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Recombinant anti-D for prevention of maternal-foetal Rh(D) alloimmunization: a randomized multi-centre clinical trial
Mayekar RV, Paradkar GV, Bhosale AA, Sachan R, Beeram S, Anand AR, Mundle SR, Trivedi Y, Md R, Patole KP, et al
Obstet Gynecol Sci. 2020;63(3):315-322
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Abstract
Objective: To compare the efficacy and safety of recombinant anti-D (R-anti-D) with conventional polyclonal anti-D (Poly anti-D) in preventing maternal-fetal rhesus D (RhD) alloimmunization and to investigate the immunogenicity of R-anti-D. Methods: This was a randomized, open-label, multi-center clinical trial conducted in RhD-negative pregnant women who did not receive antenatal anti-D who delivered RhD-positive babies and showed negative indirect Coombs tests (ICTs) at baseline. The women were randomized in a 2:1 ratio to R-anti-D or Poly anti-D groups and were administered 300 mcg (IM) of the corresponding drug within 72 hours of delivery. ICT was performed 72 hours, 90 days, and 180 days after anti-D injection. Serum samples were collected to check for the development of antibodies against R-anti-D at days 90 and 180, using bridging enzyme-linked immunosorbent assay. The proportion of subjects who had positive ICT results at days 90 and 180 were compared between the groups using Fisher's exact test. Results: A total of 144 women were randomized to the R-anti-D group and 71 to the Poly anti-D group. Three women in the R-anti-D and none in the Poly anti-D group had a positive ICT result at day 90. No woman in either group had positive ICT result at day 180. Both drugs were well tolerated with only 4 reports of adverse events in each group-all were mild, non-serious, and resolved without sequelae. No subject developed antibodies against R-anti-D. Conclusion: The studied R-anti-D is comparable in efficacy to conventional Poly anti-D and is safe and non-immunogenic.Trial Registration: Clinical Trials Registry of India Identifier: Trial Registration: Clinical Trials Registry of India Identifier: CTRI/2017/03/008101.
PICO Summary
Population
RhD-negative pregnant women who did not receive antenatal anti-D and delivered RhD-positive babies and showed negative indirect Coombs tests (ICTs) at baseline (n= 215).
Intervention
Recombinant anti-D (300 mcg), (n= 144).
Comparison
Polyclonal anti-D (300 mcg), (n= 71).
Outcome
Three women in the Recombinant anti-D and none in the Polyclonal anti-D group had a positive ICT result at day 90. No woman in either group had positive ICT result at day 180. Both drugs were well tolerated with only 4 reports of adverse events in each group-all were mild, non-serious, and resolved without sequelae. No subject developed antibodies against Recombinant anti-D.
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Antenatal and postpartum prevention of Rh alloimmunization: A systematic review and GRADE analysis
Hamel, C., Esmaeilisaraji, L., Thuku, M., Michaud, A., Sikora, L., Fung-Kee-Fung, K.
PloS one. 2020;15(9):e0238844
Abstract
BACKGROUND Existing systematic reviews of Rh immunoprophylaxis include only data from randomized controlled trials, have dated searches, and some do not report on all domains of risk of bias or evaluate the certainty of the evidence. Our objective was to perform an updated review, by including new trials, any comparative observational studies, and assessing the certainty of the evidence using the GRADE framework. METHODS We searched MEDLINE, Embase and the Cochrane Library from 2000 to November 26, 2019. Relevant websites and bibliographies of systematic reviews and guidelines were searched for studies published before 2000. Outcomes of interest were sensitization and adverse events. Risk of bias was evaluated with the Cochrane tool and ROBINS-I. The certainty of the evidence was performed using the GRADE framework. RESULTS Thirteen randomized trials and eight comparative cohort studies were identified, evaluating 12 comparisons. Although there is some evidence of beneficial treatment effects (e.g., at 6-months postpartum, fewer women who received RhIg at delivery compared to no RhIg became sensitized [70 fewer sensitized women per 1,000 (95%CI: 67 to 71 fewer); I2 = 73%]), due to very low certainty of the evidence, the magnitude of the treatment effect may be overestimated. The certainty of the evidence was very low for most outcomes often due to high risk of bias (e.g., randomization method, allocation concealment, selective reporting) and imprecision (i.e., few events and small sample sizes). There is limited evidence on prophylaxis for invasive fetal procedures (e.g. amniocentesis) in the comparative literature, and few studies reported adverse events. CONCLUSION Serious risk of bias and low to very low certainty of the evidence is found in existing RCTs and comparative observational studies addressing optimal effectiveness of Rh immunoprophylaxis. Guideline development committees should exercise caution when assessing the strength of the recommendations that inform and influence clinical practice in this area.
