Reducing the burden of surveillance in pregnant women with no history of fetal atrioventricular block using the negative predictive value of anti-Ro/SSA antibody titers.
Kaizer AM, Lindblade C, Clancy R, Tebo AE, Drewes B, Masson M, Chang M, Fraser N, Buyon JP, Cuneo BF.Am J Obstet Gynecol. 2022 Jun 8:S0002-9378(22)00442-2. doi: 10.1016/j.ajog.2022.05.071. Online ahead of print.PMID: 35690080
Take Home Points:
- In maternal patients with a commercial (ARUP) anti-Ro52 and anti-Ro60 titers < 110, no cases of fetal AV block occurred
- With research lab titers (NYU) of anti-Ro52 < 650 and anti-Ro60 < 4060, no cases of fetal AV block occurred
- Using these 100% negative predictive value (NPV) thresholds, more than 50% of anti-Ro/SSA antibody pregnancies could be excluded from continued surveillance
Commentary from Dr. Jared Hershenson (Greater Washington DC), section editor of Pediatric Cardiology Journal Watch:
Fetal complete AV heart block (f-AVB) is the most feared complication of anti-Ro/SSA positive pregnant women. While about 1% of women are antibody positive, only 1-3% of fetuses develop complete heart block (CHB), making recommendations for screening difficult. Additionally, the transition from normal rhythm to CHB can occur within 12-24 hours, so the current recommendation of weekly to bi-weekly fetal echocardiograms will not be adequate given that IVIG or steroid administration typically needs to be given before CHB occurs. Fetal ambulatory rhythm monitoring has been studied at some centers and may be useful, but it cannot detect first degree heart block or any extranodal cardiac disease. The cost and time burden of screening is also quite significant, so further elucidation of which patients are truly at higher risk would be quite useful. There is evidence that lower antibody levels are associated with a lower risk of f-AVB but there are very few commercial labs that report antibody titers, specifically anti-Ro52 and anti-Ro 60, instead of crude ranges (e.g. < 1, 1-8, or >8). This study was conducted to address whether commercially available testing and research lab testing could determine a titer below which f-CHB would be highly unlikely to occur.
This was a multi-site study of women who tested positive for anti-Ro/SSA and had their serum retested in ARUP (Associated Regional and University Pathologists) Laboratories and in the research lab of NYU school of medicine. Subjects were divided into 3 groups based on outcomes; Group 1 had no history of f-AVB and no f-AVB in the current pregnancy, Group 2 had f-AVB in the current pregnancy, and Group 3 had a history of f-AVB but no f-AVB in the current pregnancy. See Figure 1.
270 patients were studied. 113 were tested at ARUP, 70 at NYU, and 87 at both. Most patients were on hydroxychloroquine and regression analysis used to determine if titers differed significantly between those not taking. Titer thresholds were calculated using 100% NPV for anti-Ro52, anti-Ro60, and both in combination. Because the study aimed to use titers alone to determine future screening, group 3 patients were described but excluded from further analysis as they represent a much higher risk historically and surveillance is always recommended for this group.
Median titers were significantly higher in group 2 and group 3 and there were no significant differences between patients treated with hydroxychloroquine or not. 3 approaches to target 100% NPV were compared using either ARUP or NYU, anti-Ro52 alone, anti-Ro60 alone, or both. Figures 3 and 4 show the results for ARUP. Anti-Ro52 < 44 AU/ml identified 55/108 (51%) of healthy pregnancies as healthy and 0/33 with f-AVB as healthy. Anti-Ro 60 < 58 AU/ml had less specificity, and the combination of both with a titer of < 110 AU/ml was similar to anti-Ro 52 alone. For the NYU data, results were similar, but the combination of anti-Ro52 and anti-Ro60 was slightly better than anti-Ro 52 alone. Only 18 patients had titers from both labs precluding analysis between the two.
In the discussion, the authors cite other data linking low titers to both decreased risk of f-AVB as well as other cardiac complications. They also note that anti-Ro titers alone are clearly not the sole predictors of f-AVB, especially given that the titers were comparable in the current pregnancies with f-AVB vs. past pregnancies with f-AVB. A strength of this study was the use of a commercial lab, but limitations were the overall small sample size and use of only 1 commercial lab. However, as they mention, this study does provide a framework for a prospective study risk stratifying surveillance of anti-Ro positive pregnancies at risk for f-AVB, a study that is currently underway. Hopefully, with more data and more commercial lab testing available, this could markedly improve our screening, so only the highest risk patients will need the currently available surveillance.