Maternal health, neonatology and perinatology towards a standardized outcome set for clinical trials in Hemolytic Disease of the Fetus and Newborn (HDFN): preliminary findings from two European advisory boards

Abstract

Hemolytic Disease of the Fetus and Newborn (HDFN) remains a serious perinatal condition worldwide despite major advances in antenatal and postnatal care. A key gap in HDFN research is the absence of a standardized outcome set, leading to inconsistent reporting and limited comparability across studies identified during systematic literature review (SLR). Outcomes important to families, such as long-term neurodevelopment and emotional impact, are often overlooked. 2 separate European advisory boards with 7 HDFN experts were conducted to explore expert perspectives on outcomes that may inform future core outcome set (COS) development. The findings should be interpreted as a preliminary, descriptive outcome prioritization exercise rather than a finalized COS, as no joint consensus meeting, Delphi process, pre-specified consensus threshold, or patient/parent involvement was undertaken. Establishing a formal COS through a structured multi-stakeholder process could enhance research quality, support future evidence generation, and promote more consistent care.

Clinical trial number: Not applicable.

Background

Hemolytic Disease of the Fetus and Newborn (HDFN) is an alloimmune condition that occurs when maternal antibodies cross the placenta and damage fetal red blood cells. This immune reaction is usually triggered by blood group incompatibility, most commonly due to antigen mismatch between an RhD-negative mother and an RhD-positive fetus leading to hemolysis, resulting in fetal anemia, hydrops fetalis, or intrauterine death if not appropriately managed [1–4]. After birth, newborns affected by HDFN are at risk of significant hyperbilirubinemia, kernicterus, and long-term neurodevelopmental complications [4, 5].

Medical advances over the past decades have substantially improved outcomes for HDFN. These include antenatal prophylaxis with anti-D immunoglobulin for RhD incompatibility, use of middle cerebral artery Doppler velocimetry to detect fetal anemia, and intrauterine transfusions (IUT) when necessary [6, 7]. Postnatal management strategies like intensive phototherapy, exchange transfusions, and intravenous immunoglobulin have also proven effective in reducing morbidity and mortality [8]. Despite this progress, HDFN remains a significant health concern worldwide, with preventable burden particularly evident where access to prenatal care, antibody screening, fetal monitoring, and prophylaxis is inconsistent [9, 10].

As a rare condition, HDFN faces challenges associated with rare disease research, namely small patient populations and limited long-term data. To maximise learning from limited data, integrating outcomes across different study types is key. However, in HDFN, that is hindered by the lack of a standardized core outcome set (COS). Without a universally agreed-upon COS, considerable heterogeneity exists in the outcomes reported, including variation in how fetal anemia, need for intervention, neonatal complications, and long-term outcomes are measured and defined. This makes the comparison of results, conduct of robust meta-analyses, and development of evidence-based clinical guidelines challenging [11].

Relatedly, there is a paucity of relevant and validated patient-reported outcomes (PROs) in HDFN. As such, studies prioritize clinical endpoints selected by researchers, which results in the underreporting or overlooking of key aspects including quality of life (QoL), long-term neurodevelopmental outcomes, emotional impact, and parental burden [12].

Against this background, 2 advisory boards were conducted with expert health care professionals (HCPs) to explore perspectives on potential outcome components for future HDFN research and formal COS development. This manuscript reports a descriptive synthesis of those discussions and the outcomes prioritized within each board. It does not present a finalized COS. Rather, the exercise aims to support future structured, multi-stakeholder consensus work and the development of more consistent, patient-centered clinical practices and research endpoints in HDFN.

Overview

Ahead of the AdBoards, a systematic literature review (SLR) was conducted to compile all outcomes reported in recent HDFN studies [13]. Due to disease rarity, the SLR included all English-language primary studies, regardless of sample size. Overall, 238 studies were included in the final analysis [221 observational studies (retrospective and prospective cohort: n = 160, cross-sectional: n = 9, case-control: n = 16, chart reviews: n = 16, other: n = 20); 17 clinical studies (non-randomised: n = 3, randomised: n = 14)]. Among these, 104 unique outcomes were observed in varying time points within a pregnancy/birth.