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Clinical value of different anti-D immunoglobulin strategies for preventing Rh hemolytic disease of the fetus and newborn: A network meta-analysis
Xie X, Fu Q, Bao Z, Zhang Y, Zhou D
PLoS One. 2020;15(3):e0230073
Abstract
BACKGROUND Several anti-D immunoglobulin strategies exist for preventing Rh hemolytic disease of the fetus and newborn. This study systematically assessed the clinical value of those therapeutic strategies. METHODS The Web of Science, PubMed, EMBASE, China National Knowledge Infrastructure (CNKI) and Wanfang databases were searched for eligible studies that evaluated the value of different anti-D immunoglobulin strategies in preventing maternal anti-D antibody sensitization. Combined odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated. The network meta-analysis was conducted using Stata 14.2 and WinBUGS 1.4.3 software. RESULTS Twenty-four original studies involving 64860 patients were included. Among all therapeutic measures, injecting 300 mug anti-D immunoglobulin at 28 and 34 gestational weeks (antenatal 5/E) appeared to be the most effective measure for preventing maternal antibody sensitization (surface under the cumulative ranking curve [SUCRA] = 96.8%), while a single injection at 28 gestational weeks (SUCRA = 89.2%) was the second most effective. Administering no injection or a placebo (SUCRA = 0.0%) was the least effective intervention measure. CONCLUSION Among the therapeutic measures, antenatal 5/E appeared to be the best method for reducing the positive incidence of anti-D antibodies in the maternal serum; thus, it may be the most effective treatment for preventing fetal hemolytic disease.
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First line treatments for newly diagnosed primary immune thrombocytopenia in children: a systematic review and network meta-analysis
Acero-Garces DO, Garcia-Perdomo HA
Current pediatric reviews. 2019
Abstract
BACKGROUND The first-line interventions in immune thrombocytopenia (ITP) consist in intravenous polyclonal immunoglobulins (IVIg), corticosteroids and anti-D immunoglobulin (anti-D). OBJECTIVE We aimed to compare the effectiveness and safety of first line treatments for newly-diagnosed primary ITP in children to increase the platelet count. METHODS We searched MEDLINE, EMBASE, LILACS, and the Cochrane Central register of Controlled Trials (CENTRAL); we included clinical trials. We performed the statistical analysis in R. RESULTS We included 12 studies for meta-analysis. Compared with IVIG 2g/kg, response rates were lower for prednisone 2mg/kg at 72 hours [RR 0.04 (95% CI 0.0 to 0.68)] and at 7 days [RR 0.23 (95% CI 0.08 to 0.67)]; at 48 hours, methylprednisolone 30mg/kg also showed lower response rates [RR 0.72 (95% CI 0.52 to 0.99)]. IVIG 2g/kg and 2.5g/kg had less adverse effects than Anti-D, methylprednisolone and IVIG 0.8g/kg. For rising platelet count, no statistical differences were found at 24 hours or at 7 days; at 48 hours, IVIG 2g/kg showed better results than Anti-D 75microg/kg [MD -58.84 (95% CI -87.02 to -25.66)]. At one month, platelet count with IVIG 2g/kg was higher than Anti-D 50 and 75microg/kg [-82.03 (95% CI -102.60 to -61.46) and -78.77 (95% CI -97.80 to -59.74), respectively], but lower than methylprednisolone 50mg/kg [MD 118 (95% CI 3.88 to 232.12)]. CONCLUSION The total platelet count rises higher in early and late phases with IVIG than Anti-D, but in long term it is higher with methylprednisolone. Additionally, IVIG causes less adverse effects than Anti-D and corticosteroids.
