BACKGROUND: Prevention of pregnancy-related alloimmunization and the management of hemolytic disease of the fetus and newborn (HDFN) has significantly improved over the past decades. Considering improvements in HDFN care, the objectives of this systematic literature review were to assess the prenatal treatment landscape and outcomes of Rh(D)- and K-mediated HDFN in mothers and fetuses, to identify the burden of disease, to identify evidence gaps in the literature, and to provide recommendations for future research.
METHODS: We performed a systematic search on MEDLINE, EMBASE and clinicaltrials.gov. Observational studies, trials, modelling studies, systematic reviews of cohort studies, and case reports and series of women and/or their fetus with HDFN caused by Rhesus (Rh)D or Kell alloimmunization. Extracted data included prevalence; treatment patterns; clinical outcomes; treatment efficacy; and mortality.
RESULTS: We identified 2,541 articles. After excluding 2,482 articles and adding 1 article from screening systematic reviews, 60 articles were selected. Most abstracted data were from case reports and case series. Prevalence was 0.047% and 0.006% for Rh(D)- and K-mediated HDFN, respectively. Most commonly reported antenatal treatment was intrauterine transfusion (IUT; median frequency [interquartile range]: 13.0% [7.2-66.0]). Average gestational age at first IUT ranged between 25 and 27 weeks. weeks. This timing is early and carries risks, which were observed in outcomes associated with IUTs. The rate of hydrops fetalis among pregnancies with Rh(D)-mediated HDFN treated with IUT was 14.8% (range, 0-50%) and 39.2% in K-mediated HDFN. Overall mean ± SD fetal mortality rate that was found to be 19.8%±29.4% across 19 studies. Mean gestational age at birth ranged between 34 and 36 weeks.
CONCLUSIONS: These findings corroborate the rareness of HDFN and frequently needed intrauterine transfusion with inherent risks, and most births occur at a late preterm gestational age. We identified several evidence gaps providing opportunities for future studies.

UNASSIGNED: The primary objective was to explore perinatal and neonatal outcomes amongst infants who received intrauterine transfusion (IUT) for the management of hemolytic disease of the fetus and newborn (HDFN). The secondary objective was to evaluate the role of key investigations in the fetus at risk of HDFN and assess the relationship with neonatal outcomes. We hypothesized that middle cerebral artery peak systolic velocity (MCA-PSV) and corresponding multiples of the median (MoM) would be predictive of neonatal course.
UNASSIGNED: This was a retrospective observational study conducted at a tertiary center in the United Kingdom between January 2000 and August 2020. Trust approval was obtained to conduct this service review. Pregnancies requiring IUT for HDFN were identified using the fetal medicine department database. Inclusion criteria were infants who received IUT for HDFN. 67 pregnancies were eligible for inclusion in the study with 156 IUT events. Data were extracted using healthcare records. Statistical analysis was performed using SPSS version 28.0, data were assessed for normality and Spearman\'s correlation analysis was performed with p values < .05 considered significant.
UNASSIGNED: 67 pregnancies were included in the study which led to the live birth of 68 infants (one twin pregnancy). There were no fetal deaths following IUT. There was one neonatal death due to extreme prematurity following spontaneous vaginal delivery at 23 + 4 weeks gestation, occurring three days following IUT. 97% of infants required admission to the neonatal intensive care unit and 88% required phototherapy. 25% of infants required readmission for red blood cell transfusion due to anemia. There was a significant correlation between maternal anti-D antibody levels and length of neonatal admission r = 0.477, p = .014. MCA-PSV and MoM measured prior to the last IUT had a significant positive correlation with the duration of phototherapy: r = 0.527 (p < .001) and r = 0.313 (p < .05) respectively. Linear regression analysis demonstrated a significant positive relationship between MCA-PSV and corresponding MoM recorded prior to the last IUT with r2= 0.177 (p = .003) and r2= 0.101 (p = .029).
UNASSIGNED: HDFN is an important cause of fetal anemia associated with significant neonatal morbidity. MCA-PSV and MoM may be predictive of neonatal phototherapy requirements. The predictive value of MCA-PSV appears to be dependent on the timing of measurement during the antenatal period and more research is needed. Multicentre collaboration is required to generate a reliable large-scale database to further delineate the value of MCA-PSV and MoM and predict neonatal outcomes in cases of HDFN requiring IUT. This data would assist clinicians in antenatal planning and enable more informed counseling of parents in the antenatal period.

BACKGROUND: Bombay phenotype (Oh ) is a rare blood group and poses unique challenges during pregnancy, including an adequate supply of blood products in case of postpartum hemorrhage (PPH) and the risk of hemolytic disease of the fetus and newborn (HDFN). Case reports of antenatal care in this cohort are scarce. Herein, we present a case of twin pregnancy in an Oh woman and outline her multidisciplinary management. We summarize the literature to better inform decision-making and patient blood management in the antenatal care of Oh women.
METHODS: A 22-year-old G1P0 presented at 15 weeks gestation with dichorionic diamniotic twins and known Oh phenotype. Hematinics were optimized to minimize anemia. Anti-H titers were tracked and were 1:256 at both 28 and 36 weeks gestation. Regular middle cerebral artery dopplers were performed to assess for fetal anemia. There was constant communication with obstetrics and anesthetics teams. Both autologous frozen and directly donated fresh red cells were available as part of a clear, detailed transfusion plan. Transfusion was not required and neither child was affected by HDFN. The neonates were group O, DAT negative, and group A, DAT positive. Maternal anti-A was detected in the neonatal eluate.
CONCLUSIONS: To our knowledge, this is only the second report of twin pregnancy in an Oh female and the first time a detailed transfusion plan has been published. Through employing patient blood management strategies, engaging a collaborative multidisciplinary approach, and establishing a clear delivery plan, the antenatal challenges of Bombay phenotype are surmountable.

