VARIATION IN PRENATAL SURVEILLANCE AND MANAGEMENT OF ANTI-SSA/RO AUTOANTIBODY POSITIVE PREGNANCIES

Abstract

Objective:

To describe international surveillance and treatment strategies for managing anti-SSA/Ro autoantibody positive pregnancies.

Study Design:

An electronic REDCap questionnaire was distributed to Fetal Heart Society and North American Fetal Therapy Network members which queried institution-based risk stratification, surveillance methods/frequency, conduction abnormality treatments, and postnatal anti-SSA/Ro pregnancy assessment.

Results:

101 responses from 59 centers (59% US, 17% international) were collected. Most (79%) do not risk stratify pregnancies by anti-SSA/Ro titer; those that do use varied cutoff values. Many pregnant rheumatology patients are monitored for cardiac abnormalities regardless of maternal anti-SSA/Ro status. Surveillance strategies were based on maternal factors (anti-SSA/Ro status 85%, titer 25%, prior affected child 79%) and monitoring durations varied. Most respondents treat 2° and 3° fetal atrioventricular block, commonly with dexamethasone and/or IVIG.

Conclusions:

Wide variation exists in current fetal cardiac surveillance and treatment for anti-SSA/Ro autoantibody positive pregnancies, highlighting the need for evidence-based protocols to optimize care.

Introduction

Fetal 3° atrioventricular block (AVB), identified in the second trimester of pregnancy in an otherwise normally developing heart, is almost universally associated with maternal anti-SSA/Ro autoantibodies which include reactivity to both the 60kD and 52kD SSA/Ro antigens in most cases and results in death in nearly 20% of cases (1–4). According to the 2014 American Heart Association Scientific Statement on the Diagnosis and Treatment of Fetal Cardiac Disease, fetal echocardiographic screening of anti-SSA/Ro positive pregnancies is recommended either weekly or biweekly to surveil for development of anti-SSA/Ro-mediated fetal heart disease (5). While risk stratification based on maternal autoantibody titer levels and home surveillance with fetal handheld Doppler monitors are now increasingly used by select physicians caring for anti-SSA/Ro positive pregnancies (3, 6–9) We and others have recently demonstrated using both commercially available and research testing that having low titers of both anti-SSA/Ro52 and SSA/Ro60 confer a lower risk of fetal heart disease (2, 3, 10). No universal evidence-based guidelines exist for risk stratification, management, or treatment of these patients. A previous survey published in the field of rheumatology further highlighted the lack of official guidelines and variations in management (11).

Due to the paucity of data guiding clinical management of anti-SSA/Ro autoantibody positive pregnancies, we hypothesized that wide practice variations exist in both the approach to prenatal surveillance and management of detected fetal AVB and extranodal fetal cardiac disease, collectively referred to as cardiac neonatal lupus. To evaluate this hypothesis, we developed an electronic survey to collect data on current worldwide monitoring protocols and treatment strategies employed by pediatric cardiologists and maternal-fetal medicine specialists.

Materials and Methods

The electronic survey study was distributed through the Fetal Heart Society to its members as well as to the North American Fetal Therapy Network membership and maternal-fetal medicine colleagues of the study team. This study was designated as quality improvement and granted a not research determination by the Children’s Minnesota Institutional Review Board. Completion of the electronic survey was voluntary and anonymous.

Study data were collected and managed using a REDCap (Research Electronic Data Capture) electronic data capture survey hosted at the University of Colorado, Denver (12, 13). Survey questions were developed collaboratively by the author working group during a series of virtual preparatory meetings. The created survey queried institution-based patient risk stratification methods, frequency and modes of fetal cardiac surveillance, treatment of various conduction system and extranodal abnormalities, and postnatal management of offspring of anti-SSA/Ro autoantibody positive pregnancies prior to initiation of the NIH-sponsored STOP-BLOQ (Surveillance and Treatment to Prevent Fetal Atrioventricular Block Likely to Occur Quickly) clinical trial. Survey responses are described in aggregate and summarized as frequencies and percentages.

Results

The questionnaire was completed by 101 respondents (table 1), 73.3% pediatric cardiologists and 26.7% maternal-fetal medicine physicians. More than half of respondents reported >10 years’ post-training clinical experience in their medical field. The majority of respondents identified their institution as academic (79.2%), with 12.9% in private practice. The survey captured 59 unique institutions (18 duplicates, 24 did not report their center); the geographical distribution of the respondent centers is shown in Fig. 1. Most centers (53.5%) self-reported estimated annual fetal echocardiogram volumes of 500–1500. Nearly two-thirds of respondents estimated their annual anti-SSA/Ro pregnancy referrals as between 5 and 20 (61.2%), with 17.8% reporting more than 20 cases per year.

