International guidelines regarding the role of IVIG in the management of Rh- and ABO-mediated haemolytic disease of the newborn.

Haemolytic disease of the newborn (HDN) can be associated with significant morbidity. Prompt treatment with intensive phototherapy (PT) and exchange transfusions (ETs) can dramatically improve outcomes. ET is invasive and associated with risks. Intravenous immunoglobulin (IVIG) may be an alternative therapy to prevent use of ET. An international panel of experts was convened to develop evidence-based recommendations regarding the effectiveness and safety of IVIG to reduce the need for ETs, improve neurocognitive outcomes, reduce bilirubin level, reduce the frequency of red blood cell (RBC) transfusions and severity of anaemia, and/or reduce duration of hospitalization for neonates with Rh or ABO-mediated HDN. We used a systematic approach to search and review the literature and then develop recommendations from published data. These recommendations conclude that IVIG should not be routinely used to treat Rh or ABO antibody-mediated HDN. In situations where hyperbilirubinaemia is severe (and ET is imminent), or when ET is not readily available, the role of IVIG is unclear. High-quality studies are urgently needed to assess the optimal use of IVIG in patients with HDN.

Intravenous immunoglobulin in hemolytic disease of the newborn: A moving target in time.

Background: Alloimmune hemolytic disease of the newborn (AIHDN) results in hemolysis, anemia, hyperbilirubinemia with the potential for brain damage. Intravenous immunoglobulin (IVIG) has been investigated as an alternative low-risk procedure for the treatment of AIHDN in addition to traditional treatment methods such as phototherapy and exchange transfusion (ET). Aim: To evaluate the effectiveness of IVIG therapy in decreasing ET needs based on risk factors and clinical outcomes. Materials and Methods: Charts of neonates born >30 weeks of gestation who underwent phototherapy and were administered IVIG therapy due to AIHDN between January 2013 and July 2018 were retrospectively reviewed. Results: Sixty-three neonates were included in our study. Forty-three of them (68.3) % were full-term infants. ABO incompatibility (n = 33, 52.4%) was the major cause of AIHDN (n = 63). Additional risk factors for jaundice were found to coexist in 95.2% (n = 60) of the infants. Fifteen infants (23.8%) required ET, mostly due to Rh incompatibility (n = 11, 73.3%). Mortality was observed in 3.2% (n = 2) of the patients, 1.6% (n = 1) of whom were related to ET. Serum albumin value was found to be negatively correlated with the requirement for ET (r = 0.713, P < 0.001), whereas serum bilirubin albumin ratio was positively correlated (r = 0.489, _P < 0.001). Nine (14.3%) infants needed a simple transfusion during the hospitalization period, whereas five (7.9%) infants had readmission for simple transfusion after discharge. Apnea was the only complication seen in one (1.6%) patient. Conclusion: IVIG treatment should be considered due to its relative benefits when compared to exchange transfusion. In addition to its safety, it is a less complicated treatment modality with low side effect rates. It may be justified for elective use in neonates suffering from AIHDN, who will require ET with a risk of mortality by decreasing the peak of total serum bilirubin levels.

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International guidelines regarding the role of intravenous immunoglobulin (IVIG) in the management of Rh- and ABO-mediated haemolytic disease of the newborn was drafted by an international panel of experts in the fields of hematology, neonatology, and blood transfusion and was published in British Journal of Haematology on March 16, 2022. The guidelines summarize the evidence-based practice of IVIG in Rh- and ABO-mediated haemolytic disease of the newborn and propose related recommendations. The guidelines recommend that IVIG should not be applied as a routine treatment regimen for Rh- and ABO-mediated haemolytic disease of the newborn in order to reduce exchange transfusion (ET), and the best time to apply IVIG remains unclear in the situations where hyperbilirubinaemia is severe (approaching or exceeding the ET threshold) or ET cannot be implemented. These guidelines are formulated with rigorous methods, but with the lower quality of evidence.

