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IS THERE STILL ANY ROLE FOR THE USE OF INTRAVENOUS IMMUNOGLOBULIN [IVIG] IN RECURRENT SPONTANEOUS MISCARRIAGE [RSM]?

IS THERE STILL ANY ROLE FOR THE USE OF INTRAVENOUS IMMUNOGLOBULIN [IVIG] IN RECURRENT SPONTANEOUS MISCARRIAGE [RSM]?. ** Michael F.E. Diejomaoh FRCOG [1,2] Waleed Al- Jassar FACOG [1,2] Zainab Bello Khalid FWACS [2] Iman Al- Shamali FRCOG [2] Mona Al- Qenae CABOG [2]

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IS THERE STILL ANY ROLE FOR THE USE OF INTRAVENOUS IMMUNOGLOBULIN [IVIG] IN RECURRENT SPONTANEOUS MISCARRIAGE [RSM]?

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  1. IS THERE STILL ANY ROLE FOR THE USE OF INTRAVENOUS IMMUNOGLOBULIN [IVIG] IN RECURRENT SPONTANEOUS MISCARRIAGE [RSM]? ** Michael F.E. Diejomaoh FRCOG [1,2] Waleed Al-Jassar FACOG [1,2] Zainab Bello Khalid FWACS [2] Iman Al-Shamali FRCOG [2] Mona Al-Qenae CABOG [2] KavithaKarunakaran DGO, DNB [2] [1] DEPARTMENT OF OBSTETRICS and GYNAECOLOGY FACULTY OF MEDICINE, KUWAIT UNIVERSITY, KUWAIT [2] DEPARTMENT OF OBSTETRICS and GYNAECOLOGY MATERNITY HOSPITAL, KUWAIT ** PRESENTING AUTHOR PROFESSOR OF OBSTETRICS and GYNAECOLOGY

  2. PLAN OF PRESENTATION Introduction Definitions/Aetiology Role of IVIG in RSM Indications General/Costs/Side Effects Unresolved Problems of IVIG and RSM Time of Initial therapy Dosage of IVIG/Mode of Action Studies high lighting IVIG in RSM Studies in favour: Hutton et al, Christiansen et al Studies not in favour : Daya et al, Stephenson et al, Ata et al Data from Local Study Conclusions/Recommendations/Suggestions

  3. MISCARRIAGE – The most frequently encountered complication of pregnancy Ata et al FertilSteril 2011; 95:1080-85 Stephenson et al Hum Reprod 2010; 25:2203-2209 Daya et al Hum Reprod update 1999: 5:475-482 Incidence varied – 10-30%

  4. RECURRENT SPONTANEOUS MISCARRIAGE [ RSM ] Defined as the loss of 3 or more consecutive pregnancies before 20 weeks of gestation. Has a reported incidence of 0.5-1% Ata et al 2011 Stephenson et al 2010 Christiansen et al Hum Reprod 2002; 17; 809-816 May be PRIMARY 3 or more consecutive miscarriages without ANY ongoing pregnancy [VIABLE PREGNANCY] beyond 20 weeks. SECONDARY 3 or more consecutive miscarriages AFTER at least one or more pregnancies beyond 20 weeks pregnancy [VIABLE PREGNANCY] TERTIARY After episode of secondary RSM.

  5. AETIOLOGY OF RSM VARIED. May be multifactorial in the same patient Aetiological factors include Parental Karyotype anomalies [translocations/numeric errors-monosomy-trisomy-polyploidy] Endocrine disorders Uterine Structural anomalies [congenital/acquired] Antiphospholipid Syndrome [APS – Immunological – Primary/Acquired(Inherited)]

  6. In 40-50% of cases, the aetiological factor may not be identified and the cause is then described as IDIOPATHIC OR UNEXPLAINED. Ata et al 2011 Stephenson et al 2010 Diejomaoh et al JournObstetGynaecol 2002; 22:62-67 IMMUNE BASED AETIOLOGY PROPOSED AS UNDERLYING CAUSE FOR UNEXPLAINED RSM. Dosiou C et al Endo Rev 2005; 26:44-31 Mer Arch 2006; 60:129-31 “IMUNOLOGICAL DISTURBANCES SEEM TO BE A RISK FACTOR IN MANY CASES OF RSM” Christiansen et al 2002

