Slide 1
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** 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]
Kavitha Karunakaran 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
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Slide 2
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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
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Slide 3
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– The most frequently
encountered complication of
pregnancy
Ata et al Fertil Steril 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%
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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.
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Slide 5
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AETIOLOGY OF RSM
VARIED.
May be multifactorial in the same patient
Aetiological factors include
Parental Karyotype anomalies
[translocations/numeric errors-monosomy-trisomypolyploidy]
Endocrine disorders
Uterine Structural anomalies
[congenital/acquired]
Antiphospholipid Syndrome
[APS – Immunological – Primary/Acquired(Inherited)]
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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 Journ Obstet Gynaecol 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
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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
Coulam B, 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
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2. Unexplained/Idiopathic RSM.
3. 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 Reprod Immunol 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
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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; 14:353356
Chaout G et al Am J Reprod Immunol 2003;50: 177186
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
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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
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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 Gynecol Obstet Invest 2004; 58:77-83
Kottan B et al Am J Reprod Immunol 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
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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
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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.
2. 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.
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3.
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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.
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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.
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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:
Statistically
Significant for RSM
O.R. 2.71, 95% C.I. 1.09-6.73,
P=0.03
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.
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“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
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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
After pregnancy
German RSA/IVIG group17
Perino el al.12
Jablonowska et al.14
Christiansen et al.15
Overall
5
20
16
9
7
52
10
33
22
11
17
83
4
10
21
20
8
10
59
1.50 (95% CI 0.26-8.82)
31
24
9
16
80
0.58 (95% CI 0.29-1.16)
0.01
Favours
placebo
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0.2
0.5
1
Odds ratio
2
10
100
Favours IVIG
Slide 19
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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
Before pregnancy
Stephenson13
IVIG
Placebo
n
n
N
7 10
N
6 11
1.94 (95% CI0.32-11.76)
After Pregnancy
Christiansen et al.10 9
Jablonowska et al.14 8
Christiansen et al.15 6
Overall
23
14
11
12
37
2
7
3
12
10
10
13
33
3.04 (95% CI1.06-8.73)
0.01
Favours
placebo
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0.1
0.5 1 2
Odds ratio
10
100
Favours IVIG
Slide 20
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O. B. Christiansen et al. Hum. Reprod. 2002; 17: 809 – 816
Combined results of two placebo-controlled trials of Nordimmun [IVIG] versus placebo in the prevention of
recurrent miscarriage
Successful pregnancya
RR (95% Cl)
P
Padj
Placebo
All patients (n = 92)
ITT analysis
After exclusions
Secondary RM
(n = 52)
ITT analysis
After exclusionsb
IVIG
22/46 (48)
22/43 (51)
18/46 (39)
18/45 (40)
1.2 (0.8-2.0)
1.3 (0.8-2.0)
NS
NS
NS
NS
15/26 (58)
15/24 (63)
6/26 (23)
6/25 (24)
2.5 (1.2 – 5.4)
2.6 (1.2-5.6)
<0.02
<0.01
<0.02
<0.01
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Details of trials comparing intravenous immunoglobulin
(IVIG) with placebo for treatment of recurrent miscarriage
S. Daya et al. Hum Reprod. 1999; 5:475-482
A
Reference
Study design
No. of patients
In trial
No. of patients
in metaanalysis
Inclusion
criteria
Primary/secondary
recurrent
miscarriage
Treatment
versus
control
Timing and dose
of infusion
German RSA/
IVIG Group
(1994)
Multicentre,
Randomized,
double-blind,
central
allocation
64 pregnant
33 IVIG
31 placebo
23 IVIG
24 placebo
≥3 SA at 316
Weeks
Age ≤40
years
10 only
(no prior LB)
Verum
(5% IVIG)
versus 5%
human
albumin
600 ml (30 g) at
Positive
pregnancy
Test (5-8 weeks),
400 ml (20 g)
Every 3 weeks to
week 25±1
Christiansen et
al.
