Effects of maternal anti-Ro/La antibodies on fetal atrioventricular conduction evaluated with echocardiography: a state-of-the-art review

Abstract

Anti-Ro/SSA and La/SSB antibodies can cross the placenta, affecting fetal cardiac development and leading to congenital heart block (CHB), a condition characterized by rapid progression, high mortality, and poor prognosis, emphasizing the importance of timely diagnosis and treatment. Fetal echocardiography is a critical diagnostic tool for CHB. With advancements in medicine and shifting health perspectives, the incidence, diagnostic approaches, and treatment methods for CHB are evolving. This review examines the impact of maternal antibodies on offspring, including their pathogenic mechanisms and other influencing factors such as antibody levels and maternal conditions. It also evaluates the application of fetal echocardiography in diagnosing CHB, covering techniques like M-mode, tissue Doppler, and spectral Doppler, and investigates antibody-associated CHB incidence. In addition, the review discusses management strategies for anti-Ro/SSA and anti-La/SSB positive pregnancies, including fetal in-utero treatment, preventive therapy for mothers, and other pharmacologic interventions. The findings highlight that antibody-related CHB is multifactorial, necessitating comprehensive consideration of influencing factors, prenatal counseling, and preventive medication management.

Introduction

When the fetus is exposed to maternal anti-Ro/SSA and anti-La/SSB antibodies, the risk of developing congenital heart block (CHB) is significantly increased [1]. CHB is primarily characterized by atrioventricular block (AVB), which can be classified according to its severity into three categories: first-degree, second-degree, and third-degree, also known as complete atrioventricular block. Notably, at the time of initial diagnosis, the majority of affected children already present with complete atrioventricular block, a condition associated with a poor prognosis. Ten% to 29% of fetuses experience intrauterine death, and 63% to 93% require the implantation of a permanent pacemaker after birth [2]. CHB associated with maternal autoantibodies is referred to as autoantibody-associated CHB [2], with some patients concurrently developing dilated cardiomyopathy and endocardial fibroelastosis [3]. The prognosis for these conditions is generally unfavorable, with a low overall survival rate. Importantly, studies have found that autoantibody-associated CHB does not necessarily correlate with the severity of the atrioventricular block. Therefore, when a fetus presents with low-grade AVB, timely diagnosis and intervention are critical to prevent irreversible cardiac damage. This article reviews the impact of maternal antibodies on the fetus, the progress in the diagnosis of CHB using fetal echocardiography, and current approaches to the treatment of CHB.

The impact of maternal antibodies on their offspring

Maternal anti-Ro/SSA and anti-La/SSB antibodies can traverse fetal blood circulation through the placenta and impair the fetal cardiac conduction system. These antibodies are commonly found in conditions such as Sjögren’s syndrome, systemic lupus erythematosus, rheumatoid arthritis, and undifferentiated autoimmune diseases. Extensive studies have demonstrated that the development of neonatal lupus is influenced by the transmission of maternal antibodies through the placenta and additional factors, such as fetal genetics and environmental factors [4].

Pathogenic mechanism

Existing immunohistochemical data demonstrate that permanent electrical disturbances are ultimately attributable to fibrosis and calcification, while the final pathway leading to fibrosis may be variable [5]. With regard to the molecular mechanisms of CHB, two predominant theories have been proposed: the “Apoptosis Hypothesis” (Fig. 1) and the “Calcium Channel Hypothesis” (Fig. 2), as supported by evidence from multiple studies [6–8].

Fig. 1.

Molecular mechanisms of congenital heart block (CHB)—The Apoptosis Hypothesis. (1) Apoptosis triggers translocation of intracellular Ro/SSA antigens to fetal cardiomyocyte surface membranes. (2) Impaired phagocytic clearance (→ immune complex disruption of normal apoptotic debris removal) and apoptotic cell accumulation. (3) Macrophage recruitment & activation (→ TNF-α/TGF-β cytokine release). (4) TGF-β-mediated fibroblast-to-myofibroblast differentiation. (5) Progressive fibrotic scar formation. TNF-α tumor necrosis factor-alpha, TGF-β transforming growth factor-beta. The figure was drawn by figdraw.com

Fig. 2.

