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.

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.

Enfermedad hemolítica perinatal causada por anticuerpos anti-M y tratada con inmunoglobulinas intravenosas fetales / Hemolytic disease of the fetus due to anti-M antibodies treated with fetal intravenous immunoglobulin therapy

Presentamos el caso de una mujer de 28 años, con 2 abortos tardíos previos causados por anticuerpos anti-M. En la actual gestación es tratada desde la semana 23 hasta la semana 34 con inmunoglobulinas intravenosas fetales, con resultado satisfactorio. Aunque no hay estudios randomizados y controlados que indiquen que las inmunoglobulinas fetales son efectivas en el manejo de la isoinmunización, pequeñas series de casos sugieren resultados prometedores (AU)

We present the case of a 28-year-old woman with two prior late miscarriages caused by anti-M antibodies, leading to alloimmunization of her previous pregnancies. During this pregnancy, she was successfully treated with intravenous immunoglobulins administered from the 23th to the 34th week of pregnancy. There are no randomized trials to indicate whether the antenatal use of intravenous immunoglobulin is effective in the management of fetal red blood cell alloimmunization. Several case series suggest a beneficial role in preventing severe fetal anemia (AU)

Intravenous immunoglobulin in isoimmune haemolytic disease of newborn: an updated systematic review and meta-analysis.

BACKGROUND: Intravenous immunoglobulin (IVIg) is used in neonates with isoimmune haemolytic disease to prevent exchange transfusion (ET). However, studies supporting IVIg had methodological issues. OBJECTIVE: To update the systematic review of efficacy and safety of IVIg in neonates with isoimmune haemolytic disease. METHODS: MEDLINE, Embase databases and Cochrane Central Register of Controlled Trials (Cochrane Library) were searched (from inception to May 2013) for randomised or quasi-randomised controlled trials comparing IVIg with placebo/controls in neonates with isoimmune haemolytic disease without any language restriction. Three investigators assessed methodological quality of included trials. Meta-analyses were performed using random effect model and risk ratio (RR)/risk difference (RD) and mean difference with 95% CI calculated. MAIN RESULTS: Twelve studies were included, ten trials (n=463) of Rh isoimmunisation and five trials (n=350) of ABO isoimmunisation (three studies had both population). Significant variations in risk of bias precluded an overall meta-analysis of Rh isoimmunisation. Studies with high risk of bias showed that IVIg reduced the rate of ET in Rh isoimmunisation (RR 0.23, 95% CI 0.13 to 0.40), whereas studies with low risk of bias that also used prophylactic phototherapy did not show statistically significant difference (RR 0.82, 95% CI 0.53 to 1.26). For ABO isoimmunisation, only studies with high risk of bias were available and meta-analysis revealed efficacy of IVIg in reducing ET (RR 0.31, 95% CI 0.18 to 0.55). CONCLUSIONS: Efficacy of IVIg is not conclusive in Rh haemolytic disease of newborn with studies with low risk of bias indicating no benefit and studies with high risk of bias suggesting benefit. Role of IVIg in ABO disease is not clear as studies that showed a benefit had high risk of bias.

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.

Use of intravenous immunoglobulin in neonates with haemolytic disease and immune thrombocytopenia.

BACKGROUND/AIM: Intravenous immunoglobulin is a blood product made of human polyclonal immunoglobulin G. The mode of action of intravenous immunoglobulin is very complex. It is indicated in treatment of neonatal immune thrombocytopenia and haemolytic disease of the newborn. The aim of the study was to present our experience in the use of intravenous immunoglobulin in a group of term neonates. METHODS: We analysed all relevant clinical and laboratory data of 23 neonates who recieved intravenous immunoglobulin during their hospitalization in Neonatal Intensive Care Unit of Mother and Child Health Care Institute over a five year period, from 2006. to 2010. RESULTS: There were 11 patients with haemolytic disease of the newborn and 12 neonates with immune thrombocytopenia. All of them recieved 1-2 g/kg intravenous immunoglobulin in the course of their treatment. There was no adverse effects of intravenous immunoglobulin use. The use of intravenous immunoglobulin led to an increase in platelet number in thrombocytopenic patients, whereas in those with haemolytic disease serum bilirubin level decreased significantly, so that some patients whose bilirubin level was very close to the exchange transfusion criterion, avoided this procedure. CONCLUSION: The use of intravenous immunoglobulin was shown to be an effective treatment in reducing the need for exchange transfusion, duration of phototherapy and the length of hospital stay in neonates with haemolytic disease. When used in treatment of neonatal immune thrombocytopenia, it leads to an increase in the platelet number, thus decreasing the risk of serious complications of thrombocytopenia.