Table 1.

Survey respondents’ training and practice center volumes

	Respondents N = 101
Respondent Group Specialty
Pediatric or Fetal Cardiology	74 (73.3)
Maternal Fetal Medicine	27 (26.7)
Practice Type
Academic	80 (79.2)
Private Group Practice	11 (10.9)
Private Individual Practice	2 (2.0)
Other*	8 (7.9)
Years Practicing Since Completing Training
1–5 years	15 (14.9)
6–10 years	28 (27.7)
11–15 years	15 (14.9)
>15 years	42 (41.6)
No answer	1 (1.0)
Fetal echocardiograms are performed per year (by all practitioners in the practice)
<500	23 (22.8)
500–1000	34 (33.7)
1000–1500	20 (19.8)
>1500	23 (22.8)
No answer	1 (1.0)
Anti-SSA/Ro autoantibody positive pregnancies referred to group per year
<5	13 (12.9)
5–10	32 (31.7)
11–20	30 (29.7)
>20	18 (17.8)
I donť know	7 (6.9)
No answer	1 (1.0)

Format: n(%)

^*Other Responses: Academic environment in a community hospital; Affiliated with academic center, but work out of another location than main campus, Clinical; Community hospital based clinic practice; Hospital based; Hospital based; Private Health System; Regional outreach clinic

Fig. 1.

Geographical distribution of 59 unique respondent centers: 74.6% US centers, 8.5% Canadian, and 16.9% other international.

Pregnancy risk stratification.

Monitoring strategies for patients with anti-SSA/Ro positive pregnancies were based on a spectrum of maternal factors (Fig. 2), the most common being positive anti-SSA/Ro autoantibody status (85.2%) and patient history of a previously affected child (79.2%). Respondents reported that clinical experience (82.2%) and medical literature (11.9%), as well as guidance from fetal cardiology colleagues and other field experts, inform their pregnancy management decisions.

Fig. 2.

Reported monitoring strategies for anti-SSA/Ro autoantibody pregnancies.

Although positive anti-SSA/Ro autoantibody status was a primary indication for fetal monitoring, the vast majority (79.2%) of respondents indicated that their practice does not risk-stratify individual patients by autoantibody titer level. Those that considered anti-SSA/Ro titer levels for risk stratification reported a variety of thresholds for low and high cutoffs. Approximately half (44.6%) of respondents shared that their institutional lab provides test results for anti-Ro/SSA antibodies as positive if > 1 antibody index (AI) with values between 1 and 8 AI and > 8 AI (BioPlex assay) with no further titering. Only 20.8% reported the option for testing at laboratories with a broader ranges of positive values.

In addition, 33.7% of respondents reported routine fetal cardiac surveillance for pregnant patients with rheumatologic diagnoses (systemic lupus erythematosus, Sjögren’s disease, rheumatoid arthritis) regardless of anti-SSA/Ro autoantibody status. Surprisingly, 58.4% reported surveilling pregnancies with only anti-SSB/La positivity in the absence of anti-SSA/Ro.

Methods of pregnancy surveillance

Fetal echocardiography.

Fetal echocardiography was reported as the primary tool for fetal surveillance (94.1%), with monitoring frequencies of weekly (31.6% of respondents), every-other-week (51.6%), monthly (11.6%), and less than monthly (5.3%). Fetal echocardiography assessment included: fetal heart rate (98.9%), atrioventricular (AV) interval (94.7%), heart rhythm (94.7%), pericardial effusion (92.6%), AV valve regurgitation (91.6%), general cardiac function (89.5%), and evaluation for endocardial fibroelastosis (83.2%). The gestational age (GA) distributions of echo surveillance are shown in Fig. 3A with most respondents reporting surveillance initiation between 16–18 weeks and discontinuation after 28 weeks. Many respondents apply a uniform monitoring protocol that is occasionally modified based on observed individual patient risk, but the majority do not modify their monitoring protocol for perceived high-titer patients (63.2%). Of those that do, some increased echo frequency (11.6%), lengthen surveillance duration (3.2%), or both (3.2%). Additionally, most respondents do not modify their echo monitoring protocols for patients with a previously affected child (52.6%), while a minority increase echo frequency (28.4%), lengthen surveillance duration (5.3%), or both (11.6%). For findings of fetal valvar regurgitation or increased myocardial echogenicity without changes in the rhythm/mechanical PR interval, 64.2% of respondents would increase the frequency of echo surveillance.