Molecular mechanisms of congenital heart block (CHB) -The Calcium Channel Hypothesis. (1) Short-term effects: anti-Ro/SSA antibodies directly inhibit L-type and T-type calcium channels, reducing calcium currents in sinoatrial and atrioventricular nodes, leading to impaired impulse conduction. (2) Long-term effects: prolonged antibody exposure induces calcium channel internalization. (3) Pathologic consequences: calcium dysregulation triggers cardiomyocyte apoptosis, followed by inflammatory responses and fibrotic remodeling. The figure was drawn by figdraw.com

Other influencing factors

Antibodies levels

Increasing evidence demonstrates that the risk of cardiac neonatal lupus is associated with higher antibody titers, although the relationship is not strictly linear [9]. In a prospective study involving 186 fetuses and neonates with antibodies exposure, Jaeggi et al. demonstrated a dose-dependent relationship between maternal anti-Ro antibody presence and fetal tissue damage. The cutoff value determined by ELISA was 50 U/ml. They recommend that continuous echocardiographic monitoring should be reserved for women with elevated antibody titers [10]. Another study by Kan et al. involving 232 pregnancies with anti-Ro antibody ( +), demonstrated that restricting continuous fetal echocardiography to women with high levels of anti-Ro antibodies represents a safer and more cost-effective approach [11]. Buyon et al. [12] investigated 413 antibody-positive pregnancies, categorizing them into high-titer and low-titer groups. Through daily fetal heart rhythm monitoring and weekly/biweekly fetal echocardiography, they detected AVB in this population. No cases of AVB were detected in the low-titer group, whereas the incidence in the high-titer group was 3.8%. Within the high-titer group, the incidence was 7.7% among women with titers in the top 25%, and as high as 27.3% among those with a history of AVB in previous pregnancies.

Maternal status

Pregnant women with a history of delivering a child with CHB exhibit a recurrence rate of only 10%–20%, despite the persistent presence of maternal antibodies. This implies that additional factors play a critical role in the establishment of cardiac conduction block. Ambrosi et al. investigated the potential influence of fetal sex, maternal age, parity, and time of birth on the development of cardiac conduction block in 145 families with Ro/La positive (n = 190) and Ro/La negative (n = 165) maternal antibodies. Their analysis revealed that maternal age and the season of pregnancy were risk factors [13]. Skog et al. suggested that increased maternal age or parity may contribute to an elevated risk of cardiac conduction block [14]. Emerging evidence suggests a potential association between thyroid function and autoantibody-associated CHB. In a study conducted by Spence et al., the likelihood of fetal development of complete atrioventricular block in pregnant women with positive autoantibodies and concurrent hypothyroidism was found to be nine times higher than in those with positive autoantibodies but normal thyroid function [15]. Therefore, for pregnant women with positive autoantibodies, monitoring thyroid function during pregnancy and timely addressing abnormalities in those affected may help reduce the incidence of CHB. These findings may also provide valuable insights for prenatal counseling and decision-making during pregnancy. In addition, Killen et al. observed that cardiac involvement may occur in only one of the twins exposed to maternal antibodies, highlighting the significant role of intrauterine factors in the pathogenesis of CHB [16].