The outcomes identified through the SLR were grouped by time point and domain. Because some outcomes were relevant to more than one time point or domain, category totals are not additive. Outcomes were organized into pregnancy, post-pregnancy, and PRO categories. Pregnancy and post-pregnancy outcomes were further grouped using consistent domain headings: Monitoring & Diagnostics, Treatments & Interventions, Treatment Response, Morbidity & Mortality, Healthcare Resource Use (HCRU), with Birth Outcomes and Long-term outcomes included where applicable. PROs focused primarily on QoL and psychosocial impact measures.

Next, 2 AdBoards were conducted with 7 HCPs with extensive experience in HDFN. The first AdBoard took place on October 2nd, 2023, and included HCPs from Germany (1), Spain (1) and France (2). The second AdBoard took place on October 26, 2023, with HCPs from the Netherlands (2) and the United Kingdom (1). Most HCPs were specialists in antenatal management or fetal therapy, with 1 expert in hematology and another in neonatal care. Both AdBoards adhered to the same agenda and content, with discussions guided by a neutral moderator to foster open dialogue and facilitate consensus-building in case of disagreements.

The HCPs were asked to classify outcomes presented above into either “key”, “important” or “supportive”. Key outcome was defined as a critical outcome to be included as primary or key secondary outcome in future studies and as part of a COS. Important outcome was defined as a relevant outcome, to be included as secondary or exploratory outcome in future studies and should be considered being part of a COS. A supportive outcome was defined as an outcome only relevant for specific types of studies.

The discussions from both AdBoards were descriptively analysed to compare the shared perspectives and the outcomes prioritized by HCPs. This approach enabled the identification of areas of agreement, as well as any differences in opinions.

In this study, no additional experiments or follow-up consensus exercises were conducted. The findings are therefore presented as preliminary and descriptive, with explicit consideration of the implications of unresolved differences between the two advisory boards.

Which outcomes matter most in a core outcome set?

Table 1 provides a descriptive overview of outcomes classified as “key” or “important” in at least one AdBoard. The table is intended to show areas of overlap and divergence between the two separate discussions; it should not be interpreted as a finalized COS. Yellow shading and outcomes marked with an asterisk (*) indicate outcomes classified as “key” or “important” in both advisory boards;

Table 1.

Preliminary list of key and important outcomes identified during two separate advisory boards; asterisk indicates outcomes classified as key or important in both advisory boards