Tin-mesoporphyrin in the treatment of refractory hyperbilirubinemia due to Rh incompatibility.

We describe the use of tin-mesoporphyrin (SnMP) in the treatment of an infant with Rh hemolytic disease. The infant's hyperbilirubinemia responded to phototherapy but every time the phototherapy was discontinued, the serum bilirubin rebounded and repeat phototherapy was necessary. A single intramuscular dose of SnMP on day 18 eliminated the need for further phototherapy and allowed us to discharge this infant.

Hematological morbidity and management in neonates with hemolytic disease due to red cell alloimmunization.

Treatment of severe anemia with intrauterine red cell transfusions in fetuses with red cell alloimmunization has led to a dramatic increase in perinatal survival. Due to this increased survival focus is nowadays shifting towards improving postnatal treatment options. Phototherapy, exchange transfusions and intravenous immunoglobulin are used to treat hyperbilirubinemia and prevent kernicterus. Postnatal treatment of anemia consists of top-up transfusions, supplements to support erythropoiesis such as folic acid and iron, and occasionally erythropoietin treatment. In addition to anemia, other hematological complications such as thrombocytopenia, coagulation disturbances, leucopenia and iron overload have been reported. This review focuses on the hematological morbidity in neonates with red cell alloimmunization and summarizes the current evidence on management options.

Single versus multiple dose intravenous immunoglobulin in combination with LED phototherapy in the treatment of ABO hemolytic disease in neonates.

Intravenous immunoglobulin (IVIG) has been found to decrease hemolysis in neonatal jaundice due to blood group incompatibility, but a consensus on its usage has not been reached. We conducted a study to compare single versus multiple dose of IVIG in combination with light emitting diode (LED) phototherapy in patients with neonatal jaundice secondary to ABO blood incompatibility, and compared the efficacy of these treatments with that in a group of patients who received LED phototherapy solely. Thirty-nine term neonates with ABO blood group incompatibility were enrolled in the study. Group I received one dose of IVIG (1 g/kg) and LED phototherapy, and group II two doses of IVIG (1 g/kg) and LED phototherapy, whereas group III received LED phototherapy only. In group I, exchange transfusion was performed in one patient (6%) and in group II in one patient (10%). In the control group, none of the patients required exchange transfusion. Duration of LED phototherapy was 4.3 ± 0.7 days in group I + II (IVIG group), 3.9 ± 0.6 days in group III (P = 0.06). Lowest hematocrit level in group I + II was 35.0 ± 7.8 and group III was 38.9 ± 4.2, this was statistically significant (P = 0.034). IVIG therapy, single or multiple, did not affect exchange transfusion, need of erythrocyte transfusion and hospitalization time when used in combination with LED phototherapy in the treatment of ABO hemolytic jaundice in neonates.

Intravenous immunoglobulin in neonates with rhesus hemolytic disease: a randomized controlled trial.