The application of fetal echocardiography in diagnosing CHB

With advancements in technology, fetal electrocardiography, fetal magnetocardiography, and home monitoring for fetal heart rhythm [17] are being used to detect AVB. Fetal echocardiography is recommended by clinical guidelines for identifying cardiac injuries in such fetuses (Table 1) and is currently regarded as the most commonly employed and effective screening method available [18–20]. Guidelines suggest initiating routine fetal echocardiography starting from 16 weeks of gestation, conducted at intervals of every 1–2 weeks. However, some scholars argue that frequent examinations can impose substantial psychologic and financial burdens on pregnant women [21]. Kaizer et al. [22] have suggested that risk stratification based on antibody titers may diminish the necessity for costly and time-consuming fetal echocardiography examinations. However, Tingstrom et al. [23] distributed a questionnaire to 100 pregnant women with positive antibodies who required examination and found that, beyond its medical benefits, fetal echocardiography monitoring yields numerous positive effects.

Table 1.

Recommendations for ultrasound examinations in clinical guidelines

Guidelines	District	Recommendations
Interpretation on the 2022 Chinese Guideline for the Management of Pregnancy and Reproduction in Patients with Systemic Lupus Erythematous [19]	China	Recommend routine fetal echocardiography starting from 16 weeks of pregnancy, conducted every two weeks until 26–28 weeks. Emphasize the use of spectral Doppler to measure the atrioventricular conduction time (the AV interval) (1) AV Interval ≥ 140 ms: suggests potential cardiac conduction abnormalities. Consideration for intervention or close monitoring may be warranted, with follow-up intervals reduced to weekly echocardiography examinations (2) AV interval is ≥ 150 ms: it can be diagnosed as first-degree atrioventricular block, which requires active treatment to prevent progression to third-degree atrioventricular block. In addition, echocardiography can also evaluate fetal cardiac chamber size, ventricular function, and valvular function
Diagnosis and Treatment of Fetal Cardiac Disease: A Scientific Statement From the American Heart Association [18]	United States	It is recommended that women positive for anti-SSA/SSB antibodies begin fetal echocardiography monitoring early in pregnancy (16–18 weeks). The mechanical PR interval can be used to measure the atrioventricular conduction time (1) It is reasonable to conduct serial assessments every 1–2 weeks from 16 weeks of pregnancy until 28 weeks, as the potential benefits outweigh the risks (2) For women who have previously had children with the condition, it is recommended to conduct serial assessments more frequently, at least once a week
EULAR recommendations for women’s health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome [20]	Europe	(1) The guidelines specifically mention that fetal ultrasound examinations should be conducted, particularly in cases where the mother tests positive for anti-SSA or anti-SSB antibodies (2) For women who have previously given birth to infants with CHB, the recurrence rate reaches 16% when they become pregnant again. Therefore, it is recommended that they undergo continuous weekly fetal echocardiography examinations starting from the 16th week of pregnancy

CHB congenital heart block

Ultrasound diagnosis of atrioventricular block

Fetal echocardiography incorporates various imaging techniques, including M-mode, two-dimensional imaging, pulsed-wave Doppler, and tissue Doppler, which facilitate the evaluation of arrhythmias by observing cardiac mechanical activity and the movement of intracardiac and peripheral blood flow. This establishes it as the most frequently utilized examination method currently available [24]. Second-degree and third-degree atrioventricular blocks, characterized by the separation of atrial and ventricular mechanical activities and a reduction in ventricular rate, can be more readily diagnosed via fetal echocardiography. For first-degree atrioventricular block, fetal echocardiography can measure the atrioventricular conduction time (AVCT), also known as the mechanical PR interval (mPR), through cardiac mechanical activities or hemodynamic measurements, indirectly reflecting atrioventricular conduction. The measurement method is illustrated in Fig. 3. First-degree atrioventricular block often presents with a normal heart rate but an extended mPR, and a mPR greater than 0.15 s is considered a warning signal. Sonesson [25] has provided a comprehensive elaboration of the ultrasound manifestations and diagnostic criteria for varying degrees of atrioventricular block.

Fig. 3.