  7. Indications for IVIG in RSM. Intravenous Immunoglobulin [IVIG] therapy has been associated with successful pregnancies in patients with elevated NK Cells/Activity/Cytotoxicity Ruiz et al. Am J Reprod Immunol 1996; 31:125-141 Roumen et al Am J Reprod Immnol:2007; 57:262-266 CoulamB, Acacio Am J Reprod Immunol 2012; 67:296-303 Sewel W Jolles S Immunol 2002; 107:387-393 Moraru et al Am J Reprod Immunol 2012; 68:75-84

  8. Unexplained/Idiopathic RSM. • Antiphospholipid Syndrome. 4. Passive Immunization[Immunomodulation]. Pregnancy rate of 92.5% and live birth rate of 82.5% reported in one study with IVIG therapy as against preg rates/live birth rates of 25% and 12.5% respectively in those untreated with IVIG Moraru M et al AM et al Am J ReprodImmunol 20012; 68:75-84 The efficacy of IVIG in the treatment of RSM was reported as 96% Kottan B et al. Am J Reprod. Immunol 2006; 55:331-340 IVIG is quite expensive Its use can also be associated with side effects - Headaches/Nausea/Vomiting/Fever

  9. NK CELLS and RSM Successful pregnancy considered as TH1/TH2 Balance with a positive TH2 balance promoting Pregnancy and leading to progression of pregnancy Wegman TG et al. Immunol Today 1993; 14:353-356 Chaout G et al Am J Reprod Immunol 2003;50: 177-186 Chaout G et al Immunol Lett 2004; 92: 207-214 Szekeres-Bartho J Immunotherapy 2009; 1:873-82. Raghupathy R et al Hum Reprod 2000;15: 713-718. Raghupathy R Immunol Today 1997; 18:478-482

  10. Natural Killer Cells (NK) and RSM Higher levels of Natural Killer Cells [NK] cells [CD56+/16-] implicated in the aetiology of RSM. Quenby et al Hum Reprod 1999; 14:2386-2391 Kwak et al AM J Reprod Immunol 1995; 34:93-99 Higher levels of NK cells in non pregnant patients associated with increased probability of miscarriage in subsequent pregnancy. Aoki et al Lancet 1995; 135:1340-1342 Yamada et al Am J Reprod Immunol 2003;50:351-354 Coulam B, Acacio B, Am J Reprod Immunol 2012; 67:296-303

  11. NK cells reported to play important roles in TH1/TH2 activity/balance. Higher levels of NK cells linked with increased TH1 activity and progression to miscarriage . Decreased levels of NK Cells linked to enhanced TH2 activity, diminished cytotoxicity and progression of pregnancy. Dosiou C et al Endo Rev. 2005; 26:44-62 Mahmoud M et al GynecolObstet Invest 2004; 58:77-83 Kottan B et al Am J ReprodImmunol 2006;55:331-340 However, the precise mechanisms associating NK cells with unexplained RSM has not been fully established Dosiou C et al Hum Reprod 2011; 26:1971-1980

  12. MODE OF ACTION OF IVIG IN RSM Exact Mechanism of action of IVIG in the treatment of RSM and in enhancing live births in RSM include Decrease in Killing (Cytotoxcity) activity of NK cells Down regulation of systemic NK cell activity Increased activity of suppressor T cells Suppression of B cell production of auto-antibody Reduction of NK cell activity at the implantation site and ↓likelihood of miscarriage Immunomodulatory role Anti infective/Anti inflamatory Porter TF et al Cochrane Data Base Syst Rev 2006 [2] C0000112 Reprinted 2009. Leong et al Am J Health – Syst Pharm 2008; 65:1815-1824 Sewel W Jolles S Immunol 2002; 107:387-393