Hemolytic disease and reticulocytopenia of the newborn attributable to maternal immunoglobulin G anti-M reacting optimally at cold temperatures.

BACKGROUND: Hemolytic disease of the fetus and newborn (HDFN) attributable to anti-M is rare, although case reports implicate anti-M in varying severities of HDFN, including fetal hydrops and intrauterine death. CASE DESCRIPTION: We describe the case of a newborn with HDFN associated with an atypical immunoglobulin (Ig) G anti-M that reacted best at cold temperatures. The maternal antibody detected in pregnancy was not reactive at 37°C, and a direct antiglobulin test (DAT) on red blood cells (RBCs) from the newborn was negative, suggesting an anti-M that should not have been clinically relevant. However, the infant developed hyperbilirubinemia (bilirubin level, 17.6 mg/dL), hemolytic anemia (hemoglobin nadir, 5.5 g/dL), and reticulocytopenia. Laboratory testing demonstrated the presence of an IgG anti-M in maternal and neonatal samples reacting best at 4°C. This passively acquired IgG anti-M provoked hemolytic anemia in the infant and likely suppressed erythropoiesis, resulting in reticulocytopenia with prolonged anemia. He was treated for IgG anti-M HDFN with 10 intravenous Ig infusions and 10 days of oral prednisone followed by a taper. He required seven transfusions with M- RBCs. His hemoglobin level normalized at 3 months of age. Follow-up at 2 years revealed no hematologic or neuro-developmental concerns. CONCLUSION: To our knowledge, this is the second report of HDFN attributable to an IgG anti-M reacting preferentially at cold temperature with no 37°C reactivity. Clinically relevant IgG anti-M may elude standard testing. Early recognition and testing for cold-reacting IgG anti-M should be considered for newborns with hemolysis, a negative DAT, and prolonged anemia.

Use of intravenous immunoglobulin in neonates at a tertiary academic hospital: a retrospective 11-year study.

BACKGROUND: Intravenous immunoglobulin (IVIG) is used to treat a variety of diseases in the neonatal intensive care unit (NICU). Although audits have reported on the spectrum of IVIG use in adults, the indications and utilization in neonates has not been investigated. The objectives of this study were to describe the usage pattern of and indications for IVIG in a tertiary care NICU. STUDY DESIGN AND METHODS: A retrospective chart review was performed of all neonates who received IVIG in the NICU from January 2003 to December 2013. Data collected included patient demographic features, antenatal maternal details, neonatal laboratory results, treatment details, adverse events, and patient outcome. RESULTS: Thirty-seven neonates received IVIG over the 11-year period. Twenty-three (67%) were treated for hemolytic disease of the newborn (HDN); 13 treatments were ABO related, six were anti-D related, and four were for clinically significant antibodies. Fourteen (33%) were treated for non-HDN causes, including eight for septic neonates, two for neonates with necrotizing enterocolitis, two for neonates with a clinically significant antibody but without evidence of hemolysis, and two for neonates with glucose 6-phosphate dehydrogenase deficiency. A complete hemolytic workup was not performed consistently before the receipt of IVIG. CONCLUSIONS: This novel assessment of IVIG use in the NICU revealed the spectrum of disease for which IVIG is ordered. This study also found that key diagnostic tests needed to confirm an immune etiology for idiopathic jaundice are not performed routinely before IVIG receipt. Neonatal transfusion-related databases are needed to carry out pragmatic clinical trials to establish better evidence-based guidelines for IVIG therapy in the NICU.