Measurement of the mechanical PR interval by pulsed-wave Doppler. A Sample volume (SV) of the pulsed-wave Doppler is placed in the left ventricular outflow tract (LVOT) over the aortic valve and mitral valve in five-chamber view to simultaneously record the Doppler blood flow spectrum in the left ventricular inflow and outflow tracts. B Display on the same Doppler spectrum of diastolic blood flow through the mitral valve and systolic blood flow through the LVOT. Mechanical PR interval was measured from the intersection of the atrial contraction wave (A) and early diastolic wave (E) to the onset of systolic left ventricular outflow tract wave (S). RA right atrium, LA left atrium, RV right ventricle, LV left ventricle

M-mode

M-mode represents the earliest echocardiography technique utilized for the evaluation of arrhythmias [18]. The fundamental principle of M-mode involves scanning and analyzing atrioventricular wall movements and valvular activity curves under two-dimensional guidance to assess arrhythmias. A conventional approach involves positioning the sampling line through the atria and ventricles in the four-chamber heart view, while simultaneously recording the movements of the atrial wall and the ventricular free wall [26]. Within the context of second-degree and third-degree atrioventricular blocks, M-mode tracing can visually display the separation of atrial and ventricular activities and measure atrial and ventricular rates. A clear M-mode tracing can accurately diagnose third-degree atrioventricular block; however it poses significant diagnostic challenges for Type II second-degree atrioventricular block [25].

As first-degree atrioventricular block is distinguished by an elongation of the PR interval, Fouron et al. [27] have employed M-mode echocardiography to measure the mPR for evaluating first-degree atrioventricular block. Due to the difficulty in determining the exact starting point of contraction in M-mode tracings, the measured value does not strictly align with the defined mPR. In addition, M-mode echocardiography faces challenges in differentiating between first-degree and Type I second-degree atrioventricular blocks [28]. Due to fetal positioning, it can sometimes be difficult for the sampling line to simultaneously pass through the atrioventricular and valvular structures. As congenital heart conduction block can manifest as early as 18 weeks of gestation or earlier, the small gestational age at this stage often makes it challenging to obtain a clear M-mode tracing.

Pulsed-wave Doppler

Compared to M-mode, pulsed-wave Doppler offers distinct advantages in the evaluation of arrhythmias [29]. Specifically, pulsed-wave Doppler is more readily available than M-mode, provides faster diagnostic speeds, and offers superior inter-group reproducibility [27]. By observing the blood flow spectrum, it is possible to monitor cardiac rhythm, measure atrial and ventricular rates, and mPR. There are mainly two methods to acquire the pulsed-wave Doppler spectrum for assessing atrioventricular blocks: (1) Mitral-aortic spectrum: in the four-chamber view, the sample volume is positioned between the left ventricular inflow and outflow tracts. This simultaneously records the blood flow in the left ventricular inflow and outflow tracts. On the same Doppler spectrum, this setup can display the diastolic blood flow spectrum of the mitral valve in the left ventricular inflow tract, along with the systolic blood flow spectrum in the left ventricular outflow tract (E, A), and the aortic ejection wave S. The interval from the junction of the E and A peaks to the onset of the aortic ejection wave S is measured, referred to as the mitral-aortic interval. (2) Superior vena cava-aorta spectrum: in the two-dimensional view, both the aorta and the superior vena cava are displayed. By adjusting the sample volume, the blood flow in the aorta and superior vena cava can be simultaneously collected. This method records the α wave of the superior vena cava during atrial contraction and the aortic ejection wave [29]. The interval from the start of the α wave to the start of the aortic ejection wave is measured, termed the superior vena cava-aorta interval. The mPR obtained by the above two methods exhibits distinct characteristics. The mitral-aortic interval is dependent on heart rate. When the fetal heart rate is high, the E and A peaks may partially overlap. At heart rates between 160 and 170 bpm, the E and A peaks largely overlap, making the mPR difficult to measure accurately [27]. Therefore, when the heart rate is too fast and the PR interval is prolonged, the mPR might still fall within the normal range. Conversely, the superior vena cava-aorta interval is not influenced by heart rate but requires more stringent fetal positioning.

