeutic strategies40 and select the foetuses that may benefit from them.

The authors have no conflicts of interest to declare.