(1995)
Randomized
Double-blind,
Sealed
envelopes,
Allocation
method
Not stated
34 pregnant
17 IVIG
17 placebo
17 IVIG
15 placebo
≥3 SA at ≤28
weeks
20 (prior LB) or
10 with ≥1 SA
>14 weeks
Nordimmu
n (IVIG)
versus 5%
human
albumin
35g weeks 5 and
6.25g weeks 7, 8
and biweekly to
week 26.30g
biweekly weeks
28-34 (adjusted
by 5g if weight ,
<60 or >80 kg)
Coulam et al
(1995)
Multicentre,
Randomized
Double-blind
95 enrolled
61 pregnant
29 IVIG
32 placebo
24 IVIG
20 placebo
≥2 SA with
current
partner, age
18-45 years
10 (no prior
pregnancy >20
weeks) and 20
(prior LB)
IVIG
versus
0.5%
albumin
IVIG 500 mg/kg
or placebo
monthly, starting
in follicular
phase prepregnancy for up
to four cycles,
until 28-32
weeks
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B
Reference
Study design
No. of patients
In trial
No. of patients
in metaanalysis
Inclusion
criteria
Primary/secondary
recurrent
miscarriage
Treatment
versus
control
Timing and
dose of
infusion
Stephenson
et al
(1998)
Randomized,
double-bline,
central
allocation
64 enrolled,
39 pregnant
20 IVIG
19 placebo
17 IVIG
13 placebo
≥2 SA at <20
weeks
age 18-45
years
10 (no prior
pregnancy >20
weeks)
and 20 (prior
pregnancy >20
weeks)
Gamimune
N (5% IVIG)
Versus
saline
IVIG 500 mg/kg
or placebo
monthly
starting in
follicular phase
pre-pregnancy
for up to six
cycles.
Treatment in
pregnancy was
not described
Perino et al.
(1997)
Multicentre,
Randomized,
Double-blind,
Central
allocation
46 pregnant
22 IVIG
24 placebo
22 IVIG
24 placebo
≥3 SA at ≤13
Weeks
With current
Partner, age
≤42 years
10 only
(no prior LB)
IVIG versus
5% human
albumin
500 ml (25 g) on
two
consecutive
days after
positive
pregnancy test
(5-7 weeks
gestation) and
again 3 weeks
later
Jablonowska
et al.
(1999)
Multicentre,
Randomized,
Double-blind,
41 pregnant
22 IVIG
19 placebo
22 IVIG
19 placebo
≥3 SA at <20
weeks
10 (no prior LB) or
20 (prior LB)
Gammonati
v IVIG
versus
saline
400 ml (20 g) at
viable
pregnancy on
ultrasound (5-9
weeks) and
every 3 weeks
(total 5
treatments)
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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
Reference
Successful pregnancy
IVIG
Placebo
Live birth
Odds Ratio (OR)
(95% Cl)
IVIG
Placebo
Odds Ratio
(OR)
(95% Cl)
German RSA Group
(1994)
14/23
16/24
0.78
(0.24-2.56)
14/23
15/24
0.93
(0.29-3.03)
Christiansen et al.
(1995)
10/17
6/15
2.14
(0.52-8.81)
9/17
5/15
2.25
(0.54-9.45)
Coulam et al. (1995)
13/24
6/20
2.76
(0.79-9.61)
12/24
6/20
2.33
(0.67-8.12)
Stephenson et al. (1998)
8/17
7/13
0.76
(0.18-3.24)
8/17
7/13
0.76
(0.18-3.24)
Perino et al. (1997)
16/22
20/24
0.53
(0.13-2.22)
16/22
20/24
0.53
(0.13-2.22)
Jablonowska et al.