  13. IVIG ADMINISTRATION – UNRESOLVED PROBLEMS/AREAS OF CONFLICT 1. Time of Initial Therapy. - No universal agreement - VARIOUS APPROACHES IN TRIALS/STUDIES - Some studies commence IVIG Pre-conception – and then continue during pregnancy JYH Kwak et al: NK Cells (nos) and Cytotoxicity within 7 days of treatment Am J Reprod. Immunol 1996;35:363-369 - Other studies commence IVIG after successful pregnancy. • Duration of therapy/Gestational Age at Termination of Therapy - Still unresolved Some Studies – treatment end in first trimester Others – after viability of pregnancy (24+ weeks) - Others – Even into 3rd trimester of Preg.

  14. Dosage What is the right dosage of IVIG to achieve results? Different dosage regimes used in various studies. Yamada et al: achieved success with rather high dose These areas will be further high – lighted as we discuss the trials. 4. Mode of Action No single mode of treatment. Many pathways suggested as already indicated.

  15. Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a Systematic Review B. Hutton, R. Sharma, D. Fergusson, A. Tinmouth, P. Herbert, J. Jamieson, M. Walker. BJOG. 2007; 114: 134-142 • Main results We identified eight trials involving 442 women that evaluated IVIG therapy used to treat recurrent miscarriage. Overall, IVIG did not significantly increase the Odds ratio (OR) of live birth when compared with placebo for treatment of recurrent miscarriage (OR 1.28, 95% C1 0.78-2.10). There was, however a significant increase in live births following IVIG use in women with secondary recurrent miscarriage (OR 2.71, 95% Cl 1.09-6.73), while those with primary miscarriage did not experience the same benefit (OR 0.66, 95% Cl 0.35-1.26). • Author’s conclusions IVIG increased the rates of live birth in secondary recurrent miscarriage, but there was insufficient evidence for its use in primary recurrent miscarriage.

  16. HUTTON et al: BJOG 2007; 114: 134-142 [Ottawa, Canada] Live birth rates from Pooled Studies Primary RSM O.R. 0.66, 95% CI 0.35 – 1.26 [P=0.21] Not significant in favour of placebo For 10 RSM Secondary RSM: O.R. 2.71, 95% C.I. 1.09-6.73, Statistically P=0.03 Significant for RSM in favour of IVIG in RSM IVIG may be effective in women with idiopathic secondary RSM Timing of IVIG THERAPY: IVIG before preg. Live births in 10 RSM. IVIG after preg Live births in 20 RSM.

  17. “The use of IVIG appeared to have a positive effect on the likelihood of a successful live birth in women suffering from secondary recurrent miscarriage relative to placebo. However, its use for the treatment of primary recurrent miscarriage was inconclusive and may require further research” Hutton et al 2007

  18. Meta-analyses of live birth rates among all cases of primary recurrent miscarriage, stratified by treatment start time.Hutton et al . BJOG; 114; 134-142 IVIG Placebo n N n N Before pregnancy Stephenson13 5 10 4 10 After pregnancy German RSA/IVIG group17 20 33 21 31 Perinoel al.12 16 22 20 24 Jablonowska et al.14 9 11 8 9 Christiansen et al.15 7 17 10 16 Overall 52 83 59 80 1.50 (95% CI 0.26-8.82) 0.58 (95% CI 0.29-1.16) 0.01 0.2 0.5 1 2 10 100 Favours Odds ratio Favours IVIG placebo

  19. Meta-analyses of live birth rates among all cases of secondary recurrent miscarriage, stratified by treatment start time.Hutton et al BJOG; 114: 134-142 IVIG Placebo n N n N Before pregnancy Stephenson13 7 10 6 11 After Pregnancy Christiansen et al.10 9 14 2 10 Jablonowska et al.14 8 11 7 10 Christiansen et al.15 6 12 3 13 Overall 23 37 12 33 0.01 0.1 0.5 1 2 10 100 Favours Odds ratio Favours IVIG placebo 1.94 (95% CI0.32-11.76) 3.04 (95% CI1.06-8.73)