Key Outcomes	Important Outcomes
Pregnancy
Monitoring & Diagnostics
Fetal hemoglobin*	Reticulocyte count
Fetal hematocrit*	Maternal antibody titer*
Middle Cerebral Artery (MCA) Peak Systolic Velocity MoM*	Abnormal fetal heart rate/CTG*
Hydrothorax	ADCC test
Treatments & Interventions
Intrauterine transfusion (IUT)*: - Number of IUTs* - Gestational age at first IUT*	Intravenous immunoglobulin treatment
Treatment Response
Prevention and/or resolution of hydrops fetalis*	Hemoglobin levels after IUT
Survival	Decrease/normalization in MCA velocity
Morbidity & Mortality
Maternal mortality	Need for emergency cesarean section*
Fetal and perinatal mortality*	Ascites / edema (as part of hydrops)
Cardiovascular complications	Fetal distress
Infection and sepsis
Ischemic stroke or severe brain injury to the fetus*
Fetal loss before 22 weeks of gestation
Type & rate of procedure-related complications*
Fetal hydrops
Emergency delivery due to fetal distress
Very pre-term birth (< 32 weeks gestation)
Pre-term birth (< 37 weeks gestation) / premature induction of labor*
Healthcare Resource Use (HCRU)
Cost benefits	Number of neonatal visits
Reduced need for additional treatment or diagnostics	Specialist referral
	Additional treatment costs
	Parent-related costs
	Admission of mother to resuscitation unit
	High-cost therapy
	Number of transfusions (HCRU)
Post-Pregnancy
Birth Outcomes
Gestational age at delivery*	Birth weight*
Live birth*	Apgar score
Still birth
Spontaneous or assisted vaginal birth
Monitoring & Diagnostics
Total serum bilirubin*	Antiglobulin / Direct Coomb’s Test*
Neonatal hemoglobin*	Reticulocyte count
Neonatal hematocrit*	Platelet count
Treatments & Interventions
(Need for) exchange transfusion*	Intensive Phototherapy
RBC transfusion (simple transfusion/top-up transfusion)*	Erythropoietin therapy
Treatment Response
Neonatal survival*
Morbidity & Mortality
Neonatal hydrops*	Procedure-related complications
Hyperbilirubinemia*	Respiratory distress
Jaundice	Mechanical ventilation*
Kernicterus*	Bronze Baby Syndrome
Neonatal morbidity*	Infection / sepsis
Neonatal mortality*	Intraventricular hemorrhage
Apnea/need for intubation	Pulmonary hemorrhage
Need for neonatal brain imaging	Anemia
Seizures	Necrotizing enterocolitis*
Long-term outcomes
Cerebral palsy*	Dyslexia
Hearing impairment	Behavioural & emotional problems*
Mortality (beyond one year of age)	Need for therapy*
Neurodevelopmental impairment*	School performance level*
Kernicterus
Visual impairment*
Healthcare Resource Use
Number of NICU admission	Length of admission to NICU
Time until discharge from hospital	Hospitalization
	Rates and length of stay of hospitalization

*Outcomes marked with an asterisk were classified as “key” or “important” in both advisory boards. In addition, shading is used for readability. Abbreviations: ADCC: Antibody-Dependent Cell Cytotoxicity; CTG: Cardiotocography; HCRU: Health Care Resource Use; IUT: Intrauterine Transfusion; MCA: Middle Cerebral Artery; MoM: Multiples of the Median; NICU: Neonatal Intensive Care Unit; RBC: Red Blood Cell

Within the pregnancy phase, 20 outcomes were designated as “key,” indicating their perceived relevance to clinical decision-making and patient care within at least one AdBoard. Additional outcomes were classified as “important”. Many prioritized outcomes fell within the morbidity and mortality domain, reflecting the risks to fetal, neonatal, and maternal health during the antenatal period.

Although consensus was generally achieved within each AdBoard through open discussion, no joint session or structured Delphi round was conducted to reconcile differences between the two groups. Consequently, several outcomes were classified as “key” or “important” by only one AdBoard. These single-board outcomes are retained in Table 1 to reflect the breadth of expert perspectives, but they should be interpreted as preliminary signals requiring confirmation through a formal consensus process.

HCRU outcomes were discussed and classified during the second AdBoard only; they were not formally classified during the first AdBoard because of time constraints and prioritization of clinical outcome domains. Participants in the second AdBoard considered HCRU outcomes relevant for future studies because effective HDFN-targeted interventions may reduce additional diagnostics, procedures, hospital admissions, and long-term care needs. However, no economic evaluation was undertaken, and any inference regarding cost-effectiveness should therefore be interpreted solely as panel opinion rather than evidence of economic value.

In the post-pregnancy phase, 27 outcomes were designated as “key,” and an additional 23 were classified as “important.” The most prioritized outcomes in this phase were related to neonatal and infant morbidity and mortality, with particular emphasis on complications occurring after birth. Notably, long-term outcomes, such as neurodevelopmental impairments, hearing loss, and other chronic health conditions, were also identified as significant. These findings highlight growing recognition among stakeholders of the lasting impact HDFN can have well beyond the neonatal period. Despite their recognized significance, long-term outcomes remain underreported, are inconsistently measured in studies, and lack standardization in clinical practice, pointing to the need to develop standardized long-term follow-up protocols and data collection to capture the full trajectory of health for individuals affected by HDFN.