Phenobarbitone in Rh hemolytic disease of the newborn: a randomized double-blinded placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy of prophylactic oral phenobarbitone (PB) in neonates with Rh hemolytic disease of the newborn. STUDY DESIGN: In this double-blind randomized trial conducted in a tertiary care unit, we randomly allocated neonates with Rh hemolytic disease of the newborn born at or after 32 weeks' gestation to PB (10 mg/kg/day on day 1 followed by 5 mg/kg/day on days 2-5) (n = 23) or oral glucose (n = 21). The primary outcome was the duration of phototherapy. RESULTS: Baseline variables were comparable. There was no difference in the median duration of phototherapy [54 (range: 0-180) vs. 35 h (0-127); p = 0.39] and in the incidences of failure of phototherapy or significant rebounds of serum bilirubin. However, the proportion of infants with cholestasis was significantly lower in the PB group (0 vs. 19%; p = 0.04). CONCLUSIONS: PB does not reduce duration of phototherapy or its episodes. Its potential to reduce cholestasis needs validation in larger studies.

Darbepoetin Alfa for Late-onset Anemia in Neonates with Rhesus Hemolytic Disease.

Neonates with Rhesus hemolytic disease can present with anemia beyond 1 wk of age due to bone marrow suppression and low erythropoietin secretion. Erythropoietin stimulating agents (ESA) were tried to manage anemia in these neonates. Darbepoetin alfa (DA) is a long-acting ESA used to treat anemia in premature neonates and in children with chronic kidney disease or on cancer chemotherapy. The authors present their experience of using DA to treat late-onset hyporegenerative anemia in 3 neonates with Rhesus isoimmunization. Darbepoetin alfa 4 mcg/kg was given subcutaneously at a 1-2-wk interval to target hemoglobin of 10-12 g/dL. No adverse effects were observed, and the treated infants had a reduced need for the packed red blood cell transfusions.

Early intravenous immunoglobin (two-dose regimen) in the management of severe Rh hemolytic disease of newborn--a prospective randomized controlled trial.

Phototherapy is the standard treatment in moderately severe hemolytic disease of newborn (HDN), whereas exchange transfusion (ET) is the second line in progressive cases. Intravenous immunoglobin (IVIG) has been suggested to decrease the need for ET. We aimed at assessing the efficacy of early two-dose regimens of IVIG to avoid unnecessary ET in severe Rh HDN. The study included 90 full-term neonates with Rh incompatibility unmodified by antenatal treatment and not eligible for early ET and which were randomly assigned into one of three groups: group (I), treated by conventional method; groups IIa and IIb received IVIG once at 12 h postnatal age if PT was indicated, in a dose of 0.5 and 1 g/kg, respectively. Analysis revealed 11 neonates (22%) in the conventional group and 2 (5%) in the intervention group who administered low-dose IVIG at 12 h, while none in group IIb required exchange transfusion (p = 0.03). Mean bilirubin levels were significantly lower during the first 96 h in the intervention group compared to the conventional group (p < 0.0001). Shorter duration of phototherapy (52.8 ± 12.39 h) and hospital stay (3.25 ± 0.71 days) in the IVIG group compared to conventional group (84 ± 12.12 h and 4.72 ± 0.78 days, p < 0.0001, respectively) were observed. We conclude that IVIG administration at 12 h was effective in the treatment of severe Rh HDN; the low-dose IVIG (0.5 g/kg) was as effective as high dose (1 g/kg) in reducing the duration of phototherapy and hospital stay, but less effective in avoiding exchange transfusion.

Effect of intravenous immunoglobulins to postpone the gestational age of first intrauterine transfusion in very severe red blood cell alloimmunization: A case-control study.

BACKGROUND: Early intrauterine transfusion (IUT) is associated with a higher risk of fetal loss. Our objective was to evaluate the efficiciency of intravenous immunoglobulins (IVIG) to postpone the gestational age at first IUT beyond 20 weeks of gestation (WG) compared to the previous pregnancy in case of very severe red blood cell (RBC) alloimmunization. STUDY DESIGN AND METHODS: Very severe RBC alloimmunization was defined by a high titer of antibodies and a previous pregnancy complicated by a first IUT before 24 WG and/or perinatal death directly related to alloimmunization. We performed a single-center case-control study. Cases and controls were patients respectively treated with weekly IVIG infusions started before 13 WG, and without. RESULTS: Twenty cases and 21 controls were included. Gestational age (GA) at first IUT was postponed after 20 WG in 18/20 (90 %) of patients treated with IVIG and in 15/21 (71 %) in the control group (p = 0.24). Compared to the previous pregnancy, the GA at first IUT was postponed by a median of 22 [+11; +49] days in the IVIG group and occurred in average 2 days earlier [-17 ; +12] in the non-treated group (p = 0.02). There was no difference between number of IUT and need for exchange-transfusion. IVIG treatment was associated with a significant decrease of antibodies' quantitation. CONCLUSION: In our series, IVIG tends to differ first IUT beyond 20 WG and have a significant effect in postponing the gestational age of the first IUT in patients with very severe RBC alloimmunization.