  20. O. B. Christiansen et al. Hum. Reprod. 2002; 17: 809 – 816

  21. Details of trials comparing intravenous immunoglobulin (IVIG) with placebo for treatment of recurrent miscarriageS. Dayaet al. Hum Reprod. 1999; 5:475-482 A

  22. B

  23. IVIG for recurrent miscarriage Results of meta-analysis of Intravenous Immunoglobulin (IVIG) versus placebo for recurrent miscarriage S. Daya et al Hum Reprod. 1999:5:475-482

  24. Daya’s Critical Analysis: Hum. Reprod. Update 1999; 5:475-482Daya et al. [Hamilton, Ontario, Canada Salt Lake, Utah, USA] IVIG Group Placebo Group Overall success Rate 62.4% [78/125] 61.7% [71/115] O.R. 1.08:95% C.I = 0.63-1.86 [p= 0.78] Pregnancy Loss Before 20 wks 47 44 Primary RSM 64.7% 64.0% Preg.Success Rate *O.R. 1.04, C.I=0.54-2.01 [P= 0.90] Secondary RSM 57.5% 55.2% Preg. Success Rate **O.R.1.18,c.i=0.43-3.21 [P=0.74]

  25. THERE IS A MARGINAL ADVANTAGE OF SECONDARY RSM OVER PRIMARY RSM "From Meta-analysis and logistic regression analysis of individual data, the results indicate that there is insufficient evidence at present to demonstrate that the use of IVIG in the treatment of unexplained RSM is efficacious” Daya et al. Hum. Reprod. Update 1999;5:475-482. “Treatment may be helpful but IVIG therapy should be administered as part of a trial”

  26. CHARACTERISTICS OF INCLUDED TRIALSB. Ata et al. Fertil Steril 2011; 95; 1080-5 A

  27. B

  28. The German PSA/IVG Group. Br J Obstet Gynaecol 1994; 101: 1072-7 • Coulam CB et al. Am J Reprod Immunol 1995; 34: 333-7 • Perino A et al. Hum Reprod 1997; 12: 2388-92 • Stephenson MD et al. Am J Reprod Immunol 1998; 39: 82-88 • Jablonowska B et al. Hum Reprod 1999; 14: 838-41 • Stephenson MD et al. Hum Reprod 2010; 25: 2203-9

  29. B. Ata et al: FertilSteril 2011; 95:1080-5 Montreal, Canada. “A beneficial effect of IVIG in treatment of RSM was not observed” Overall Live birth O.R. 0.92, 95% C.I 0.55-1.54 Does not suggest an increase in the probability of live birth with IVIG treatment Further Analysis of Live birth Primary RSM O.R. 0.67, 95% C.I 0.32 – 1.39 Secondary RSM O.R.1.15,95% C.I 0.47 – 2.84 Is there some benefit for 20 RSM???

  30. Timing of Treatment Live birth rates IVIG treatment before conception O.R.1.21, 95% C.I 0.58-2.51 IVIG after conception O.R. 0.71, 95% C.I 0.34 – 1.47 “Although it can be possible that IVIG can differentially affect women with 10 and 20 RSM………… In our opinion currently available evidence does not support IVIG administration for 20 RSM outside research context” “IVIG administration can be justified only in the context of a properly designed randomized controlled and preferably a double-blind trial of adequate size”

  31. Live birth rate with IVIG in women with recurrent miscarriageAta et al Fertil Steril 2011;95:1080-5 0.01 0.1 1 10 100 Favors control Favors IVIG

  32. Live birth rates stratified by type of miscarriage. (A) Primary recurrent miscarriage. (B) Secondary recurrent miscarriage , Ata et al Fertil Steril 2011;95:1080-5 A Primary recurrent miscarriage 0.01 0.1 1 10 100 Favors control Favors IVIG