Are patient-reported outcomes being overlooked in HDFN research?

Of the 17 clinical studies included in the SLR, none reported the use of PROs. This may reflect that many studies focused on clinical management, procedures, or observational outcomes rather than interventions designed with patient-reported impact as a primary objective. Nonetheless, findings from other areas of research suggest that including PROs is important for supporting more patient-focused care [12]. In the first AdBoard, three PROs were identified as “key” outcomes: infant health-related QoL, cognitive and emotional challenges in children treated with IUT, and the long-term impact of HDFN on the QoL of both mother and child. The second AdBoard did not rank PROs as “key” or “important”, but participants discussed the need to measure emotional impact, including mother–baby separation, delayed bonding, feelings of guilt, and anxiety about future pregnancies. Because these outcomes were not ranked consistently across both boards, they are discussed here rather than presented as finalized COS components in Table 1.

The discussions pointed to a larger issue: there are currently very few well-developed or validated PRO tools that could be used to reflect the unique challenges of HDFN, which affects both mother and baby across different stages of care. Available validated PROs include the Perinatal Anxiety Screening Scale (PASS) [14], the Infant and Toddler Quality of Life Questionnaire (ITQOL) [15], the Generalized Anxiety Disorder scale (GAD-7) [16], and the Family-Reported Outcome Measure (FROM-16) [17]; however, they are not widely used within HDFN research. Because of this, more research is needed to create or improve PRO measures that can capture the full range of experiences specifically related to HDFN. Furthermore, including these tools in future studies will help ensure that the outcomes most meaningful to patients and families are better understood and used to guide care.

Limitations

Several limitations should be considered. First, the findings are based on two small expert advisory boards, with four participants in the first board and three in the second. Second, the boards were held separately and no joint meeting, modified Delphi round, pre-specified consensus threshold, or reconciliation process was conducted to resolve differences between them. Outcomes classified as “key” or “important” by only one board therefore represent preliminary expert signals rather than agreed consensus items. Third, patients and parents were not directly involved in outcome prioritization, which is an important limitation given the relevance of QoL, emotional impact, and long-term family burden in HDFN. Fourth, the process did not fully adhere to COS-STAD recommendations and should not be considered a completed COS development exercise. Finally, the study was funded by Johnson & Johnson, which has an active clinical development program in HDFN; the sponsor supported the selection, presentation, and descriptive classification of outcomes for advisory board discussion. These limitations mean that the findings should be used to inform, not replace, a future structured, independent, multi-stakeholder COS process.

Conclusion

The AdBoards highlight the need for more standardized outcome reporting in HDFN research. The SLR and advisory board discussions identified variation in reported outcomes, limited long-term follow-up data, and insufficient use of patient-reported outcomes. The preliminary outcome list presented here may help inform future COS development, but it should be validated through a structured, multi-stakeholder process that includes patients and parents. Continued research and stakeholder collaboration are essential to develop outcome measures that are clinically meaningful, feasible, and relevant to families affected by HDFN.

Author contributions

MM, TV, WN, and AS were involved in the conceptualization and methodology of this study. AS, EL, EJTV, and KM were involved in data collection. AS wrote the original draft of the manuscript. All authors were involved in reviewing and editing the manuscript and contributed to the final manuscript in terms of intellectual content.

Funding

This study was funded by Johnson & Johnson.

Data availability

The data that support the findings of this study are not publicly available due to data privacy. The data were collected during an advisory board meeting and sharing them could compromise participant confidentiality. Requests for additional information about the study may be directed to the corresponding author and will be considered on a case-by-case basis in accordance with participant confidentiality agreements.

Declarations

Ethics approval and consent to participate

Ethical approval was obtained from the Ethics Committee at the Medical Faculty of the University of Rostock (Ethikkommission an der Universitätsmedizin Rostock). Written informed consent to participate in this study was obtained from all participants in accordance with the Declaration of Helsinki and institutional ethical guidelines.

Competing interests

The authors declare no competing interests.

Consent for publication

Not applicable.