For diagnosing first-degree atrioventricular block, pulsed Doppler has distinct advantages compared to M-mode [29]. However, for diagnosing second-degree and third-degree atrioventricular blocks, the mitral-aortic method sometimes encounters challenges due to the presence of the E peak interfering with the assessment of the relationship between the A peak and the aortic ejection wave, making it challenging to diagnose and differentiate second-degree from third-degree blocks. Although the superior vena cava-aorta method avoids this limitation, it is less readily obtainable than the mitral-aortic method [25].

Tissue Doppler

Tissue Doppler imaging is primarily utilized for the diagnosis of first-degree atrioventricular block in the context of CHB associated with autoantibodies. In the four-chamber view, the sampling volume is positioned in the right ventricle, left ventricular free wall, or basal segment of the interventricular septum to record myocardial motion, with two indicators reflecting mechanical PR interval (mPR): (1) a’-IV interval refers to the time interval from the junction of the atrial contraction wave and early diastolic wave to the onset of the isovolumetric contraction wave, (2) the a'-s' interval extends from the same junction to the onset of the ventricular ejection wave. Both the a'-IV and a'-s' intervals can serve as mechanical PR intervals. The measurement method is illustrated in Fig. 4. Research [30] indicates that, when compared to the PR interval obtained through electrocardiography, the a'-s' interval is, on average, 32.8 ± 17.2 ms longer, while the a'-IV interval is shorter by 8.0 ± 13.9 ms. Consequently, the a'-IV interval is superior to the a'-s' interval for the early diagnosis. In addition, the study found that the mechanical PR interval measured from the blood flow spectrum in the left ventricular inflow and outflow tracts, as illustrated in Fig. 3, is longer than the PR interval from electrocardiography by 18.7 ± 14.8 ms. Nii et al. [30] prospectively compared the fetal AV intervals measured by tissue Doppler imaging, MV-Ao, and SVC-Ao, and juxtaposed these with fetal electrocardiography, which served as the “gold standard”. In this extensive study involving 131 pregnant women, featuring 196 fetal echocardiograms and 158 fetal electrocardiograms, the time intervals obtained through tissue Doppler imaging demonstrated a stronger correlation with the PR intervals observed in fetal electrocardiograms compared to other Doppler techniques.

Fig. 4.

Measurement of fetal atrioventricular time intervals by tissue Doppler. A Sample volume of the tissue Doppler imaging is placed in the basal segment of the right ventricular free wall in the four-chamber view. B The tissue Doppler spectrum displayed four distinct waveforms: early diastolic filling (e’) and atrial contraction (a’), followed by isovolumic contraction (IV) and ventricular systole (s’). a’-IV was measured as time interval between a’ onset and IV onset, a’-s’ was measured as time interval between a’ onset and s’ onset. Both a’-IV and a’-s’ intervals can be used as mechanical PR interval. RA right atrium, LA left atrium, RV right ventricle, LV left ventricle

In addition to the aforementioned methods, Rein et al. [31] developed a more complex method to analyze AVB. In the four-chamber view, tissue Doppler spectra are simultaneously collected from the posterior superior walls of the left and right atria and the basal segments of the left and right ventricular free walls. This allows for the determination of the contraction initiation times for both the left and right atria and ventricles for each cardiac cycle. A fetal kinetocardiogram (FKG) was then generated. The fetal kinetocardiogram visually displays the contraction initiation times of the right atrium, left atrium, left ventricle, and right ventricle across multiple consecutive cardiac cycles. Based on the fetal kinetocardiogram, it is possible to observe cardiac rhythm, measure AVCT, and assess fetal heart rate, with good repeatability and high accuracy. It can be used for the diagnosis of various arrhythmias. Subsequent research conducted in pregnant women with positive autoantibodies further confirmed that fetal kinetocardiograms can accurately diagnose first-degree atrioventricular block.