Successful management of anti-Jra alloimmunization in pregnancy: a case report.

BACKGROUND: Hemolytic disease of the fetus/newborn due to Jr(a) immunization is very rare and considered to be mild, and only routine obstetrical care is recommended for pregnant women sensitized to the Jr(a) antigen. CASE REPORT: A 20-year-old nulliparous woman was referred to our hospital for perinatal management. Her indirect Coombs test was positive for anti-Jr(a) antibody (1:64). At 33 weeks' gestational age, we observed that fetal growth was mildly restricted and the peak systolic velocity of the fetal middle cerebral artery (PSV-MCA) was above the upper limit of the reference range (1.55 multiples of the median). Amniocentesis was also carried out and the DeltaOD450 value was in the lower mid-zone of the Liley curve. We continued to carefully observe the patient because we observed PSV-MCA values within 1.50-1.60 multiples of the median and no other findings of fetal anemia. She vaginally delivered a female infant weighing 2,136 g at 37 weeks' gestational age. The infant received treatment with both iron and recombinant erythropoietin without developing hyperbilirubinemia and blood transfusion. CONCLUSION: PSV-MCA should be monitored for the detection of fetal anemia, even in pregnant women sensitized to some antigens for which only routine obstetrical care is recommended.

Mechanisms of anti-D action in the prevention of hemolytic disease of the fetus and newborn: what can we learn from rodent models?

PURPOSE OF REVIEW: Hemolytic disease of the fetus and newborn can be effectively prevented by administration of anti-D to the mother. In this setting, the IgG purified from the plasma of D-alloimmunized donors prevents the maternal immune response to D-positive red blood cells (RBC). Several monoclonal anti-D antibodies have recently been developed for potential use in the setting of hemolytic disease of the fetus and newborn; the functional assays used to assess the potential success of these antibodies have often assumed antigen clearance as the predominant mechanism of anti-D. Unfortunately, the in-vivo success of these monoclonal antibodies has thus far been limited. A similar inhibitory effect of IgG has been observed in animal models with a vast array of different antigens, referred to as antibody-mediated immune suppression (AMIS). Here, studies of AMIS are reviewed and the relevance of these findings for anti-D-mediated immunoprophylaxis is discussed. RECENT FINDINGS: In animal models of AMIS, IgG-mediated antigen clearance was not sufficient for prevention of the antibody response to RBC. Furthermore, anti-RBC IgG inhibited B-cell priming to foreign RBC, but failed to prevent a T-cell response and immunological memory. SUMMARY: The applicability of AMIS models for determining the true mechanism of anti-D, though uncertain, may nevertheless provide knowledge as to potential mechanisms of action of anti-RBC antibodies.

[An alternative method of treatment for the icteric-anemic form of neonatal iso-immunization to rhesus factor].

Neonatal iso-immunization to rhesus factor is a rather well studied pathology. Negative rhesus factor in a pregnant women is a ground to determine anti-D-antibody titers during pregnancy, which allows one to define the tactics of pregnancy management and neonatal treatment just after birth.

Severe hemolytic disease of the newborn from anti-e.