  33. B Secondary recurrent miscarriage 0.01 0.1 1 10 100 Favors control Favors IVIG

  34. Index pregnancy outcomes in women who received IVIG and in controlsM.D. Stephenson et al. Hum Reprod. 2010; 25:2203-2209 Odds ratio (95% confidence interval)

  35. Meta analysis of randomized controlled trials of IVIGD. A. Clark. Hum Reprod. 2011; 26:2586-2591 Odds Ratio 95% Cl 0.01 0.02 0.05 0.1 0.2 0.5 1 2 5 10 20 50 Study Year Pts 1 Christianson 1995 24 2 Christanson 2002 26 3 Stephenson 1998 21 4 Jablonsta 1999 21 5 Stephenson 2010 47 Overall 139 Z = 2.05 2P = 0.040

  36. Introduction: Previous trials with intravenous immunoglobulin (IVIG) in recurrent spontaneous miscarriage (RSM) have yielded conflicting results. Some trials reported improved pregnancy outcome in secondary RSM, others reported no benefits for IVIG therapy in RSM, while some authors have suggested a limited role for such therapy. The objective of our study was to evaluate the outcome of pregnancy in patients with RSM treated with IVIG. Methods: All the patients admitted for treatment with IVIG at Maternity Hospital, Jan-Dec 2010, were identified and their records were analyzed in detail. The social bio data, the past obstetric and gynaecological/ medical/surgical histories were extracted and the diagnostic tests, indications and the dosage regimens for IVIG for the index pregnancy were recorded. The course/outcome of the pregnancies were established. Results: 47 patients received IVIG during the study period but only 36 case files were available for review and form the basis of this study. The mean age and parity of the study population were 33.28 + 5.311 and 1.60 + 1.958 respectively. 10 out of the 36 cases were diagnosed as rhesus iso-immunization and 26, RSM; 65.4% of the RSM patients presented as secondary, and 34.6%, primary RSM. 76.9% of the miscarriages occurred in the first trimester. 92.3% of all patients received their initial IVIG dose in the first trimester. The pregnancies ended again in miscarriages in 34.6%, but progressed to preterm/term deliveries of living babies in 65.4%; the positive pregnancy outcome achieved using IVIG was double the rate of pregnancy loss, and significantly higher, p<0.001. No significant adverse reactions were recorded in the patients treated with IVIG. Conclusions: The use of IVIG in RSM resulted in a favourable pregnancy outcome and has a positive role in RSM and it should be offered to selected patients.

  37. *** During study period 47 patients identified as having received IVIG therapy *** 36 case files could be identified *** Data from these cases formed the basis of this analysis *** Patients divided into 3 groups for further analysis Group A: Patients admitted with Rhesus isoimmunization 10 patients - 9 patients (25.0%) (27.8%) - 1 patient with ITP (2.8%) Patients with RSM, 26 patients (72.2%), SPLIT into 2 Grps. Group B: Primary RSM 10 patients (38.5%) Group C: Secondary RSM 16 patients (61.5%) *** 76.9% if the miscarriages previously recorded had occurred in the first trimester. *** The incidence of favourable pregnancy outcome was significantly higher in group C patients, p=0.0461 *** 92.3% of all patients received their initial IVIG dose in the first trimester of pregnancy.

  38. *Thrombophilia Protein S, Factor V, Elevated Natural Killer Cells +Mean ± SD All other data expressed as n(%)

  39. Total Number of Miscarriages in RSM Patients : 9/26 = 34.6 % Total number of Term/Preterm Pregnancies in RSM Patients: 17/26 = 65.4% * The positive pregnancy outcome achieved using IVIG was double the rate of pregnancy loss and significantly higher. P<0.001

  40. Conclusions/ Recommendations/ Suggestions • The use of IVIG in RSM remains controversial. • IVIG has a limited role in the treatment of selected cases of RSM. • It should be used in limited specialized RSM research based trial-oriented clinics. • IVIG may contribute towards an enhanced pregnancy outcome in patients with secondary RSM. • IVIG is still been used by experts treating patients with RSM.

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