In addition to this, when measuring the mPR, it is also necessary to consider the fetal heart rate and gestational age. This is based on findings that the mPR exhibits a negative correlation with fetal heart rate and a positive correlation with gestational age [32]. They believe that the larger the ventricular size, the longer the time required for myocardial depolarization/repolarization. However, as the heart develops, the functions of the sinoatrial node, atrioventricular node, and bundle of His undergo development. Whether the changes in atrioventricular size alone can fully explain the variations in AVCT requires further research and validation. The negative correlation between mPR and fetal heart rate seems theoretically reasonable: a higher fetal heart rate leads to a shorter cardiac cycle, and consequently, the PR interval, which constitutes part of the cardiac cycle, becomes shorter. However, some studies hold a different perspective: the mPR remains independent of gestational age and fetal heart rate [28, 33].

Study on the incidence of autoantibody-associated congenital heart block

Brucato et al. [34], through echocardiographic observing the separation of atrial and ventricular movements in fetal hearts, identified 2 cases of congenital complete atrioventricular block (2%) among100 anti-Ro/SSA antibody-positive pregnant women. With advancement in diagnostic technologies, Sonesson et al. [35] conducted the first prospective study utilizing the mechanical PR interval to identify such conditions. Among the 24 antibody-positive pregnant women included in the study, 8 exhibited prolonged AVCT (33%). This differs from the incidence observed later by Friedman et al., who found 3 cases of first-degree atrioventricular block and 3 cases of complete atrioventricular block among 98 pregnant women (6%). The primary explanation for this discrepancy lies in the differing cutoff values employed for defining the mPR in the two studies [36]. In the study conducted by Rein et al. [31], the incidence of first-degree atrioventricular block was determined to be 9%. Subsequently, two scholars have further investigated this topic, as shown in Table 2.

Table 2.

Fetal echocardiography diagnosis of autoantibody-associated congenital heart block

	Brucato [34]	Friedman [36]	Rein [31]	Bergman [56]	Yani [57]
Participants (incidence)	100 (2%)	98 (6%)	70 (9%)	95 (29%)	22 (18%)
Diagnostic method	Fetal echocardiography	Spectral Doppler (mitral-aortic)	Tissue Doppler	Spectral Doppler	Spectral Doppler
Diagnostic criteria	Separation of atrial and ventricular movements	> 150 ms (three standard deviations)	≥ 2 standard deviations	≥ 95% confidence interval	–
Incidence status	2 cases of complete AVB (2%)	3 cases of first-degree AVB (3%) → A–C 3 cases of complete AVB (3%) → D–F	6 cases of first-degree AVB (9%)	24 cases of first-degree AVB (25%) 2 cases of second-degree AVB (2%) → A/B 2 cases of third-degree AVB (2%) → C/D	2 cases of second-degree AVB (9%) → A/B 2 cases of third-degree AVB (9%) → C/D
Detection time	A → 22W B → 20W	A → 22W B → 20W C → missed diagnosis D → 23W E → 21W F → 19W	3 cases → 21–26W 2 cases → 32–33W 1 case → 34W	24 cases < 24W	A → 27W B → 24W C → 29W D → 25W
Treatment	Dexamethasone 4 mg/d	Dexamethasone 4 mg/d	Dexamethasone 4 mg/d	?	A → dexamethasone 4 mg/d B → dexamethasone + hydroxychloroquine C/D → no intervention
Outcome	A → implantation of a pacemaker (8 months) B → implantation of a pacemaker (3 years)	A–C → normal D → 24W pregnancy terminated E → pacemaker implanted at birth F → 20.5W pregnancy terminated	6 cases → normal	24 cases → normal A/B → normal C/D → third-degree AVB	A → no improvement after treatment, pregnancy terminated B → second-degree AVB diagnosed two months after cesarean section C/D → pregnancy terminated

AVB atrioventricular block; A–F cases in the study; W weeks

When including cases of first-degree atrioventricular block, the incidence of autoantibody-associated CHB spans a range of approximately 2% to 29%. As previously mentioned, the incidence is influenced by the interaction of maternal antibodies transmitted through the placenta and additional factors, including antibody titers, the health and treatment status of the pregnant woman, age, as well as history of CHB pregnancy and pregnancy-related complications. Therefore, a comprehensive assessment of these factors is necessary when evaluating the risk of autoantibody-associated CHB.