Maternal antibody-mediated fetal red blood cell destruction secondary to non-D Rhesus (Rh) antibodies is a significant cause of hemolytic disease of the newborn (HDN). Here, we report a rare case of severe HDN associated with maternal antibody to Rh e. In addition to severe anemia, the infant developed thrombocytopenia, conjugated hyperbilirubinemia and cholelithiasis. Resolution of the infant's cholelithiasis occurred following treatment with ursodeoxycholic acid.

Efficacy of two dose regimes of intravenous immunoglobulin in Rh hemolytic disease of newborn--a randomized controlled trial.

OBJECTIVE: To compare the effect of two dose regimes of IVIg (0.5 g/kg vs. 1g/kg given soon after birth) on duration of phototherapy in Rh-isoimmunized neonates 32 week and above gestation. DESIGN: Randomized controlled trial. SETTING: Tertiary care hospital. SUBJECTS: Rh positive blood group neonates of gestation 32 weeks and above born to Rh negative mothers having positive Direct Coombs test and without any major malformation. INTERVENTION: Intravenous immunoglobulin (IVIg) infusion over 2 h either 0.5 g/kg (low dose group, n=19) or 1.0 g/kg (high dose group, n=19). PRIMARY OUTCOME VARIABLE: Duration of phototherapy. RESULTS: The mean duration of phototherapy was 77.3+/-57.2 h in low dose group versus 55.4+/-49 h in high dose group (mean difference=21.9; 95% CI-13.1 to 56.9). There was no difference in need for exchange transfusion (21% in both the groups) and requirement of packed red blood cells transfusion (12 transfusions in both groups). The duration of hospital stay was similar [8.4+/-6.9 and 13.6+/-14.8 days, respectively (mean difference=-5.1; 95% CI-12.8 to 2.5)]. No adverse effects of IVIg administration were noted. CONCLUSION: Two regimens of IVIg (0.5 g/Kg or 1 g/Kg) had comparable effect on duration of phototherapy, duration of hospital stay and exchange transfusion requirement, in Rh isoimmunized neonates of gestation 32 weeks and above.

Efficacy of intravenous immunoglobulin in the management of haemolytic disease of the newborn.

Intravenous immunoglobulin (IVIG) is indicated for use in Rhesus and ABO hemolytic disease of the newborn (HDN) to reduce the need for exchange transfusion, to decrease hospital stay and the duration of phototherapy. 11 infants received IVIG and the effect of IVIG on the total serum bilirubin (TSB) level, and its effect on the rate of rise of TSB was quantified. There was a statistically significant decrease in bilirubin levels before and after treatment with IVIG from 234 to 219 micromol/L (p = 0.001). In addition, the rate of change in bilirubin level significantly altered from an upward to a downward trend. (p = 0.001). The Number Needed to Treat (NNT) to prevent an exchange transfusion was 2.75--comparable with the recent systematic review of IVIG with a NNT of 2.7.

Single-stranded DNA aptamer targeting and neutralization of anti-D alloantibody: a potential therapeutic strategy for haemolytic diseases caused by Rhesus alloantibody.

BACKGROUND: Rhesus (Rh) D antigen is the most important antigen in the Rh blood group system because of its strong immunogenicity. When RhD-negative individuals are exposed to RhD-positive blood, they may produce anti-D alloantibody, potentially resulting in delayed haemolytic transfusion reactions and Rh haemolytic disease of the foetus and newborn, which are difficult to treat. Inhibition of the binding of anti-D antibody with RhD antigens on the surface of red blood cells may effectively prevent immune haemolytic diseases. MATERIALS AND METHODS: In this study, single-stranded (ss) DNA aptamers, specifically binding to anti-D antibodies, were selected via systematic evolution of ligands by exponential enrichment (SELEX) technology. After 14 rounds of selection, the purified ssDNA was sequenced using a Personal Genome Machine system. Haemagglutination inhibition assays were performed to screen aptamers for biological activity in terms of blocking antigen-antibody reactions: the affinity and specificity of the aptamers were also determined. RESULTS: In addition to high specificity, the aptamers which were selected showed high affinity for anti-D antibodies with dissociation constant (Kd) values ranging from 51.46±14.90 to 543.30±92.59 nM. By the combined use of specific ssDNA aptamer 7 and auxiliary ssDNA aptamer 2, anti-D could be effectively neutralised at low concentrations of the aptamers. DISCUSSION: Our results demonstrate that ssDNA aptamers may be a novel, promising strategy for the treatment of delayed haemolytic transfusion reactions and Rh haemolytic disease of the foetus and newborn.

