http://www.ncbi.nlm.nih.gov/pubmed/7473429?dopt=Abstract
http://www.fertilitymemphis.com/intro_IVIG_study.asp
http://www.usmamed.com/02fertility/news_IVIG.htm
http://www.earlypregnancy.org/EPBM/EPBM%20IV/Vol.%20IV,%20Num%202/EPBM11
33.htm
http://www.obgyn.net/firstcontroversies/prague1999daya4.htm
http://www.blackwell-synergy.com/links/doi/10.1111/j.8755-8920.2001.450309.x/abs/
http://www.recurrentmiscarriages.com/out_frame.php?PHPSESSID=3f04c448439d2807
874090655e34d56a&ID=77
http://www.recurrentmiscarriages.com/out_frame.php?PHPSESSID=3f04c448439d2807
874090655e34d56a&ID=239
http://www.recurrentmiscarriages.com/out_frame.php?PHPSESSID=3f04c448439d2807
874090655e34d56a&ID=330
http://repro-med.net/papers/2ndabor.php
http://www.earlypregnancy.org/EPBM/EPBM%20IV/Vol.%20IV,%20Num%202/EPBM12
88.htm
1. de la C-mara C, Arrieta R, Gonz-lez A, Iglesias E, Ome-aca F. High dose intravenous immunoglobulin as
the sole prenatal treatment for severe Rh immunization. N Engl J Med 1988;318:519-520.
2. Smith CIE, Hammarstrom L. Intravenous immunoglobulin in pregnancy. Obstet Gynecol 1985;66:39s.
3. Scott JR, Branch W, Kochenour NK, Ward K. Intravenous immunoglobulin treatment of pregnant
patients with recurrent pregnancy loss caused by antiphospholipid antibodies and Rh immunization. Am
J Obstet Gynecol 1988;159:1055-1056.
5. Bustillo M. Goodman C.: Assisted reproductive technologies and immune infertility. Am. J. Reprod.
Immunol., 35:205-289, 1996.
6. Matzner W. Presentation at Pacific Coast Infertility Meeting, 1998.
4. Parke A, Maier D, Wilson D, Andreoli J, Ballow M. Intravenous gammaglobulin, antiphospholipid
antibodies, and pregnancy. Ann Int Med 1989;110:495-496.
5. Rose V, Gordon Ll. Idiopathic thrombocytopenic purpura in pregnancy. Successful management with
immunoglobulin infusion. JAMA 1985;254:2626-2628.
6. Bussell JB, Pham LC, Aledort L, Nachman R. Maintenance treatment of adults with refractory immune
thrombocytopenic purpura using repeated intravenous infusions of gamma globulin. Blood 1988;72:121127.
7. Mannhalter JW, Ahmad R, Wolf HM, Eibl MM. Effect of polymeric Edge on human monocyte
functions. Int Arch Allergy Appl Immunol 1987;82:159-167.
8. Sultan Y, Maisonneuve P, Kazatchkine MD, Nydegger UE. Anti-idiotypic suppression of autoantibodies
to factor VIII b high dose intravenous gammaglobulin. Lancet 1984;i:765-768.
9. Sher G, Feinman M, Zouves C, Kuttner G, Maassarani G, Salem R, Matzner W, Ching W, Chong P. High
fecundity rates following in vitro fertilization and embryo transfer (IVF/ET) in antiphospholipid antibody
(APA) seropositve women treated with heparin and aspirin. Human Reproduction 1994;11.
10. Tsubakio T, Kurato Y, Katageri S, et al. Alteration in T cell subset and immunoglobulin synthesis in
vitro during high dose gammaglobulin therapy in patients with idiopathic thrombocytopenic purpura.
Clin Exp Immunol 1983;53:697-702.
11. Wapner RJ, Cowchock SF, Shapiro SS. Successful treatment in two women with antiphospholipid
antibodies and refractory pregnancy losses with intravenous immunoglobulin infusions. Am J Obstet
Gynecol 1989;161:1271-1272.
12. Kwak JYH, Gilman-Sachs A, Beaman KD, Beer AE. Reproductive outcome in women with recurrent
spontaneous abortions of alloimmune and autoimmune etiologies; pre vs. post conception treatment.
Am J Ostet Gynecol 1992;166:1975-1987.
13. Kwak JYH, Gilman-Sachs A, Beaman KD, Beer AE. Autoantibodies in women with primary recurrent
spontaneous abortion of unknown etiology. J. Reprod Immunol 1992;22:15-31.
> ------------------------------------------------->
> 3) Early Pregnancy 2000 Apr;4(2):154-64
>
> Immunoglobulin G infusion treatment for women with recurrent
> spontaneous abortions and elevated CD56+ natural killer cells.
