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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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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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Editor's Choice
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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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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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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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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Recombinant factor VIIa analog in the management of hemophilia with inhibitors: results from a multicenter, randomized, controlled trial of vatreptacog alfa
Lentz SR, Ehrenforth S, Abdul Karim F, Matsushita T, Weldingh KN, Windyga J, Mahlangu JN, adept2 investigators
Journal of Thrombosis & Haemostasis. 2014;12((8):):1244-53.
Abstract
BACKGROUND Vatreptacog alfa, a recombinant factor VIIa (rFVIIa) analog with three amino acid substitutions and 99% identity to native FVIIa, was developed to improve the treatment of hemophilic patients with inhibitors. OBJECTIVES To confirm the safety and assess the efficacy of vatreptacog alfa in treating bleeding episodes in hemophilic patients with inhibitors. PATIENTS AND METHODS In this international, multicenter, randomized, double-blind, active-controlled, crossover, confirmatory phase III trial (adept() 2) in patients with hemophilia A or B and inhibitors, bleeds were randomized 3 : 2 to treatment with vatreptacog alfa (one to three doses at 80 mug kg(-1) ) or rFVIIa (one to three doses at 90 mug kg(-1) ). Treatment failures after three doses of trial product (TP) were managed according to the local standard of care. RESULTS In the 72 patients enrolled, 567 bleeds were treated with TP. Both vatreptacog alfa and rFVIIa gave 93% effective bleeding control at 12 h. Vatreptacog alfa was superior to rFVIIa in secondary efficacy outcomes, including the number of doses used to treat a bleed and sustained bleeding control 24-48 h after the first dose. Eight patients (11%) developed antibodies against vatreptacog alfa, including four with cross-reactivity against rFVIIa and one with an in vitro neutralizing effect to vatreptacog alfa. CONCLUSIONS This large randomized controlled trial confirmed the well-established efficacy and safety profile of rFVIIa, and showed that vatreptacog alfa had similar or better efficacy than rFVIIa. However, because of the development of anti-drug antibodies, a positive benefit-risk profile is unlikely to be achieved with vatreptacog alfa. 2014 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.
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Comparison of anti-D immunoglobulin, methylprednisolone, or intravenous immunoglobulin therapy in newly diagnosed pediatric immune thrombocytopenic purpura
Celik M, Bulbul A, Aydogan G, Tugcu D, Can E, Uslu S, Dursun M
Journal of Thrombosis and Thrombolysis. 2013;35((2):):228-33.
Abstract
This study aimed to evaluate the efficacy, cost, and effects of anti-D immunoglobulin (anti-D Ig), methylprednisolone, or intravenous immunoglobulin (IVIG) therapy on the development of chronic disease in children who are Rh-positive with diagnosed immune thrombocytopenic purpura (ITP). Children with newly diagnosed ITP and platelet count <20,000/mm(3) were prospectively randomized to treatment with anti-D Ig (50ug/kg), methylprednisolone (2mg/kg/day), or IVIG (0.4g/kg/day, 5days). Sixty children with a mean age of 6.7years were divided into three equal groups. No difference was observed between platelet counts before treatment and on day 3 of treatment. However, platelet counts at day 7 were lower in the methylprednisolone group than in the IVIG group (P=0.03). In the anti-D Ig group, hemoglobin and hematocrit levels were significantly lower at the end of treatment (P<0.05). Chronic ITP developed in 30% of the anti-D Ig group, 35% of the methylprednisolone group, and 25% of the IVIG group, but no significant difference was noted among the groups. The cost analysis revealed that the mean cost of IVIG was 7.4 times higher than anti-D Ig and 10.9 times higher than methylprednisolone. In the treatment of ITP in childhood, one 50ug/kg dose of anti-D Ig has similar effects to IVIG and methylprednisolone. Among patients who were treated with anti-D Ig, serious anemia was not observed, and the cost of treatment was less than that of IVIG treatment.
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10.
A comparison of intravenous immunoglobulin (2g/kg totally) and single doses of anti-D immunoglobulin at 50ug/kg, 75ug/kg in newly diagnosed children with idiopathic thrombocytopenic purpura: Ankara hospital experience
Alioglu B, Ercan S, Tapci AE, Zengin T, Yazarli E, Dallar Y
Blood Coagulation & Fibrinolysis. 2013;24((5):):505-9.
Abstract
We conducted this prospective randomized trial of intravenous immunoglobulin (IVIG) treatment in children with newly diagnosed immune thrombocytopenic purpura (ITP) to compare the efficacy of IVIG to standard and higher doses of anti-D IVIG. Seventy-eight patients who were previously untreated and between the age of 1 and 18 years with newly diagnosed acute ITP and a platelet concentration less than 20x10/l were eligible for enrollment. In this study IVIG treatment was compared with two different doses of anti-D. Study patients were randomized to receive treatment according to one of the two single anti-D IVIG doses [50ug/kg (n=19) or 75ug/kg (n=20)] or 2g/kg (400mg/kg per day, 5 day) total dose of IVIG (n=39). There is a significant increase of 24th hour, 48th hour, 72nd hour, 7th day and 30th day platelet counts in IVIG (2g/kg, total dose) group compared to anti-D IVIG 50ug/kg and anti-D IVIG 75ug/kg groups. However, there were no difference between 24th hour, 48th hour, 72nd hour, 7th day and 30th day platelet counts across anti-D IVIG 50ug/kg and anti-D IVIG 75ug/kg groups. In conclusion, this study suggests that IVIG is well tolerated and significantly more effective than standard and high-dose anti-D IVIG for the treatment of newly diagnosed ITP in children. Apart from this, we believe that IVIG might be the first-line treatment of these patients. Regarding this issue further prospective studies comparing different IVIG treatment regimens with anti-D IVIG treatment regimens are needed.