Management of pregnancies with positive anti-Ro/SSA and anti-La/SSB antibodies

Intrauterine treatment of the fetus

Fluorinated corticosteroids, such as dexamethasone, are considered potential therapeutic options for CHB due to their minimal metabolism in the placenta. Nevertheless, research on their efficacy has yielded inconsistent results. One study indicated that fluorinated corticosteroids do not demonstrate superior efficacy compared to other treatments in improving survival rates among CHB patients and may result in adverse effects, suggesting that their clinical application requires cautious consideration [37]. In addition, another study found that although dexamethasone can temporarily restore atrioventricular conduction in certain fetuses, this effect is not lasting, and in certain cases, a pacemaker may need to be implanted [38]. Mawad et al. [39] reviewed 130 consecutive cases, including 108 cases of third-degree atrioventricular block, and ultimately concluded that fetuses receiving dexamethasone ± other treatments following CHB diagnosis exhibited a lower risk of perinatal mortality and postnatal cardiomyopathy. In summary, while fluorinated corticosteroids may exhibit therapeutic effects in certain cases of CHB, their efficacy and safety necessitate further research and validation. In clinical practice, individual assessment and management based on specific cases are recommended [40].

Previous reports have demonstrated that initiating treatment with fluorinated corticosteroids, either alone or in combination with intravenous immunoglobulin (IVIG), within 12 h after detecting second-degree atrioventricular block, can prevent progression to third-degree atrioventricular block or restore normal sinus rhythm [41]. Furthermore, intravenous immunoglobulin (IVIG) therapy has demonstrated efficacy in newborn populations. In specific instances, administration of IVIG has facilitated reversion to a normal sinus rhythm in fetuses with second-degree atrioventricular block, with no evidence of relapse following treatment discontinuation [42]. The successful implementation of this treatment strategy highlights the importance of early diagnosis and timely intervention to prevent the progression to irreversible third-degree atrioventricular block. Studies suggest that a treatment regimen combining intravenous immunoglobulin, plasmapheresis, and corticosteroids can improve the prognosis for fetuses and newborns with second-degree and third-degree atrioventricular block [43].

Several peptide-based therapies are currently under investigation. These therapies aim to reduce antibody binding to cellular targets (calcium channels), thereby mitigating damage. Peptide-based treatments represent one of the emerging therapeutic approaches and this treatment pathway requires further development and advancement [44]. In addition, β-agonists are utilized to increase fetal heart rate, although their efficacy and impact on mortality remain under investigation [40].

Preventive treatment for pregnant women

Hydroxychloroquine (HCQ), initially developed as an antimalarial drug, is now also employed in the treatment of autoimmune diseases. Given its minimal risks to both the fetus and the mother, HCQ is frequently continued during pregnancy. Faehat et al. [45] have confirmed the safety of HCQ during pregnancy. Multiple retrospective studies have indicated that HCQ can reduce the risk of neonatal lupus, including its cardiac manifestations [46]. Research has indicated that preventive treatment with HCQ can decrease the recurrence rate of CHB in subsequent pregnancies by approximately 50% [47]. Kaizer et al. [22] observed no significant difference in antibody titers between pregnant women in the HCQ treatment group and the non-treatment group, confirming that HCQ use does not affect antibody levels. Instead, HCQ works by inhibiting downstream Toll-like receptor signaling, thereby reducing the pathologic effects of the antibodies.