>
> Kwak JY, Kwak FM, Gilman-Sachs A, Beaman KD, Cho DD, Beer AE.
>
> Reproductive Medicine, Department of Obstetrics and Gynecology,
Finch
> University of Health Sciences/The Chicago Medical School, North
> Chicago, IL 60064, USA. kwakj@m...
>
> We aimed to investigate the clinical effect of intravenous
> immunoglobulin G (IVIg) treatment in recurrent aborters with
elevated
> peripheral blood CD56+ NK cell levels while on lymphocyte
> immunization, anticoagulation and prednisone treatment, with
respect
> to subsequent live birth and reproductive outcome. Thirty-three
women
> with recurrent abortions achieved alloimmune recognition after
> lymphocyte immunizations. All had autoimmune abnormalities and
> received preconception anticoagulation and prednisone treatment.
At
> the time of positive pregnancy testing, 18 women with normal NK
cell
> levels (<12%) and 6 with elevated NK cell levels (>12%) continued
> anticoagulation and prednisone treatment, and 9 with elevated NK
cell
> level initiated additional IVIg treatment. The live birth rates of
> women with elevated NK cell level (>12%) who initiated post> conception IVIg treatment in addition to anticoagulation and
> prednisone (100.0%), women with normal NK cell levels (<12%) who
> continued anticoagulation and prednisone (83.3%) and women with
> elevated NK cell level (>12%) who continued anticoagulation and
> prednisone (33.3%) are significantly different (P=0.0065).
Prevalence
> of intrauterine growth retardation and preterm delivery among 3
study
> groups were not different. In conclusion, post-conception IVIg
> treatment significantly improves reproductive outcome in women
with
> elevated CD56+ NK cells with pregnancy who received preconception
> lymphocyte immunization, anticoagulation and prednisone treatment.
>
> PMID: 11723544 [PubMed - indexed for MEDLINE]
>
> ----------------------------------------->
> 4) Am J Reprod Immunol 2001 Oct;46(4):268-73
>
> Further experience with intravenous immunoglobulin in women with
> recurrent miscarriage and a poor prognosis.
>
> Carp HJ, Toder V, Gazit E, Ahiron R, Torchinski A, Mashiach S,
> Shoenfeld Y.
>
> Department of Obstetrics and Gynecology, Sheba Medical Center, Tel
> Hashomer, Israel. carp@n...
>
> PROBLEM: Women with three or more unexplained miscarriages have a
60%
> chance of a subsequent live birth. Intravenous immunoglobulin
(IVIG)
> has not been conclusively shown to improve this prognosis. This
study
> assessed the effect of IVIG in patients expected to have a poor
> outcome if untreated, i.e. women with five or more abortions, who
> have aborted after paternal leukocyte immunization or who continue
to
> abort despite expressing anti-paternal complement dependent
antibody.
> METHODS: Seventy-six women received IVIG in a dose of 400 mg/kg
body
> weight, in one day (total 30-45 g) in the follicular phase of a
cycle
> in which pregnancy was planned. A booster dose was administered
when
> pregnancy was diagnosed. Their results were compared to an
untreated
> control group of 74 women. RESULTS: Thirty-five (49%) pregnancies
in
> treated women have resulted in live births or passed their
previous
> stages of abortion compared to 23 (31%) in control patients (P =
> 0.04). CONCLUSIONS: These figures indicate that IVIG may prevent
> further miscarriages in this poor prognosis population. These
figures
> are especially significant considering the doubt concerning the
> efficacy of IVIG in patients with three miscarriages and therefore
a
> relatively good prognosis.
>
> Publication Types:
>
> Clinical Trial
> ------------------------> 5)
>
> 1: Scand J Rheumatol Suppl 1998;107:97-102
>
> Utilization of intravenous immunoglobulin therapy to treat
recurrent
> pregnancy loss in the antiphospholipid syndrome: a review.
>
> Harris EN, Pierangeli SS.
>
> Academic Affairs, Morehouse School of Medicine, Atlanta, GA 30310> 1495, USA.
>
> Although experience is still limited, intravenous immunoglobulin
> therapy for recurrent pregnancy loss in the Antiphospholipid
Syndrome
> (APS) may represent a significant advance. APS was widely
recognized
> only fifteen years ago. Pregnancy loss and thrombosis are the
> prominent clinical features. Initially, prednisone was used for
> treatment of pregnancy loss, but matemal and fetal complications
> stimulated searches for alternative therapy. Subcutaneous heparin
and
> low dose aspirin was next utilized, but although efficacious,
there
> is still a 30% failure rate, and intrauterine growth retardation,
> prematurity, and pre-eclampsia are relatively frequent. In the
late
> 1980's, there were a number of case reports of successful
pregnancy
> outcomes after treatment with intravenous immunoglobulin (IVIg)
but
> regimens differed. Series from two centers have confirmed these
> initial findings and treatment regimens have become more
consistent.