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Efficacy and Safety of Anti-D Immunoglobulins versus Intravenous Immunoglobulins for Immune Thrombocytopenia in Children: Systematic Review and Meta-analysis of Randomized Controlled Trials
Lioger B, Maillot F, Ternant D, Passot C, Paintaud G, Bejan-Angoulvant T
The Journal of Pediatrics. 2018;204:225-233 e8.
Abstract
OBJECTIVES To compare the efficacy and safety of intravenous immunoglobulins (IVIG) and anti-D immunoglobulin (anti-D) in pediatric immune thrombocytopenia (ITP). STUDY DESIGN We conducted a systematic review and meta-analysis following PRISMA guidelines, including all randomized controlled trials that have assessed the efficacy and safety of anti-D and IVIG in children with ITP. We searched Medline, Embase, and Cochrane databases. Primary outcomes were the proportion of children achieving platelet count responses as defined in each study and bleeding response. Other safety outcomes included infusion reactions and hemolysis. RESULTS Eleven studies with 558 children were included. Anti-D was significantly inferior to IVIG at increasing platelet counts, both for thresholds of >20 x 10(9)/L at 24-72 hours (response rate ratio for anti-D vs IVIG 0.85, 95% CI 0.78-0.94) and >50 x 10(9)/L at 24-72 hours (response rate ratio for anti-D vs IVIG 0.75, 95% CI 0.61-0.92). Bleeding response was assessed in 4 studies, but some heterogeneity in reporting leads to unclear conclusion. General symptoms after anti-D infusion were less frequent than after IVIG (Peto OR 0.39, 95% CI 0.25-0.62). Hemolysis was more frequent after anti-D. The overall quality of the studies was low. CONCLUSIONS Compared with anti-D, IVIG led to a better response in terms of platelet count and may be preferred as a first-line treatment of ITP in children with acute hemorrhagic symptoms. However, the clinical significance of IVIG superiority on platelet count remains unclear.
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Clinical effect of anti-D immunoglobulin in treatment of childhood immune thrombocytopenia: a meta analysis
Qin W, Huang SL, Li TT
Zhongguo Dang Dai Er Ke Za Zhi = Chinese Journal of Contemporary Pediatrics. 2017;19((10)):1070-1076.
Abstract
OBJECTIVE To investigate the clinical effect and safety of anti-D immunoglobulin (anti-D) in the treatment of children with newly diagnosed acute immune thrombocytopenia (ITP) through a Meta analysis. METHODS PubMed, EMBASE, Cohrane Library, Ovid, CNKI, and Wanfang Data were searched for randomized controlled trials (RCTs) published up to April 2017. Review Manager 5.3 was used for the Meta analysis. RESULTS Seven RCTs were included. The Meta analysis showed that after 72 hours and 7 days of treatment, the intravenous immunoglobulin (IVIG) group had a significantly higher percentage of children who achieved platelet count >20x109/L than the anti-D group (P<0.05). There were no significant differences in platelet count after 24 hours, 72 hours, and 7 days of treatment between the anti-D (50 mug/kg) group and the IVIG group (P>0.05), and there were also no significant differences in platelet count after 24 hours and 7 days of treatment between the 50 mug/kg and 75 mug/kg anti-D groups (P>0.05). The anti-D group had a significantly greater reduction in the hemoglobin level than the IVIG group after treatment, but did not need transfusion. No children in the anti-D group or the IVIG group experienced serious adverse reactions. CONCLUSIONS Intravenous injection of anti-D may have a similar effect as IVIG in improving platelet count in children with acute ITP, but it may be slightly inferior to IVIG in the rate of platelet increase after treatment. The anti-D dose of 50 mug/kg may have a similar effect as 75 mug/kg. The recommended dose of anti-D for treatment of ITP is safe.
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Safety and efficacy of a single dose of anti-D (WinRho(R)) in severe thrombocytopenia secondary to dengue virus infection
Pannu AK, Bhalla A, Singhal M, Suri V, Shafiq N, Varma S
Indian Journal of Critical Care Medicine : Peer-Reviewed, Official Publication of Indian Society of Critical Care Medicine. 2017;21((2)):80-84.
