A critical moment: Standardizing red blood cell antibody reporting to reduce hemolytic disease of the fetus and newborn risk

Red blood cell (RBC) alloimmunization occurs when an individual develops antibodies against foreign red cell antigens, most commonly after exposure via blood transfusion, intravenous drug use, organ transplant, or pregnancy.1 Females of childbearing potential (FCPs) who develop clinically significant alloantibodies face the risk of pregnancy complicated by hemolytic disease of the fetus and newborn (HDFN).2 In addition, alloimmunization limits the availability of compatible products for transfusions for all affected patients, including the postpartum patient in the setting of hemorrhage. RBC alloimmunization occurs in approximately 1.5% of pregnancies in the United States, most commonly involving anti-D, anti-K, and anti-c, followed by any number of the more than 50 clinically significant RBC antibodies known to cause HDFN.3 During pregnancy, these maternal antibodies can cross the placenta, target fetal RBCs that express the corresponding antigen, and cause fetal hemolysis. If hemolysis becomes significant, the fetus may require intrauterine transfusions (IUTs) to treat fetal anemia every 2–3 weeks until delivery. Newborns with HDFN often require close monitoring and treatment for hyperbilirubinemia and hemolytic anemia until clearance of maternal antibodies, generally by 3 months of age.4 In cases of high antibody titer (≥512 for anti-D, ≥64 for anti-K), previous fetal loss due to HDFN, or previous history of early onset HDFN prior to 24 weeks gestational age (WGA), weekly maternal intravenous immunoglobulin (IVIG) infusions initiated in the first trimester sometimes in conjunction with plasma exchange may delay the onset of fetal anemia to a later gestation, increasing the chance of successful IUT if or when it is required.5, 6 Approximately one fourth of alloimmunized pregnancies with antigen positive fetuses and critical antibody titers (generally ≥16 for all clinically significant antibodies; ≥4 for anti-K; some centers additionally consider a titer of ≥4 to be critical for anti-c) are severe enough to require treatment with IUT.7, 8 While pre-pregnancy or first-trimester antibody titers are informative, they are not definitive predictors of HDFN severity.9 Prompt referral to a maternal fetal medicine (MFM) provider with experience in management of alloimmunization in pregnancy is critical to ensure early and appropriate risk assessment, monitoring, and timely intervention. Outcomes depend heavily on provider expertise in HDFN management, as preventable deaths due to delayed IUT, IUT related complications, or inadequate monitoring still occur even in a modern healthcare climate.10 Recently published consensus guidelines on pregnancy management of HDFN emphasize the time-sensitivity of alloimmunized pregnancy management and include prompt referrals to maternal fetal medicine (MFM), fetal antigen typing, proactive and frequent titer and Middle Cerebral Artery Peak Systolic Velocity (MCA-PSV) Doppler monitoring, and use of IVIG when indicated in severe cases.6 The successful implementation of these practices hinges on timely and informed diagnosis of at-risk pregnancies through initial laboratory reports. HDFN is highly survivable with close monitoring and specialized, timely treatment.11, 12 Ensuring proper care hinges on how clinicians interpret and respond to a newly identified RBC antibody. Ideally, the positive RBC antibody result is communicated promptly, interpreted accurately, and acted upon without delay. However, some practitioners may not be familiar with RBC alloimmunization, especially those who are not formally trained in HDFN diagnosis and management, and may not understand the critical time-sensitive nature of the test result. Early identification of red cell alloimmunization is essential, as certain interventions must be initiated within narrow gestational windows. Failure to move the patient to appropriate care in a timely fashion can result in irreversible harm, especially once the developing fetus enters the period of risk for anemia. Since fetal anemia can present as early as 15 WGA in some cases,13, 14 the timeframe for initiating appropriate screening and treatment is narrow. Diagnosis typically follows the first trimester pregnancy appointment which may not occur until 12–13 WGA, leaving just 2–4 weeks to assess fetal antigen status and begin ultrasound monitoring, and even less time in cases where the mother is eligible for IVIG. Figure 1 outlines the time sensitive and critical management steps that must take place before and during the window of risk for fetal anemia. Important steps include determination of fetal antigen status (through NIPT available beginning at 10 WGA for the D, K, E, C, c and Fya antigens in the United States and/or paternal antigen phenotyping, which can take 1–2 weeks in some cases), referral to MFM which at times is a significant distance for the family, and initiation of weekly MCA-PSV Doppler ultrasounds by 16 WGA. In cases of suspected severe HDFN, the use of IVIG should ideally begin prior to 13 WGA,15, 16 and often includes a laborious insurance approval process and surgical scheduling for port placement for the mother. Given that practitioners handling early pregnancy care may be unfamiliar with alloimmunization management, clear and standardized language in the RBC alloantibody test result offers an opportunity to ensure timely referral and begin the cascade of necessary monitoring and treatment. The 21st Century Cures Act, which requires direct release of results to patients, provides a framework for understanding and action. The federal statute emphasizes the importance of reports that are not only clinically precise but also clear and understandable to patients. Such clarity may also mitigate disparities related to healthcare professional familiarity