Prednisone works by suppressing overactive immune responses, which is essential for managing autoimmune disease activity. Research has shown that prednisone can partially reverse the activated state of immune cells, regulate gene expression, and intercellular communication, thereby restoring balance to the immune system to some extent [48]. In pregnant women, maintaining disease stability is crucial for reducing pregnancy complications and improving pregnancy outcomes. Prednisone is relatively safe when used at low doses [49]. Shinohara et al. [50] suggest that proactively administering prednisone to the mother in early pregnancy (before 16 weeks of gestation) may reduce the risk of offspring developing antibody-mediated CHB, though it cannot treat or reverse it. Subsequent studies have found that antibody-positive pregnant women, who use HCQ or low-dose prednisone daily throughout pregnancy, can provide protective benefits to the fetus [51]. However, there are arguments against the prophylactic use of prednisone for several reasons: prednisone cannot cross the placenta; the incidence of CHB is relatively low; and there may be potential risks to both the fetus and the mother [52].

Other medicinal treatments

Apart from asymptomatic antibody carriers, most antibody-positive pregnant women have systemic autoimmune diseases. Before pregnancy, to alleviate their conditions, they may have already received treatments such as immunosuppressive therapy, anti-inflammatory treatment, and prophylactic antithrombotic therapy. Fredi et al. found that among pregnant women with autoimmune diseases who are antibody-positive, the incidence of CHB in their offspring is only 0.3%. This low incidence is speculated to be possibly related to the long-term immune modulation and/or immunosuppressive treatments that these women received [53]. Tian Huagu et al. observed 101 pregnant women with systemic autoimmune diseases in stable phase, who regularly attended prenatal check-ups and delivered at their institution. The results found no cardiac abnormalities [54]. It can be speculated that for patients with diagnosed autoimmune diseases, long-term immune modulation or immunosuppressive therapy may impair the production of autoantibodies and help reduce the inflammatory environment, which clearly can interfere with the normal development of intrauterine cardiac conduction [55]. Therefore, pre-pregnancy counseling, management by a multidisciplinary team, planning pregnancy, and using appropriate medication treatments to keep the autoimmune disease activity low are necessary steps to consider.

Summary and outlook

Autoantibody-associated congenital heart block is characterized by rapid progression, and the prognosis for affected children is generally poor, with a notably low survival rate once complete atrioventricular block (CAVB) is established. Fetal echocardiography is currently recommended as the preferred diagnostic method. In recent years, advancements in medical science and heightened health awareness have led to a paradigm shift in the clinical management of this condition. The majority of pregnant women are no longer diagnosed as antibody carriers after being diagnosed with CHB, but are already aware of their systemic autoimmune diseases and positive antibody status. Consequently, they receive comprehensive prenatal counseling, are managed by multidisciplinary teams, and undergo aggressive therapeutic interventions to optimize disease control prior to conception. The pathogenesis of autoantibody-associated congenital heart block is multifactorial, with emerging evidence suggests that prophylactic pharmaceutical interventions in mothers, such as HCQ administration prior to the onset of atrioventricular block, may significantly reduce the risk. However, several critical questions remain unresolved regarding the other immunosuppressive treatments, anti-inflammatory treatments, and prophylactic antithrombotic treatments in preventing autoantibody-associated congenital heart block. The optimal timing, dosage, and duration of these preventive treatment require further investigation through well-designed clinical studies. Furthermore, the low incidence rate of CHB, combined with the variable efficacy and potential risks associated with pharmacologic interventions, has resulted in ongoing controversy regarding optimal treatment strategies. Large-scale, multicenter studies are warranted to establish evidence-based guidelines for the prevention and management of this complex condition.

Author contributions

F. Y.-T. 和 D. Y.-B. contributed significantly to the submitted work, including: (1) Study conception and design; (2) Material preparation and literature search; and (3) Manuscript writing/editing and figure preparation. All authors reviewed and approved the final manuscript.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publish

Not applicable.