LAUSR

Rhesus D antigen (RH1)negative women, when exposed to RH1positive red blood cells (RBC), are at risk of developing antiRH1 antibodies. If their offspring are RH1positive, there is a risk of haemolytic disease of the fetus and newborn (HDFN). Prevention of RH1mediated HDFN is achieved with (i) RH/KEL compatible transfusion in women of childbearing age, and (ii) administration of antiRH1 immunoglobulin prophylaxis.1– 3 Once RH1 alloimmunization is established, its management in pregnancy is challenging and relies mainly on intrauterine transfusions (IUTs).3 Intravenous immunoglobulin (IVIG), with or without therapeutic plasma exchange (TPE), may be used as a bridge to IUT.4– 10 Blockade of the fetal/neonatal Fc receptor (FcRn) to reduce transplacental IgG transfer is a promising therapy currently under investigation.11 Disparate therapeutic approaches are utilized clinically due to a lack of clear evidence supporting specific protocols, and significant fetal morbimortality persists despite ‘optimal therapy’. Here, we present a case of RH1 immunization postallogeneic stem cell transplant (HSCT), which was successfully managed during pregnancy with IVIG and PE, allowing for a latepreterm birth of a transfusionindependent neonate. Regular antibody level monitoring allowed us to tailor therapy for this challenging case. The patient was diagnosed with chronic myeloid leukaemia (CML) at the age of 26. Despite treatment with tyrosine kinase inhibitors, the disease evolved to acceleratedphase CML with an additional genetic mutation of dismal prognosis, prompting HSCT. Fertility preservation prior to conditioning chemotherapy resulted in the cryopreservation of nine embryos, as previously described.12 The patient developed posttransplantation amenorrhoea with premature ovarian insufficiency. HSCT from a donor with blood group O, RH: −1, −2, −3, 4, 5 to a B, RH: 1, 2, 3, 4, 5 recipient induced RBC alloimmunization, with antiRH1, antiRH2, and antiRH3 antibodies detected 6 months posttransplantation. The patient successfully conceived following transfer of the couple's last blastocyst at 41 years of age, resulting in their only pregnancy. Initial antibody screening at eight weeks gestation (WG) identified a critical titre of antiRH1 antibodies (1/2048, Figure 1A) and a low titre for antiRH3 (1/1) and antiRH2 (detectable solely by enzymatic techniques). AntiRH1 quantification by continuous flow analysis (CFA)13 at 12 WG, prior to treatment initiation, was 9.2 IU/ mL (≈2 μg/mL, Figure 1B), confirming the presence of a high antiRH1 titre. The father was identified to have a RH1 heterozygous genotype. Noninvasive fetal genotyping at 12 WG, was uninterpretable due to maternal origin cellfree DNA contamination (data not shown). Reanalysis of a cryopreserved preHSCT bone marrow sample demonstrated a homozygous RH1 genotype in the mother. Consequently, the fetus was considered RH1positive and no invasive testing was performed. International guidelines remain elusive for the optimal management of pregnancies at high risk of HDFN.1,3 Considering the high antiRH1 antibody titre, the absence of remaining embryos, and the couple's wishes, we initiated weekly IVIG therapy at 1 g/kg starting at 12 WG and TPE 3×/ week starting at 15 WG after determination of the fetal RH1positive status. Therapy was well tolerated. A decline of the antiRH1 antibody titre assessed by indirect antiglobulin test (IAT) (Figure 1A) and CFA (Figure 1B) demonstrated effectiveness. IVIG monotherapy reduced the antiRH1 antibody concentration from approximately 2 to about 1 μg/mL; the addition of TPE further reduced antiRH1 antibody concentration below the critical threshold (Figure 1B).14,15 Between 17 and 23 WG, the antiRH1 antibody concentration remained at 1 μg/mL or less. After 25 WG, antiRH1 antibody titres raised exponentially (Figure 1B), suggesting that TPE could no longer counterbalance the antiRH1 antibody production and was discontinued. IVIG was maintained as monotherapy. The fetus was followed by weekly ultrasonography including Doppler studies,16 never meeting criteria for IUT (Figure 1C), and from 32 WG, nonstress tests. The pregnancy remained uneventful and induction of labour at 36 WG resulted in the birth of a latepreterm male neonate [weight 2520 g (10– 25th percentile)] with adequate neonatal transition. The placenta was underweight (5th percentile) with histological signs of fetal vascular hypoperfusion. Cord blood analysis showed severe, yet compensated, haemolysis [Hb 129 g/L, haematocrit 42%, reticulocytes 401 109/l, total bilirubin 116 μmol/l, lactate dehydrogenase (LDH) 1175 iu/L]. Neonatal blood group was B RH1positive with a highly positive direct antiglobulin test (>1/1024). Elution confirmed the presence of antiRH1, antiRH2, and antiRH3 antibodies Received: 24 February 2023 | Accepted: 25 February 2023