AFFILIATIONS
1 Oslo University Hospital, Oslo, Norway
2 Weill Cornell Medicine, New York City, New York, United States
3 Columbia University Irving Medical Center, New York City, New York, United States
4 St. Francis Medical Center, Lynnwood, California, United States
5 Lund University, Lund, Sweden, Skane University Hospital, Barnmorskestationen Rosengard, Sweden
6 Rallybio Inc, New Haven, Connecticut, United States
7 OBGGYN Medical Center Associates, Houston, Texas, United States
8 Rallybio Inc, New Haven, Connecticut, United States
9 Boonshoft School of Medicine, Wright State University, Dayton, Ohio, United States
10 University of Toronto, Toronto, Ontario, Canada
11 Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, United States
12 Yale School of Medicine, New Haven, Connecticut, United States
13 Rallybio Inc, New Haven, Connecticut, United States
14 Clinical Trial Consultants, Uppsala, Sweden, Uppsala University, Uppsala, Sweden
15 McGovern Medical School at UTHealth, The University of Texas Health Science Center, Houston, Texas, United States
16 St Thomas' Hospital, London, United Kingdom
17 University of Miami Miller School of Medicine, Miami, Florida, United States
18 Saint Peter's University Hospital, New Brunswick, New Jersey, United States
19 Cooper Medical School of Rowan Universit, Glassboro, New Jersey, United States
20 Leids Universitair Medisch Centrum, Leiden, Netherlands
21 Jena University Hospital, Friedrich-Schiller-University, Jena, Germany
22 Weill Cornell Medicine/New York Presbyterian Queens Hospital, New York City, New York, United States
23 Karolinska Institute, Stockholm, Sweden
24 Rutgers New Jersey Medical School, Newark, New Jersey, United States
25 UiT The Arctic University of Norway, Norway., Tromso, Norway, Universitetssykehuset Nord Norge, Tromso, Norway
26 Leids Universitair Medisch Centrum, Leiden, Netherlands
27 Weill Cornell Medicine, New York City, New York, United States
28 Weill Cornell Medicine, New York City, New York, United States
ABSTRACT
Introduction:
Fetal and Neonatal Alloimmune Thrombocytopenia (FNAIT) is caused by HPA-1a incompatibility in 80% of cases in Caucasians. Affected cases range from 1:500 to 1:1000 overall, with marked thrombocytopenia in perhaps 1:3000 to 1:5000. Intracranial hemorrhage (ICH) in 10-20% of the latter would range from 1:15,000 to 1:50,000. De Vos 2024 and McFarland 2025 - suggest there are adverse neurodevelopmental outcomes including autism in up to 30% of affected children who did not have an ICH. This extends the potential benefits of screening, treatment, and prophylaxis from prevention of ICH to potential prevention of neurodevelopmental injury.
Aims:
To explore a novel screening algorithm for anti-HPA-1a-mediated FNAIT and identify differences in results according to ethnicity and race.
Methods:
A multicenter multi-continent multiethnic screening study of HPA-1a FNAIT. All pregnant women were eligible who did not have past FNAIT and were > 18 years of age. Screening was performed between 10-14 weeks. Following consent, blood was drawn and the algorithm followed (Bussel 2021). If the mother was HPA-1bb, she was tested for DRB3*01:01. If she was also DRB3*01:01, she was tested for anti-HPA-1a. If she were positive for anti-HPA-1a, she was removed from the study and referred for management. If she were HPA-1bb, DRB3*01:01 positive and anti-HPA-1a negative, her fetus would be tested for HPA-1a using cell-free fetal DNA (cffDNA). This defined higher risk women as HPA-1bb, DRB3*01:01 positive, anti-HPA-1a negative with an HPA-1a+ fetus. Anti-HPA-1a was reported as positive or negative and not quantified. Self-reported ethnicity and race were obtained. No statistical testing was performed.
Results:
Among the 14,114 women screened, 49 were identified as potentially at higher risk. Of these 18 were already sensitized to anti-HPA-1a. All 18 were among the 9,188 pregnancies in which this was at least the second pregnancy; no cases were seen in the 4,926 first pregnancies. Since they were removed from the protocol, no outcomes are available for the sensitized women. Of 31 remaining women without anti-HPA-1a, 7 had HPA-1bb fetuses. Of the 24 remaining women 5 were lost to f/u leaving 19 women. Only 2 were identified with anti-HPA-1a antibody and both delivered newborns with normal platelet counts.
The study closed early (RallyBio press release) after 14,114 were screened instead of the 20-40,000 initially planned. Furthermore, two doses of prophylaxis were administered to 1 woman without identifying any blood levels of anti-HPA-1a after either injection.
2,088 Blacks were enrolled, more than all other previous studies combined, and approximately 1% were identified as HPA-1bb. The rate of positivity of DRB3*01:01 was similar to that of Caucasians. No differences were observed comparing Hispanic to non-Hispanics. Few cases of HPA-1bb were seen in Asians with no Chinese or Japanese women identified as HPA-1bb but individual numbers by countries were too small to provide reliable estimates.
Conclusions:
No previous screening studies had included both DRB3*01:01 and especially cffDNA HPA-1ab typing and none performed screening in the sequential manner described here. Despite the reduced incidence of HPA-1bb in Blacks, the results suggest that screening should include them in the future. How to handle Asian patients would require further study although Eastern Asian countries (China and Japan) are thought to have very low rates of HPA-1bb women from other studies. Only 2 higher risk women (of 19) made anti-HPA-1a and both of their children were not thrombocytopenic at birth. In contrast, 17 women (or more than 1:1000) were found to already have anti-HPA-1a early in pregnancy suggesting persistent antibody arising from sensitization at previous delivery. All 17 were screened in the second or later pregnancy, but without evidence of FNAIT in a previous child. A major limitation of the study is the absence of quantification of the anti-HPA-1a and that the 17 already sensitized women were not included in the study. The findings (albeit with only 2 doses of prophylaxis) suggest that the administered anti-HPA-1a may have bound to the placenta. If so, this would have implications for antenatal prophylaxis and suggest that initial studies be post-partum only, similarly to the way that anti-D prophylaxis was initially developed. Screening would have value not only in identifying high risk women but those already sensitized as well.