> Both centers have reported success with doses of 400 mg/kg/day for
5
> days or 1 g/kg/day for two days each month initiated during the
first
> or early second trimester. Success rates of 70-100% have been
> reported, and complications such as pre-eclampsia, intrauterine
> growth retardation, and premature births appear reduced, when
> compared to prednisone and low dose aspirin or heparin and low
dose
> aspirin. Several patients who were treated with IVIg also received
> heparin, making it uncertain whether heparin may also need to be
> added to IVIg. Intravenous immunoglobulin is safe, but expensive.
> Despite its expense, if IVIG is shown to markedly decrease matemal
> and fetal morbidity, it may be the logical treatment of choice to
> prevent pregnancy loss in APS.
>
> Publication Types:
>
> Review
> Review, Tutorial
>
> PMID: 9759143 [PubMed - indexed for MEDLINE]
>
> ----------->
> 6)
>
> Fertil Steril 2000 Mar;73(3):536-40
>
>
>
> Successful treatment of immunologic abortion with low-dose
> intravenous immunoglobulin.
>
> Stricker RB, Steinleitner A, Bookoff CN, Weckstein LN, Winger EE.
>
> California Pacific Medical Center, San Francisco, California
94108,
> USA. rstricker@u...
>
> OBJECTIVE: To evaluate the efficacy of low-dose intravenous
> immunoglobulin (IVIG) treatment in older women with immunologic
> abnormalities and recurrent spontaneous abortion (RSA), a
condition
> referred to as immunologic abortion. DESIGN: Prospective clinical
> trial. SETTING: Outpatient referral practice. PATIENT(s): Fortyseven
> women were enrolled in the study. The mean age of the women was 37
> years (range, 28-45 years), and the mean number of prior
miscarriages
> was 3.7. Immunologic abnormalities included antiphospholipid
> antibodies (32%), antithyroid antibodies (53%), antinuclear
> antibodies (28%), antiovarian antibodies (2%), increased natural
> killer cells (40%), increased immunoglobulin (Ig)M level (28%),
and
> increased CD4/CD8 T-cell ratio (15%). One patient had IgA
deficiency,
> and three women had endometriosis. Thirty-one of the 47 patients
> (66%) had more than one immunologic abnormality. INTERVENTION(s):
> Treatment with IVIG at a dose of 0.2 g/kg within 2 weeks of
attempted
> conception. Once conception was achieved, IVIG treatment was
> continued on a monthly basis at the same dose through 26-30 weeks
of
> gestation. MAIN OUTCOME MEASURE(s): Successful pregnancy or
recurrent
> abortion.Result(s): Of the 47 women, 36 received initial IVIG
> treatment, and 24 subsequently became pregnant. Of these women, 20
> continued IVIG treatment through 26-30 weeks of gestation, and 19
> (95%) had a successful term pregnancy. Four women discontinued
IVIG
> therapy after 10-12 weeks of gestation, and 3 (75%) had a
successful
> pregnancy outcome. Of the 11 women who refused IVIG therapy, 7
became
> pregnant, and all 7 miscarried. The difference in pregnancy
success
> rate between the IVIG-treated and untreated groups was significant
> (P=.001). Three women had adverse reactions during the low-dose
IVIG
> infusion, and these reactions resolved when the IVIG brand was
> changed. Fetal abnormalities were not observed. CONCLUSION(s): Low> dose IVIG therapy is beneficial for older women with immunologic
> abortion. The optimum duration of IVIG treatment in these women
> requires further study.
>
> Publication Types:
> Clinical Trial
>
> PMID: 10689009 [PubMed - indexed for MEDLINE]
> ------------------------------>
> 7)
>
> Intravenous Immunoglobulin G (IVIG) Is Associated with Markedly
> Improved IVF Outcome in Patients with Elevated Peripheral Natural
> Killer Cell Activity (NKa+) and Prior Unexplained IVF Failure.
> 1, 2, G Sher, 1JD Fisch, 1, 2G Maassarani, 1L Danner. 1Sher
Institute
> for Reproductive Medicine, Las Vegas NV, 2Dept. of Ob/Gyn,
University
> of Nevada School of Medicine, Reno NV.