UNASSIGNED: Anti-Rh17 is a rare red blood cell (RBC) antibody to high-frequency antigens that may cause severe hemolytic disease of the fetus and newborn (HDFN). Despite the rarity of HDFN caused by Anti-Rh17, this antibody was reported in many different populations. Emergency transfusions, especially exchange transfusions, present a huge problem if no compatible RBCs of phenotype D- are available.
UNASSIGNED: Here we report obstetrical histories of three women and describe their pregnancies complicated by anti-Rh17 antibodies. We summarized published cases of pregnancies complicated by anti-Rh17 and reviewed transfusion treatment and outcomes. Additionally, a simplified flowchart for the management of such pregnancies is proposed.
UNASSIGNED: Four pregnancies were affected by severe HDFN, and three of them ended with perinatal death. In the fourth case, the baby was born hydropic and icteric and the condition was rapidly deteriorating. Emergency exchange transfusion was performed with incompatible O-negative RBC units in AB-negative plasma. The baby was discharged on the 14th day in good health. In the available literature, 15 women and 22 pregnancies were reported, 20 of them developed severe HDFN. According to the data, intrauterine transfusion for treatment of HDFN was the most common form of treatment with the donation of the mother\'s blood. Different options for exchange transfusion were described, including incompatible RBCs.
UNASSIGNED: In more than 90% of described pregnancies of HDFN caused by anti-Rh17 antibody, transfusion treatment was required. Therefore, RBC from D- phenotype has to be available. According to published data, in emergent circumstances when maternal and blood from donor with phenotype D- is not available, incompatible exchange transfusion is a better choice than delaying transfusion when it is necessary. It is of essential importance that pregnancies with high risk of HDFN due to anti-Rh17 are managed by a multidisciplinary team (transfusion medicine specialist, obstetrician, neonatologist) in a highly specialized tertiary institution.

The Jra antigen of the JR blood group system is a highly prevalent red blood cell antigen. Although anti-Jra-associated hemolytic disease of the fetus and newborn (HDFN) is generally considered mild-to-moderate, a rare fatal case was recently reported. We report the third example of HDFN-related anti-Jra with fatal outcomes. The clinical significance of anti-Jra antibody as a cause of HDFN should be reassessed.

The severity of the hemolytic disease of the fetus and newborn (HDFN) due to Jra mismatch ranges from no symptoms to severe anemia that requires intrauterine and exchange transfusions. We encountered a newborn, born to a healthy mother having anti-Jra at 38 weeks of pregnancy, who had moderate anemia, a positive direct antiglobulin test (DAT) result, no increased erythropoiesis, and no jaundice at birth. Flow cytometry revealed that the Jra antigen of red cells in the infant was nearly negative at birth, biphasic at 5 weeks, and lowly expressed at 7 months of life. We searched online for previous case reports on HDFN due to Jra incompatibility. Among 63 reported cases, excluding 25 cases, 38 were included with the present case for analysis. Of 39 newborns, 10 developed clear anemia (hemoglobin <10.0 g/dL), and 1 died, 5 developed hydrops fetalis, 4 needed intrauterine transfusion and/or exchange transfusion, and 3 received red cell transfusion after birth; overlaps were included. Among 29 neonates with no anemia, 8 needed interventions including phototherapy and γ-globulin infusion, and the remaining 21 received conservative supports only. The maternal anti-Jra titer, ranging between 4 and 2048, did not correlate with the severity of anemia, levels of bilirubin, or any interventions required. The DAT of red cells was positive in 29 of 36 fetuses/newborns tested, whereas it was often negative among anemic neonates (4 of 9) (P < .05). Hematopoiesis did not increase effectively, as indicated by reticulocyte ratios between 1.7% and 22.3%, even with the increase in reticulocytes in anemic neonates compared with nonanemic neonates (P < .05). Total bilirubin levels ranged broadly between 0.2 and 14.3 mg/dL but were generally low. The maternal anti-Jra titer and IgG3 subclass did not correlate with the morbidity of the newborns. Being identical/compatible between mothers and their infants may possibly enhance infants\' morbidity, as a weak tendency was observed (P = .053). Maternal anti-Jra may suppress erythropoiesis in fetuses via a mechanism different from the established HDFN, such as anti-D, as evidenced by the lower reticulocyte count and small increase in bilirubin in neonates. As the anti-Jra titer, IgG subclass, and DAT were not correlated with the severity, the mechanism of anti-Jra-induced HDFN remains to be elucidated.

BACKGROUND: Hemolytic disease of the fetus and newborn (HDFN) remains a serious pregnancy complication which can lead to severe fetal anemia, hydrops and perinatal death. Areas covered: This review focusses on the current prenatal management, treatment with intrauterine transfusion (IUT) and promising non-invasive treatment options for HDFN. Expert commentary: IUTs are the cornerstone in prenatal management of HDFN and have significantly improved perinatal outcome in the past decades. IUT is now a relatively safe procedure, however the risk of complications is still high when performed early in the second trimester. Non-invasive management using intravenous immunoglobulin may be a safe alternative and requires further investigation.