with the topic, geographical access to advanced care services, or patient health literacy. In countries with modern healthcare systems, providers typically order a type and screen and obtain a blood sample that is sent to the laboratory at the first prenatal visit. “Type and Screen” is the accepted colloquial term for a suite of blood tests performed by the blood transfusion laboratory that consists of the blood type (includes the ABO and RhD blood groups) and the antibody detection test (usually referred to as antibody screen, Indirect Coombs Test or Indirect Antiglobulin Test). The antibody screen is the critical test to detect RBC alloantibodies. When an antibody screen is positive, the laboratory should proceed to identify the specific RBC alloantibody and titer for pregnant patients or those of childbearing potential. While this is a reflexive follow-up procedure in most laboratories, it is not consistently practiced as a national standard. Results are reported to the ordering provider, typically through electronic interfaces to the patient's record, through laboratory result portals or by faxed reports. While federal regulations (e.g., CLIA) require test reports to include elements such as test name, patient name, date of testing, sample type, and test result,17 there is no standardized language for how to interpret and communicate the results of a Type and Screen and its subsequent sub-parts. For example, some RBC alloantibodies are prone to cause HDFN (and thus are considered clinically significant), while others are not. The RBC antibody titer, which is critical for fetal risk assessment, may not always be performed, and if performed, clearly explained. Even when included, the wording and interpretation may not be understood by the ordering provider and patient, which can delay or prevent appropriate referral. Under the 21st Century Cures Act,18 patients have the right to receive their laboratory results directly, often through electronic portals. This makes clarity in laboratory reporting especially important, as language must both inform the provider and help patients understand the significance of their results and next steps.18 Despite the clinical significance of RBC alloimmunization, there is a lack of standardization in how antibody information is documented and communicated across care settings, and a potential for the ordering provider to not understand the next steps for the patient. Due to the multi-layered information (screen results, antibody ID, titers), RBC antibody reports usually use unstructured custom fields without critical flags. Deidentified report excerpts provided by patients at the time of alloimmunization diagnosis illustrate this variability (Table 1). Reports often lack reference to HDFN risk, include inconsistent terminology, do not define what constitutes a critical titer, and rarely include interpretation. For many patients, these reports were their first opportunity to learn about their diagnosis. If not understood, there can be a delay in referral to appropriate care which can lead to serious consequences for a fetus affected by HDFN. A series of anonymized real-life cases are provided by a patient advocacy group, demonstrating various consequences of gaps in initial management of HDFN. These cases highlight the urgent need for prescriptive antibody reporting language to help reduce the risk of preventable morbidity and mortality. A pregnant person's antibody screen at 9 WGA stated “Anti-E; weakly positive.” The ordering clinician interpreted this as a negative result and did not inform the patient of the laboratory finding. The patient did not have access to electronic medical records and was not aware of the test result. No referral or follow-up antibody titer assessment occurred during the pregnancy. The patient experienced a stillbirth due to HDFN at 33 WGA. Her subsequent pregnancy was successfully managed with serial IUTs by an MFM who serves as a referral clinician for HDFN. Comment: A laboratory report with no critical value flagged and no further context can lead to confusion for a health care practitioner (HCP) that is unfamiliar with the clinical implications of RBC alloimmunization. An output with informative next steps for the HCP and patient may have resulted in prompt referral to an MFM experienced in HDFN care who could monitor and treat with IUT, preventing fetal death. A positive outcome in the subsequent pregnancy further emphasizes the impact of timely management and specialist care on HDFN survival. A pregnant person with no history of transfusion or pregnancy with a previous partner was notified after her first prenatal visit that she tested positive for anti-K antibodies. She was referred to her nearest MFM and was seen 2 weeks after the initial diagnosis. To determine fetal antigen status, paternal bloodwork was ordered by her local obstetrician. At this time, she was informed that her anti-K titer was 1024. The next day, the father presented at the local obstetrician's office for bloodwork and was later informed via phone that he had tested negative for the Kell antigen. After learning more about alloimmunization over the next 2 weeks, the patient reached out to her MFM's office to ask follow-up questions about how she may have become sensitized with no prior transfusion history and a partner who does not carry the K antigen. At this time, the test was reviewed and confirmed that an antibody screen, rather than RBC antigen zygosity evaluation for the K antigen, was ordered on her partner. After waiting an additional 4 days to receive the results for the correct test, her partner was confirmed to carry the K antigen. The patient requested IVIG treatment, which was declined. Middle cerebral artery Dopplers were scheduled 2 weeks later. Upon her arrival for her first MCA Doppler ultrasound, it was confirmed that her son had severe fetal hydrops and died of HDFN. Comment: Treatment