Use of recombinant erythropoietin for the management of severe hemolytic disease of the newborn of a K0 phenotype mother.

Very few people do not express any Kell antigens on their red blood cells (K0 phenotype). They can be immunized by transfusion or pregnancy and develop antibodies against Kell system antigens. These maternal antibodies can cause severe hemolytic disease of the fetus/newborn, as a result of the suppression of erythropoiesis and hemolysis. Multiple intrauterine transfusions in the management of severe hemolytic disease have been shown to cause erythropoietic suppression as well. Recombinant erythropoietin has been successfully used in the management of late anemia of infants with Rh hemolytic disease and in 1 case of KEL1 (Kell)-associated hemolytic disease. The authors present the case of severe hemolytic disease of a newborn due to KEL5 (Ku) isoimmunization of his K0 phenotype mother. Regular intrauterine transfusions were performed to manage the severe fetal anemia (Hb 3 g/dL). A male infant was born at the 36th week of gestation having normal hemoglobin (15.8 g/dL) and developed only mild hyperbilirubinemia. On the 15th day of life, the infant's hematocrit had fallen to 27.3%, with low reticulocyte count and low erythropoietin level. The infant was managed successfully with recombinant erythropoietin.

Intravenous immunoglobulin in the management of a rare cause of hemolytic disease of the newborn: Anti-SARA antibodies.

Hemolytic disease of newborn (HDN) is a condition that develops in a fetus, when the IgG molecules produced by the mother pass through the placenta and attack the fetal red blood cells. HDN can occur due to Rh and ABO incompatibilities between the mother and the fetus as well as due to other allo-immune antibodies belonging to Kell (K and k), Duffy (Fya), Kidd (Jka and Jkb), and MNS (M, N, S, and s) systems. Role of intravenous immunoglobulin in management of HDN is not clear.SARA red blood cell antigen, first discovered in 1990 is a low frequency antigen. We report, a multiparous female whose pregnancy was complicated by HDN due to anti-SARA antibodies requiring both exchange transfusion and intravenous immunoglobulin. The response was sustained after intravenous immunoglobulin (IVIG) rather than after exchange transfusion.

Impact of specific medical interventions on reducing the prevalence of mental retardation.

OBJECTIVE: To explore the impact of medical interventions on reducing the prevalence of mental retardation (MR) in the United States over the last 50 years. DESIGN: We reviewed the medical literature and other data from 1950 to 2000 to construct estimates of the general and condition-specific prevalence of MR in the United States over time. We further explored the existing literature to document historically important influences on condition-specific prevalence, including the year that an effective intervention was introduced, the likelihood of success of the intervention, and the availability of such interventions nationwide. Specific conditions included congenital syphilis, Rh hemolytic disease of the newborn, measles, Haemophilus influenzae type B meningitis, congenital hypothyroidism, phenylketonuria, and congenital rubella syndrome. SETTING: Twentieth-century North America. PARTICIPANTS: Children with MR or 1 of the 7 specific conditions listed earlier. MAIN OUTCOME MEASURES: Case-specific and general prevalence of MR from 1950 to 2000. RESULTS: The prevalence of MR caused by a number of specific medical conditions has decreased sharply over the last 50 years. However, the incidence of each of these conditions is relatively low, and cases of MR due to these conditions represent, at most, 16.5% of the total number of cases of MR in 1950. CONCLUSION: Although specific medical interventions have prevented thousands of cases of MR, their contribution to the overall prevalence of MR is relatively small.