Weighing the risk of hemolytic disease of the newborn versus the benefits of using of RhD-positive blood products in trauma.

Hemostatic resuscitation is a blood-based transfusion approach for the treatment of patients with traumatic hemorrhagic shock. Data in both the prehospital and in-hospital settings have demonstrated improved survival with a balanced approach to transfusion with either whole blood or blood components given early and in a balanced ratio, such as 1:1:1.1-9 Similar results have been published for children, indicating that the use of low titer group O whole blood (LTOWB) or high ratios/low deficits of blood components are independently associated with improved survival in patients with life-threatening hemorrhage.3 This is important since a recent prospective, observational study reported that the 28-day mortality rate for children with traumatic life-threatening hemorrhage is higher than in adults (36% vs. 24%, respectively).10, 11 At the beginning of the resuscitation when the patient's RhD-type is unknown, ideally, RhD-negative red blood cells (RBC) and/or LTOWB would be provided especially to females of childbearing potential (FCP); however RhD-negative units are very scarce (only 7% can donate O RhD-negative RBCs and 3%–5% can donate RhD-negative LTOWB at two large American blood collectors, personal communication M. Yazer and Pampee Young, December 2022) and are unlikely to be widely available prehospital and perhaps even during the early in-hospital phases of the resuscitation. However, if more available RhD-positive blood products are to be used, there is the risk of D-alloimmunization in the recipient. Providing RhD-positive transfusions to FCP is controversial and the decision to do so is nuanced and complex as other authors have summarized.12 The rate of D-alloimmunization is not currently known in children. Estimates for the risk of D-alloimmunization in injured adolescents and adults ranges from 7.8%13 to 42.7%,14 with many studies finding rates between 10% and 30% for general hospitalized patients.15 Thus, relative to healthy people, where the rate of D-alloimmunization is 80%,16-18 the rate of D-alloimmunization is much lower in injured patients. While the risk of causing future immediate or delayed hemolytic reactions due to an anti-D that was stimulated by an RhD-positive transfusion administered during trauma resuscitation is very low,19, 20 the main concern is that this antibody could lead to hemolytic disease of the fetus and newborn (HDFN) if a FCP becomes alloimmunized. Prospective studies on this outcome in this population have not been performed, but the overall risk of causing HDFN in this setting has been modeled. In a simple model of RhD-negative FCPs who were transfused with RhD-positive products during their resuscitation, the risk of fetal death from HDFN was calculated to be 0.3% using the following assumptions21: 76% of women survive hemorrhage due to trauma; 21% become sensitized to the D antigen; 86% of females in the United States become pregnant; 60% of fetuses are Rh(D)-positive; 4% of fetuses affected by HDFN die. In RhD-negative FCPs who were transfused with RhD-positive products, if other severe neonatal/fetal outcomes of HDFN, such as requiring intrauterine transfusion or exchange transfusion (occurs in 25% of affected pregnancies),22 are also included along with fetal death, then the overall risk of the fetus/neonate experiencing a severe outcome as a result of maternal D-alloimmunization rises to 2%.21 Thus, with major advancements in maternal-fetal medicine, the worst outcomes of HDFN are uncommon. A more comprehensive model that accounted for a variety of other societal factors affecting trauma survival, D-alloimmunization, and HDFN risks found that the overall risk of HDFN of any severity was approximately 3% for RhD-negative FCPs who were transfused with RhD-positive blood products during their resuscitation.23 This comprehensive model was also used to estimate the overall risk of HDFN of any severity for 1 million RhD-negative girls/women between the ages of <1 month and 49 years who were transfused with RhD-positive products during trauma resuscitation. The overall risk of developing HDFN of any severity ranged from 0% in neonates <30 days of age to between 1% and 6.5% in women aged 18–20 years based on the lowest and highest adult D-alloimmunization rates, respectively.24 Essentially, the rate of future HDFN increased as the child's age increased, largely due to the increasing rates of alloimmunization as the child's age increased, until the rate plateaued between 18 and −20 years old. The London, UK air ambulance service predicted if the 5561 patients transfused prehospital per year were exclusively transfused RhD-positive products, it would take 5.7 years for one HDFN death or disability event to occur.25 Currently, the question is which blood product should be selected to begin resuscitation. LTOWB has many advantages over component therapy (Table 1). In the literature, composed mainly of observational studies, a 1.2-fold to 2.0-fold reduction in mortality or improved survival in trauma patients following LTOWB transfusion has been demonstrated compared to using conventional components for the resuscitation (Table 2; see also reference 26). In addition, several studies have also found reduced conventional component transfusion requirements following LTOWB transfusion in a variety of different patient populations (Table 3). The use of LTOWB instead of blood components can therefore be considered a blood conservation strategy. These encouraging results have led to 123 trauma centers to adopt the use of LTOWB as their first-choice resuscitation fluid for injured trauma patients.27-29 There are also 10 pediatric trauma centers routinely using LTOWB. Finally, several surveys have asked the public about their willingness to accept an urgent transfusion if the transfusion could complicate a future pregnancy. Over 90% of women surveyed in the St. Louis, MO metropolitan area were willing to accept an RhD-positive transfusion when the HDFN risk ranged from 0.1% to 4%.30 At the University of Alabama's Department of Surgery and School of Nursing, 89% of female members indicated that they would accept a life-saving transfusion that could cause harm to a future fetus even when the magnitude of that risk was not specifically specified.31 It has been demonstrated that prehospital and early in-hospital transfusions save lives and that the risks associated with using RhD-positive blood products are minimal compared to their lifesaving benefits. (Figure 1) The availability of RhD-negative LTOWB is very low and some blood suppliers are not able to provide it. Moreover, maintaining a RhD-negative LTOWB inventory alongside a RhD-positive LTOWB inventory in every hospital is simply not possible and, as the statistics demonstrate, is unnecessary given the low risk of severe HDFN outcomes following the transfusion of RhD-positive products during the resuscitation. As a result, hospitals need to decide if they should use RhD-positive LTOWB for the potential 1.2–2.0-fold improvement in survival and accept the 0.3% risk of future fatal HDFN as described above. The Massive Transfusion in Children-2 (MATIC-2) trial will be a randomized control trial designed to compare mortality outcomes amongst injured children who are resuscitated with either LTOWB or conventional components. While there are several studies with a similar design in adults that are currently underway or are in advanced planning, MATIC-2 is the only trial of its kind in pediatric patients and its results will form the basis for how to optimally resuscitate injured children. It is important for the timely completion of this study that the use of RhD-positive LTOWB is permitted if RhD-negative LTOWB is unavailable given the low risk of D-alloimmunization in this critically ill population. This study aimed to determine the rate of D-alloimmunization in a prospective cohort of children. Surveys of women have revealed that they overwhelmingly prefer to receive a product that might improve their survival despite a small risk to a future pregnancy.30, 31 The medical community must thoughtfully consider the benefits of transfusing LTOWB in this vulnerable population against the very small future risk of HDFN. No funding was obtained to write this commentary The authors have disclosed no conflicts of interest.