BACKGROUND: Despite limited data, international guidelines recommend the use of intravenous immunoglobulin (IVIg) in neonates with rhesus hemolytic disease. OBJECTIVE: We tested whether prophylactic use of IVIg reduces the need for exchange transfusions in neonates with rhesus hemolytic disease. DESIGN AND SETTING: We performed a randomized, double-blind, placebo-controlled trial in neonates with rhesus hemolytic disease. After stratification for treatment with intrauterine transfusion, neonates were randomly assigned for IVIg (0.75 g/kg) or placebo (5% glucose). The primary outcome was the rate of exchange transfusions. Secondary outcomes were duration of phototherapy, maximum bilirubin levels, and the need of top-up red-cell transfusions. RESULTS: Eighty infants were included in the study, 53 of whom (66%) were treated with intrauterine transfusion(s). There was no difference in the rate of exchange transfusions between the IVIg and placebo groups (7 of 41 [17%] vs 6 of 39 [15%]; P = .99) and in the number of exchange transfusions per patient (median [range]: 0 [0-2] vs 0 [0-2]; P = .90) or in duration of phototherapy (4.7 [1.8] vs 5.1 [2.1] days; P = .34), maximum bilirubin levels (14.8 [4.7] vs 14.1 [4.9] mg/dL; P = .52), and proportion of neonates who required top-up red-cell transfusions (34 of 41 [83%] vs 34 of 39 [87%]; P = .76). CONCLUSIONS: Prophylactic IVIg does not reduce the need for exchange transfusion or the rates of other adverse neonatal outcomes. Our findings do not support the use of IVIg in neonates with rhesus hemolytic disease.

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.

[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.

Intravenous immunoglobulin and necrotizing enterocolitis in newborns with hemolytic disease.

OBJECTIVE: The objective of this study was to assess whether the use of high-dose intravenous immunoglobulin (IVIG) in late-preterm and term newborns with severe isoimmune hemolytic jaundice caused by Rh and ABO incompatibility was a risk factor for necrotizing enterocolitis (NEC). METHODS: An observational, retrospective study that encompassed 16 years was conducted. A total of 492 liveborn infants who were of >or=34 weeks' gestation and had severe isoimmune hemolytic jaundice caused by Rh (n = 91) and ABO (n = 401) incompatibility and were treated with phototherapy were included in the study. IVIG (500 mg/kg over 2-4 hours) was indicated when total serum bilirubin level plus 2 points reached 85% of the cutoff value for performing exchange transfusion. RESULTS: A total of 167 (34%) infants received IVIG. NEC was diagnosed in 11 (2.2%) patients: 10 (6%) in the IVIG-treated group and 1 (0.3%) in the non-IVIG-treated group. Five patients required urgent operation, and 1 of them died as a result of massive intestinal necrosis. Another patient died 2 years later as a result of short bowel syndrome. In the multivariate analysis, cesarean delivery (odds ratio [OR]: 3.76 [95% confidence interval (CI): 1.10-12.90), Apgar test at 5 minutes (OR: 0.50 [95% CI: 0.40-0.64), and IVIG (OR: 31.66 [95% CI: 3.25-308.57]) were independent factors significantly associated with NEC. CONCLUSIONS: The use of high-dose IVIG for severe isoimmune hemolytic jaundice in late-preterm and term infants was associated with a higher incidence of NEC.

[High-dose intravenous immunoglobulin therapy and neonatal jaundice due to red blood cell alloimmunization]. / Immunoglobulines polyvalentes intraveineuses et ictère néonatal par allo-immunisation érythrocytaire.

Neonatal jaundice resulting from immunological hemolysis is not uncommon. While it is possible to prevent a large number of Rh-isoimmune hemolytic diseases by administration of specific anti-D immunoglobulins to the mother, the prevention of incompatibility in the ABO groups is not feasible. In spite of advances made in the use of phototherapy, and in order to avoid kernicterus, the treatment of these jaundices can require one or several exchange transfusions (ET), a therapy which is not devoid of risk. For some time now, the data concerning the efficiency of high-dose intravenous immunoglobulin therapy (HDIIT) in the treatment of these jaundices have been increasing. A review of the literature shows that, if used as soon as possible in newborn infants over 32 weeks of gestation age, afflicted with Rh or ABO hemolytic disease, the HDIIT brings about, with no undesirable side effects, a significant decrease in the ET number as well as a significant reduction in the length of phototherapy and hospitalization. The data suggesting that HDIIT could increase the risk of late transfusion is open to controversy.

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.

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.