was delayed for this patient after incorrect laboratory testing was ordered for the father, leading the care team to assume the fetus was antigen negative and not at risk for HDFN. Additionally, the patient was seen by a MFM who was not aware that IVIG is a plausible treatment option to delay the onset of fetal anemia in cases at risk of severe HDFN with high antibody titers.6 A prompt referral to a clinician with specific expertise in severe HDFN may have resulted in proper risk assessment and a more timely, tailored treatment. The patient presented to her local obstetrician at 12 WGA for pregnancy management and was informed of anti-D antibodies which were too low to titer and was told “don't worry about it.” Again at 16 and 20 WGA, the patient returned for titer assessment and was not informed of results. The patient reports not knowing the name of her condition. The patient coincidentally logged in to her online patient portal 19 days after her 20 WGA titer assessment to see an anti-D titer of 2048. The next day, she called her doctor's office, who then realized a referral to MFM was never sent. She was seen the next day by her local MFM at 23 WGA. Ultrasound revealed MCA Doppler value of 2.4 Multiples of the Median (MoM) (well over the 1.5 MoM threshold for IUT) and fetal hydrops. The patient received a same-day referral to an MFM with a specialty in HDFN treatment, who held the clinic open late to await her arrival. The specialist MFM informed the patient for the first time of the name of her condition and conducted three IUTs over the course of 1 week to avoid fetal cardiac failure (starting hematocrit 10%; ending hematocrit 38% after three IUTs). Six total IUTs were necessary, and a healthy baby boy was born at 35 WGA requiring double volume exchange transfusion at 2 days of age, phototherapy, 37 days in the NICU, and two top-up blood transfusions at 5 and 9 weeks of age. Comment: The antibody result of “too low to titer” resulted in missed referral and lack of communication to the patient of her condition. The rescue effort which took place after the patient recognized the referral failure was intensive and available to the patient due to her proximity to a highly specialized MFM with specific expertise in early-onset HDFN. While this is an extraordinary outcome, it was contingent on the patient's coincidental proximity to highly specialized care. A timely referral to MFM would have allowed for proper treatment planning. One promising solution to potential discontinuities in the HDFN care continuum is the adoption of synoptic reporting, an approach widely used in surgical pathology that presents key data elements in a structured, standardized format for patients with cancer and other diagnoses.19, 20 The synoptic report system was devised fundamentally for the same reason as the RBC alloimmunization reporting challenge: critical information was being provided in different ways, which led to misunderstanding of what the results meant for the patient's care. Synoptic reports use a “data element: response” structure (e.g., “RBC Antibody identified: anti-c”), ensuring critical information is complete and easy to locate. Structured antibody reporting could be particularly beneficial for early prenatal care, emergency settings, and transitions of care where time and clarity are critical. Such language should be implemented in the case of any clinically significant RBC antibodies as defined by the laboratory in FCP (biologically female at birth, age 0–49). Critical components of an RBC antibody notification are described with rationale in Table 2. Positive (Normal result = Negative) If currently pregnant, prompt referral to maternal fetal medicine independent of titer and gestation is necessary. In individuals who are not currently pregnant, referral to maternal fetal medicine for pre-pregnancy consult is suggested if future pregnancy is desired. Consistently applying the above report's components can dramatically improve the clarity, visibility, and interoperability of antibody-related documentation. An example that includes all the above report components is available in Figure 2. The positive antibody screen test result should be flagged as a critical value, and the reference range of “negative” should be included in the report. Implementing standardized reporting for red cell antibodies will require institutional support, updates to EMR templates, and collaboration between the software developers of laboratory information systems (LIS), transfusion medicine and pathology physicians, and clinical informatics. The synoptic approach is intended to communicate essential clinical and laboratory information clearly. It should be succinct, thorough, and sufficient so that it may be actionable by a provider, therefore enabling a proper management trajectory for the at-risk patient. It should include fixed and automated features when possible in Table An example of if is a which the antigens as on the synoptic report. If an to antigen is but is not in the then a (e.g., in could be which the to type in the care must be when in results the significant between and antigens (e.g., K and and antigens that are by one and or and A patient notification is available as and should also include the synoptic report When a is an interpretation is for patients who not only have the right to their laboratory data the report but also to understand what it that are or sent through an electronic health records system can be especially in cases of antibody screening blood or blood transfusion of their care or obstetrician's office, when patients are therefore for their HCP of their alloimmunization. it is to the HCP who the synoptic report to it to patients. a phone number for direct communication between the patient and the ordering provider or laboratory can help to reduce confusion and for the patient. 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