(1999)
17/22
16/19
0.64
(0.13-3.11)
17/22
15/19
0.91
(0.20-4.01)
Overall
78/125
71/115
1.08
(0.63-1.86)
76/125
68/115
1.14
(0.66-1.95)
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Daya’s Critical Analysis: Hum. Reprod. Update 1999; 5:475-482
Daya 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
Secondary RSM
Preg. Success Rate
*O.R. 1.04, C.I=0.54-2.01 [P= 0.90]
57.5%
55.2%
**O.R.1.18,c.i=0.43-3.21 [P=0.74]
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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”
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Slide 26
A
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CHARACTERISTICS OF INCLUDED TRIALS
B. Ata et al. Fertil Steril 2011; 95; 1080-5
Trial
Number and
definition of
miscarriages
Type of
miscarriage
IVIG dosagea
IVIG start
time
Control
Outcome
measure
reported
German
RSA/IVIG
study group,
1994 (15)
≥ 3 miscarriages
≤ 16 wk gestation
Primary only
30 g after
positive
pregnancy test,
then 20 g every
3 wk until 25 wk
gestation; total
dose of 140-170
g
As soon as
pregnancy
was
diagnosed
5% albumin
Pregnancy >
28 wk gestation
or delivery
Coulam et al.,
1995 (17)
≥2 miscarriages
< 20 wk
gestationb
Primary and
secondary
(defined as
RM after a
prior live birth)
500 mg/kg/4 wk,
until 28-32 wk
gestation;
approximate
total dose of
240-300 g
Follicular
phase of
conception
cycle
0.5% albumin
Live birth;
gestational age
not specified
Perino et al.,
1997 (18)
≥ 3 miscarriages
≤ 12 wk gestationb
Primary only
25 g/day for 2 d
upon diagnosis
of pregnancy, 25
g 3 wk later; total
dose of 75 g
As soon as
pregnancy
was
diagnosed
5% albumin
Live birth;
gestational age
not specified
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B
Trial
Number and
definition of
miscarriages
Type of
miscarriage
IVIG dosagea
IVIG start
time
Control
Outcome
measure
reported
Stephenson
et al., 1998
(14)
≥ 2 miscarriages
≤ 20 wk gestation
Primary and
secondary (at
least one prior
pregnancy
proceeding
after the 20 wk
gestation was
required for
secondary RM)
500 mg/kg/4
weeks, until 2832 wk gestation;
approximate total
dose 240-300 g
Follicular
phase of
conception
cycle
Saline
Live birth
Jablonowska
et al., 1999
(16)
≥ 3 miscarriages
≤ 20 wk gestation
Primary and
secondary
(defined as RM
after a live
birth)
20 g/3 wk, five
times; total dose
of 100 g
As soon as
pregnancy
was
confirmed
with
ultrasound
Saline
Live birth>28
wk gestation
Stephenson
et al., 2010
(20)
≥3 miscarriages
≤ 20 wk gestationb
Secondary
only
500 mg/kg/4
weeks until 18-20
wk gestation;
approximate total
dose of 150-180
g
Follicular
phase of
conception
cycle
Saline
Live birth
a
Dosage calculated for a woman weighing 60 kg.
partner required
bSame
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Slide 28
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1. The German PSA/IVG Group. Br J Obstet Gynaecol
1994; 101: 1072-7
2. Coulam CB et al. Am J Reprod Immunol 1995; 34: 333-7
3. Perino A et al. Hum Reprod 1997; 12: 2388-92
4. Stephenson MD et al. Am J Reprod Immunol 1998; 39:
82-88
5. Jablonowska B et al. Hum Reprod 1999; 14: 838-41
6. Stephenson MD et al. Hum Reprod 2010; 25: 2203-9
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B. Ata et al: Fertil Steril 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???
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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”
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Slide 31
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Live birth rate with IVIG in women with recurrent
miscarriage
Ata et al Fertil Steril 2011;95:1080-5
Study or
Subgroup
Coulam 1995
German RSA/IVIG
1994
Jablonowska 1999
Perino 1997
Stephenson 1998
Stephenson 2010
Total (95% Cl)
IVIG
Events
10
20
17
16
9
16
Total
21
33
22
22
18
23
Control
Events
7
21
15
20
9
15
139
Total
Odds Ratio
M-H,Fixed,95% Cl
19
31
19
24
16
24
1.56 [0.44, 5.53]
0.73 [0.26, 2.05]
0.91 [0.20, 4.01]
0.53 [0.13, 2.22]
0.78 [0.20, 3.01]
1.37 [0.41, 4.61]
133
0.92 [0.55, 1.54]
Odds Ratio
M-H, Fixed, 95% Cl
0.01
0.1
Favors control
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1
10
100
Favors IVIG
Slide 32
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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
Study or Subgroup
IVIG
Events
German RSA/IVIG 1994
Jablonowska 1999
Perino 1997
Stephenson 1998
20
9
16
4
Total (95% Cl)
Total events
49
Total
Control
Events
33
11
22
8
21
8
20
5
74
Total
Odds Ratio
M-H,Fixed,95% Cl
31
9
24
9
0.73 [0.26, 2.05]
0.56 [0.04, 7.44]
0.53 [0.13, 2.22]
0.80 [0.12, 5.40]
73
0.67 [0.32, 1.39]
54
0.01
0.1
Favors control
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Odds Ratio
M-H, Fixed, 95% Cl
1
10
100
Favors IVIG
Slide 33
© 2003 By Default!