Fig. 3.

Distribution of the survey respondents ‘recommended gestational ages to start and complete various monitoring strategies: A) fetal echocardiography, B) home handheld fetal heart rate monitoring, and C) in-office weekly or bi-weekly fetal heart rate monitoring.

At-home handheld Doppler monitoring.

Home handheld fetal heart rate monitoring (FHRM) is used by 27.7% of respondents to monitor anti-SSA/Ro pregnancies. Of those respondents who utilize home FHRM, Doppler monitors are provided to patients who are anti-SSA/Ro autoantibody positive (71.4%), have had a previously affected child (57.1%), and/or have a perceived high anti-SSA/Ro autoantibody titer (42.9%); 92.9% of respondents that utilize handheld FHRM for surveillance have a group 24-hour on-call cardiologist to respond to abnormal FHRM calls. Gestational age range for handheld FHRM surveillance initiation and completion is shown in Fig. 3B. Similar to the reported echo surveillance windows, most respondents using FHRM recommend initiating home monitoring between 16–18 weeks and discontinuing after 26 weeks.

In-office fetal heart rate monitoring.

Nearly half (45.5%) of respondents report using weekly or biweekly in-office FHRM using either Doptone or ultrasound to surveil anti-SSA/Ro autoantibody pregnancies for development of 3° AVB. Respondents reported commencing the in-office monitoring around 16 weeks and continuing until ≥ 28 weeks (Fig. 3C).

Maternal lab assessment.

Only a small proportion of respondents (18.8%) recommended routine laboratory electrolyte testing and, if needed, replenishing maternal 25(OH) Vitamin D, calcium, and magnesium levels. Nearly 40% of respondents said their practice recommended checking thyroid studies (TSH/free T4) and anti-thyroglobulin antibodies if these have not already been obtained.

Detection and treatment of affected pregnancies.

Sixty-three percent of respondents reported that their current surveillance protocols have successfully detected incomplete (1° or 2°) AVB. On the other hand, 75.2% of respondents reported that they have had patients who were not undergoing routine surveillance present with fetal 1°, 2°, or 3° AVB. Once AVB is detected, the respondents reported a wide variety of medical treatment strategies, outlined in table 2.

Table 2.

Variation in treatment of fetal atrioventricular block

1°		2°		3°
Does your group treat AVB?
Yes	40 (40)	Yes	79 (78)	Yes	68 (67)
No	54 (54)	No	13 (13)	No	24 (24)
I don’t know	7 (7)	I don’t know	9 (9)	I don’t know	9 (9)
For what indications does your team treat ___ AVB? (select all that apply)
Prolonged AV interval without other abnormalities	34 (85)	Type 1 2° block without other abnormalities	55 (70)	3° block without other abnormalities	48 (71)
Prolonged AV interval with endocardial fibroelastosis	28 (70)	Type 1 2° block with endocardial fibroelastosis	59 (75)	3° block with endocardial fibroelastosis	55 (81)
Prolonged AV interval with mild-to-moderate tricuspid regurgitation	28 (70)	Type 1 2° block with mild-to-moderate tricuspid regurgitation	57 (71)	3° block with atrioventricular valve insufficiency	54 (79)
Prolonged AV interval with any degree of mitral regurgitation	27 (68)	Type 1 2° block with any degree of mitral regurgitation	56 (71)	3° block with ventricular dysfunction	56 (82)
Prolonged AV interval with pericardial effusion	26 (65)	Type 1 2° block with pericardial effusion	58 (73)	3° block co-occurring with other atrial or ventricular arrhythmias	50 (74)
I don’t know	0 (0)	Type 2 2° block without other abnormalities	61 (77)	3° block with pericardial effusion, hydrops, or other signs of fetal hemodynamic compromise	55 (81)
		Type 2 2° block with endocardial fibroelastosis	61 (77)	I don’t know	1 (1)
		Type 2 2° block with mild-to-moderate tricuspid regurgitation	60 (76)
		Type 2 2° block with any degree of mitral regurgitation	60 (76)
		Type 2 2° block with pericardial effusion	59 (75)
		I don’t know	5 (6)
What drugs does your group use to treat AVB?
Dexamethasone	31 (78)	Dexamethasone	41 (52)	Dexamethasone	28 (41)
IVIG	0 (0)	IVIG	0 (0)	IVIG	0 (0)
IVIG and Dexamethasone	9 (23)	IVIG and Dexamethasone	36 (46)	IVIG and Dexamethasone	36 (53)
Other	0 (0)	Other	0 (0)	Other (Dexamethasone and Terbutaline, Salbutamol)	2 (3)
I don’t know	0 (0)	I don’t know	2 (0)	I don’t know	2 (3)

Format: n (%)

Routine postnatal care for uneventful anti-SSA/Ro positive pregnancies also varied for respondents, with 77.2% reporting routine postnatal ECGs, 36.6% obtaining postnatal echocardiograms, 18.8% conducting neonatal complete blood count and liver enzyme assessment, and 6.9% recommending minimizing sun exposure in the first 6 months of life.

