Strengths and limitations
The major strength of our study is the unselected study population: as coverage of the national screening program is near 100% in the Netherlands8 and serological assessment (titers and ADCC tests) for the risk on HDFN is performed at Sanquin Diagnostic services only, all women with D antibodies in the Netherlands that were pregnant during our study period were identified.
Another strong point of this study was our response rate of 73%. Furthermore, no selection bias seems to be induced by selecting women with two or more subsequent pregnancies only (supplemental text and Table S1).
A limitation of this study is however that cut-offs for the disease categories are somewhat arbitrary, as the clinical rationale for treatment decisions is not always clear in retrospect and might vary over time. Our main finding that disease severity increases in the majority of subsequent pregnancies at risk is however supported by the increase in almost all raw disease characteristics in Table S3.
CONCLUSION
The severity of anti-RhD mediated HDFN increases in the majority of subsequent pregnancies with RhD-positive foetuses. The risk of severe HDFN in a subsequent pregnancy can be estimated using the moment of antibody detection, antibody characteristics as reflected by ADCC test results and the severity of HDFN in the first immunized pregnancy. Mothers with antibodies occurring during their first pregnancy of a RhD-positive child, who never received RhIg, detected at 27th week screening, are more at risk for developing severe disease in a subsequent pregnancy. Further research should focus on identifying this group of ‘high-responders’ to establish whether an additional, early administration of RhIg could be beneficial. Furthermore, the development of more effective non-invasive treatment options for foetuses affected by HDFN could possibly ameliorate outcome.
ACKNOWLEDGEMENTS
Thanks to Fleur Zwanenburg and Cindy de Jong, department of Obstetrics, LUMC, Leiden, the Netherlands, for their efforts in collecting and transforming study data without financial compensation.
DISCLOSURE OF INTEREST
Authors report no conflict of interest.
AUTHOR CONTRIBUTION STATEMENT
CZ and YMS: conception, planning, carrying out, analyzing and writing. JK, IvK, EL, DO, MdH: conception, planning, reviewing. PL: planning and analysing. JGvdB: conception, analysing, reviewing. EvdS: conception, reviewing. All authors have read and approved the final manuscript.
DETAILS OF ETHICS APPROVAL
The medical ethics committee of the Leiden University Medical Center approved the protocol (P15.101/NV/nv). Written informed consent was obtained from all mothers included in this study.
FUNDING
This research was supported by a grant from Sanquin Blood Supply (L2181). The design, conduct or publication of the study was not influenced by this financial support.
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