B Secondary recurrent miscarriage
Study or Subgroup
Jablonowska 1999
Stephenson 1998
Stephenson 2010
Total (95% Cl)
Total events
IVIG
Events
8
5
16
Total
Control
Events
11
10
23
7
4
15
44
29
Total
Odds Ratio
M-H,Fixed,95% Cl
10
7
24
1.14 [0.17, 7.60]
0.75 [ 0.11, 5.24]
1.37 [ 0.41, 4.61]
41
1.15 [0.47, 2.84]
Odds Ratio
M-H, Fixed, 95% Cl
26
0.01
0.1
1
Favors control
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10
100
Favors IVIG
Slide 34
© 2003 By Default!
Index pregnancy outcomes in women who received IVIG
and in controls
M.D. Stephenson et al. Hum Reprod. 2010; 25:2203-2209
Outcome
IVIG group (n=23)IVIG
Control group (n=24)
OR (95% Cl)*
P-value
Live birth rate
16/23 (70%)
15/24 (63%)
1.37 (0.41-4.61)
0.760
Live birth rate, excluding
biochemical miscarriages
16/20 (80%)
15/20 (75%)
1.33 (0.30-5.93)
>0.999
Live birth rate, excluding
miscarriages <6 weeks of
gestation
16/17 (94%)
15/16 (94%)
1.07 (0.0618.62)
>0.999
Odds ratio (95% confidence interval)
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Slide 35
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Meta analysis of randomized controlled trials of IVIG
D. A. Clark. Hum Reprod. 2011; 26:2586-2591
Odds Ratio 95% Cl
0.01
Study
Year
0.05
0.1
0.2
Pts
1 Christianson
1995
24
2 Christanson
2002
26
3 Stephenson
1998
21
4 Jablonsta
1999
21
5 Stephenson
2010
47
Overall
0.02
139
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Z = 2.05 2P = 0.040
0.5
1
2
5
10
20
50
Slide 36
© 2003 By Default!
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.
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Slide 37
***
© 2003 By Default!
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.
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Slide 38
EVENT
© 2003 By Default!
STUDY POPULATION
[N=36]
Age
Range
33.28±5.311
[22-42]
Parity
Range
1.60±1.958
[0-7]
Ethnicity:
Kuwaitis
Non-Kuwaitis
28 (77.8)
8 (22.2)
Indications for IVIG
RSM
Rhesus Isoimmunisation
ITP
26 (72.2)
9 (25.0)
1 (2.8)
Type of Miscarriages:
Primary
Secondary
10 (38.5)
16 (61.5)
Aetiology of RSM:
Unexplained
Antiphospholipid Syndrome
* Others
10 (38.5)
11 (42.3)
5 (19.2)
+Gestational Age at 1st dose of IVIG (wks)
12.31 ± 9.884
+Gestational age at last dose of IVIG (wks)
21.69 ± 9.969
*Thrombophilia Protein S, Factor V, Elevated Natural Killer Cells
+Mean ± SD
All other data expressed as n(%)
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Slide 39
© 2003 By Default!
TABLE 2. CLINICAL DATA ON MAJOR SUB-GROUPS OF THE
POPULATION STUDIED
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Slide 40
© 2003 By Default!
TABLE 3. OUTCOME OF PREGNANCY
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
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Slide 41
© 2003 By Default!
Conclusions/ Recommendations/ Suggestions
1. The use of IVIG in RSM remains controversial.
2. IVIG has a limited role in the treatment of
selected cases of RSM.
3. It should be used in limited specialized RSM
research based trial-oriented clinics.
4. IVIG may contribute towards an enhanced
pregnancy outcome in patients with secondary
RSM.
5. IVIG is still been used by experts treating
patients with RSM.
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