Abstract
OBJECTIVE To evaluate the efficacy of a single intravenous (IV) dose of anti-D in severe thrombocytopenia (<20,000) due to dengue virus (DEV) infection. MATERIALS AND METHODS An open label, investigator-initiated, randomized interventional study was conducted that included thirty dengue patients (all positive for IgM enzyme-linked immunosorbent assay) with severe thrombocytopenia (<20,000/mm3). Patients were randomized to receive anti-D (50 mug/kg single IV dose) plus supportive therapy or supportive therapy alone. RESULTS The rate of rise in platelet count was significantly high in the intervention group at 24, 36, and 48 h. At the end of 48 h, 60% patients in the intervention group achieved a platelet count of ≥50,000/mm3 as compared to 6.7% in the control group (P = 0.0019). The requirement of the platelet concentrate infusion in the control group was significantly higher, i.e. 342 ml (+/-193) as compared to the intervention group requiring only 187 ml (+/-79). The intervention group showed a significant improvement in bleeding manifestations in all the patients by 24 h in Grade 2 bleed (P = 0.032) and by 48 h in Grade 1 bleed (P = 0.014). CONCLUSIONS Severe thrombocytopenia (≤20,000/mm3) secondary to DEV infection was rapidly and safely reversed by administration of a single dose of 50 mug/kg (250 IU/kg) anti-D IV.
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Comparison between IV immune globulin (IVIG) and anti-D globulin for treatment immune thrombocytopenia: a randomized open-label study
Eghbali A, Azadmanesh P, Bagheri B, Taherahmadi H, Sadeghi Sedeh B
Fundamental & Clinical Pharmacology. 2016;30((4):):385-389. 385
Abstract
OBJECTIVE To compare the effect of IV immune globulin (IVIG) and anti-D globulin (anti-D) for treatment of immune thrombocytopenia (ITP) in children. METHODS A randomized, open-label, single center clinical trial was done in Amir-Kabir Hospital (Arak, Iran). The study was performed on 60 children with ITP, aged from 1 to 15 years. Patients were randomly assigned (1:1) to 50 mug/kg Anti-D or 1g/kg IVIG. Platelet counting was done at baseline, and 3 days, 7 days and 14 days after treatment termination. Safety assessment was done in all patients. RESULTS Anti-D caused a quicker response on the 3rd day of treatment (P <0.001). Both drugs caused a significant rise in number of platelets on the 7th and the 14th day of treatment. Compared to IVIG, except a significant drop in hemoglobin concentration (P < 0.001), anti-D had lower rate of side effects including fever (P < 0.05), allergy (P < 0.01), and headache (P < 0.001). CONCLUSION Our results showed that anti-D was associated with rapid rise of platelets compared to IVIG. In addition, anti-D treatment had acceptable safety profile. This article is protected by copyright. All rights reserved.
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High dose intravenous anti-D immune globulin is more effective and safe in Indian paediatric patients of immune thrombocytopenic purpura
Swain TR, Jena RK, Swain KP
Journal of Clinical and Diagnostic Research : Jcdr. 2016;10((12)):FC12-FC15.