Sub-specialty Practice Differences.

No major difference in risk-stratification by titer, monitoring strategy, or use of echocardiography were found between cardiologist and maternal-fetal medicine physicians. Maternal-fetal medicine respondents monitored with echocardiography slightly more frequently than cardiology practitioners (44% vs 23% weekly, 37 vs. 53% bi-weekly, 7% vs. 20% monthly or less).

Discussion

Our survey results demonstrate that wide practice variation currently exists worldwide in patient risk stratification, surveillance, and treatment approaches for affected offspring of anti-SSA/Ro autoantibody positive pregnancies, in spite of scientific statements that provide care recommendations (5). Recent publications by the maternal fetal medicine and fetal cardiology communities continue to highlight the ongoing controversies and dearth of evidence-based guidelines regarding optimal prenatal surveillance and management for this disease (14–16). Based on our survey results, most physicians rely on individual clinical experience, rather than on medical literature, to drive decision-making.

We were surprised to find that approximately half of survey respondents routinely surveilled pregnant patients afflicted with rheumatologic diagnoses in the absence of anti-SSA/Ro autoantibodies. It is well accepted that the presence of maternal anti-La/SSA autoantibodies in the absence of anti-SSA/Ro is uncommon. A previous study by Brito-Zeron et al. found that fetal 3° AVB resulting from isolated anti-La/SSA autoantibodies is exceptionally rare with <1% of reported cases in the published literature (17).

Routine screening for anti-SSA/Ro and anti-SSB/La antibodies among pregnant women is important, as in addition to the impact on the fetus, anti-SSA/Ro antibodies in asymptomatic mothers have also been associated with a new-onset atrioventricular conduction disturbance without a medical history of neonatal lupus (18). Further study is needed to optimize screening recommendations in anti-SSA/Ro autoantibody positive pregnancies to not only standardize practice, but to minimize potential cost burden as surveillance may not be necessary in pregnancies with titers below a certain antibody threshold (2).

Currently, two studies are underway that will lead to necessary evidence-based guidelines. The first is the ongoing prospective AVB study STOP BLOQ (Surveillance and Treatment to Prevent Fetal Atrioventricular Block Likely to Occur Quickly; ClinicalTrials.gov identifier: NCT04474223). The STOP BLOQ study risk stratifies pregnancies by anti-SSA/Ro autoantibody titer (low risk, <1,000 ELISA units [EU] and high risk, >1,000 EU), employs thrice-daily home Doppler monitoring in high-titer pregnancies, and investigates the efficacy of rapid initiation of steroid and IVIG treatment on fetal 2° AVB to restore normal rhythm or prevent progression to 3° AVB and/or extranodal disease (10). The second study is the Slow Heart Registry of Fetal Immune-mediated High Degree Heart Block (ClinicalTrials.gov identifier: NCT04559425), which prospectively compares morbidity and mortality between treated and untreated fetuses with AVB through the first 2 years of life.

The primary limitation of this study is the limited responses received, of which the vast majority of respondents were from medical practices in the US. The results of this study primarily reflect the experience of physicians in developed economies; there were only a few respondents from developing economies including Asia, South America, or Africa, and we therefore cannot report how physicians in these areas manage these pregnancies with more limited resources. In addition, since the majority of responses were from academic medical groups, it is difficult to draw conclusions on management differences that may occur in private practice maternal fetal medicine and pediatric cardiologist groups.

Although a rare disease, affecting only ~2–5% of pregnancies complicated by anti-SSA/Ro autoantibodies, cardiac neonatal lupus is associated with significant morbidity and mortality, including lifelong permanent pacing, dilated cardiomyopathy, heart failure, heart transplantation, and/or premature death (15, 16). Without consistent and collaborative surveillance and management of pregnancies complicated by anti-SSA/Ro autoantibodies, patients may receive inequitable and inadequate surveillance and/or treatment. Evidenced-based clinical practice guidelines are needed to detect disease in time for treatment and to assure physicians that the risk benefit ratio favors surveillance and in most cases, in utero treatment.

Availability of Data and Materials

There is no publically available data for this study.