Abstract
INTRODUCTION Immune Thrombocytopenia (ITP) is characterised by an autoimmune antibody-mediated destruction of platelets and impaired platelet production. Few controlled trials exist to guide management of patients with ITP in Indian scenario for which patients require an individualized approach. Anti-D (Rho (D) immune globulin) at a higher dose can prove to be a cost effective and safe alternative for Indian patients with ITP. AIM: To compare the safety and efficacy of higher dose (75mug/kg) intravenous Anti-D immune globulin against the standard dose of 50mug/kg for the management of ITP in Indian patients. MATERIALS AND METHODS One hundred and sixty four children with newly diagnosed ITP between 4-14 years were randomly selected for inclusion and were treated with 50mug/kg (standard dose) or 75mug /kg (higher dose) of Anti-D to compare the efficacy and safety of higher dose intravenous anti-D immune globulin. Efficacy of Anti-D was measured in terms of rate of response and median time to response for increase in platelet counts. Any adverse event was noted. A decrease in haemoglobin concentration suggested accompanying haemolysis. RESULTS Seventy one out of 84 patients treated with Anti-D at 75mug/kg produced complete response (85%) with median time of response being 2.5 days. On the contrary, 45 patients (70%) patients treated with 50mug/kg had complete response. However, there was no significant increase in haemolysis with higher dose. A significant correlation was found between dose and peak increase in platelet count measured at 7th day following administration. However, there was no relationship between the decrease in haemoglobin and the dose given, or between the increase in platelet count and fall in haemoglobin. CONCLUSION A 75mug/kg dose of Anti-D is more effective with acceptable side effect in comparison to 50mug dose for treatment of newly diagnosed Indian patients of ITP.
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Anti-D administration in pregnancy for preventing Rhesus alloimmunisation
McBain RD, Crowther CA, Middleton P
Cochrane Database of Systematic Reviews.. 2015;((9)):CD000020.
Abstract
BACKGROUND During pregnancy, a Rhesus negative (Rh-negative) woman may develop antibodies when her fetus is Rhesus positive (Rh-positive). These antibodies may harm Rh-positive babies. OBJECTIVES To assess the effects of antenatal anti-D immunoglobulin on the incidence of Rhesus D alloimmunisation when given to Rh-negative women without anti-D antibodies. SEARCH METHODS We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2015) and reference lists of retrieved studies. SELECTION CRITERIA Randomised trials in Rh-negative women without anti-D antibodies given anti-D after 28 weeks of pregnancy, compared with no treatment, placebo or a different regimen of anti-D. DATA COLLECTION AND ANALYSIS Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS We included two trials involving over 4500 women, comparing anti-D prophylaxis with no anti-D during pregnancy in this review. Overall, the trials were judged to be at moderate to high risk of bias. The quality of the evidence for pre-specified outcomes was also assessed using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach.In regards to primary review outcomes, there did not appear to be a clear difference in the risks of immunisation when women who received anti-D at 28 and 34 weeks' gestation were compared with women who were not given antenatal anti-D: risk ratio (RR) for incidence of Rhesus D alloimmunisation during pregnancy was 0.42 (95% confidence interval (CI) 0.15 to 1.17, two trials, 3902 women; GRADE low quality evidence); at birth of a Rh-positive infant the RR was 0.42 (95% CI 0.15 to 1.17, two trials, 2297 women); and within 12 months after birth of a Rh-positive infant the average RR was 0.39 (95% CI 0.10 to 1.62, two trials, 2048 women; Tau2: 0.47; I2: 39%; GRADE low quality evidence). Neither of the trials reported on incidence of Rhesus D alloimmunisation in subsequent pregnancies.Considering secondary outcomes, in one trial, women receiving anti-D during pregnancy were shown to be less likely to register a positive Kleihauer test (which detects fetal cells in maternal blood) in pregnancy (at 32 to 25 weeks) (RR 0.60, 95% CI 0.41 to 0.88; 1884 women; GRADE low quality evidence) and at the birth of a Rh-positive infant (RR 0.60, 95% CI 0.46 to 0.79; 1189 women; GRADE low quality evidence). No clear differences were seen for neonatal jaundice (RR 0.26, 95% CI 0.03 to 2.30; 1882 infants; GRADE very low quality evidence). Neither of the trials reported on adverse effects associated with anti-D treatment. AUTHORS' CONCLUSIONS Existing studies do not provide conclusive evidence that the use of anti-D during pregnancy benefits either mother or baby in terms of incidence of Rhesus D alloimmunisation during the pregnancy or postpartum, or the incidence of neonatal morbidity (jaundice) (low to very low quality evidence). However women receiving anti-D may be less likely to register a positive Kleihauer test in pregnancy and at the birth of a Rh-positive infant (low quality evidence). Fewer women who receive anti-D during pregnancy may have Rhesus D antibodies in a subsequent pregnancy, with benefits for the baby, however this needs to be tested in studies of robust design.