>
> Objective: We previously reported increased IVF pregnancy rates
among
> Antiphospholipid Antibody (APA) positive patients in whom
> immunomodulation with Heparin alone was unsuccessful. We also
> reported an association of APAs among infertile women with
elevated
> Natural Killer cell activity (NKa+). This study evaluated the
effect
> of IVIG therapy on IVF outcomes in a group of NKa+ patients with
> prior unexplained IVF failures.
>
> Design: Retrospective cohort.
>
> Materials and Methods: Between January and December, 2001, 20
> infertile NKa+ women <40 years of age, with an otherwise normal
> uterine cavity (Group A, n=24) underwent 24 fresh IVF cycles using
> their own eggs and standard stimulation protocols with the
addition
> of IVIG (40 g) prior to egg retrieval and a second infusion after
> confirming conception. In all cycles the patient had at least 2
Grade
> A embryos (7 or more cells and <20 fragmentation on day 3 of
culture)
> available for transfer. All patients had elevated peripheral blood
NK
> cell activity as measured by a K562 cell assay with more than 10%
> killing considered abnormal. In addition, all patients had a least
> one prior failed ART attempt (mean 1.8). Group A was compared to a
> matched cohort of 22 historical NKa+ controls (Group B) who were
> offered IVIG treatment between October 1998 and December 2001, but
> who declined therapy. Differences in rates between groups were
> analyzed using Chi Squared tests. Significance was set at p<0.05.
>
> Results: The overall on-going pregnancy rate among the two groups
was
> 35% (16/46). In Group A the pregnancy rate was 63% (15/24), which
was
> significantly higher, than for Group B (1/22; 4%) (p<0.001). There
> were no other significant differences between the 2 groups in
terms
> of age, diagnosis, number of embryos transferred or number of
> previous ART failures.
>
> Conclusions: IVIG treatment was associated with improved IVF
outcome
> in NKa+ patients with prior unexplained IVF failure. Among NKa+
> patients treated with IVIG, 63% conceived an on-going gestation,
> while only 1 pregnancy (4%) occurred among the 22 NKa+ patients
who
> declined IVIG treatment. While these findings are retrospective
and
> should not be used to draw definitive conclusions, these data
support
> the ideas that immunologic factors can negatively impact IVF
outcome
> and that selective immunotherapy with IVIG can mitigate those
> effects. A randomized controlled trial is currently under way atv
> SIRM to directly and definitively assess the effect of IVIG
therapy
> on IVF outcome in NKa+ patients.
>
>
>
> --------------------->
> 8)
>
>
>
> Am J Reprod Immunol 1998 Feb;39(2):82-8
>
>
>
> Prevention of unexplained recurrent spontaneous abortion using
> intravenous immunoglobulin: a prospective, randomized, double> blinded, placebo-controlled trial.
>
> Stephenson MD, Dreher K, Houlihan E, Wu V.
>
> Department of Obstetrics and Gynaecology, Faculty of Medicine,
> University of British Columbia, Vancouver, Canada.
>
> PROBLEM: The efficacy of intravenous immunoglobulin (IVIG) for
> treatment of unexplained recurrent spontaneous abortion was
assessed
> in a prospective, randomized, double-blinded, and placebocontrolled
> study. METHOD OF STUDY: The study took place in a provincial
> recurrent pregnancy loss clinic, located in a tertiary/quaternary
> care academic center. The study subjects were women with a history
of
> two or more documented consecutive spontaneous pregnancy losses
under
> 20 weeks of gestation, excluding any associated with aneuploidy by
> karyotype analysis, and with no evidence of genetic, endocrine,
> infectious, anatomic, or autoimmune factors associated with a
history
> of recurrent spontaneous abortion. The subjects were randomized to
> receive either intravenous immunoglobulin (Gamimune N) as
treatment
> or normal saline as placebo. Randomization was stratified for
> primary, secondary, and unclassified unexplained recurrent
> spontaneous abortion. Success was defined as an ongoing pregnancy
> beyond 20 weeks of gestation. RESULTS: Sixty-two subjects enrolled
in
> the trial. There were 37 index pregnancies and 6 cross-over
> pregnancies. There was no clinically significant difference
between
> the treatment arm and the placebo arm in terms of subsequent
> pregnancy success. There seemed to be a higher success rate with
the
> stratified analysis of couples with secondary unexplained
recurrent
> spontaneous abortion, but the trial did not have sufficient power
to
> confirm this. CONCLUSIONS: Based on this trial and three similar
> trials in the literature, a multicentered trial is needed to
> determine conclusively whether IVIG is effective in the treatment
of
> unexplained recurrent spontaneous abortion.
>
> Publication Types:
> Clinical Trial
> Randomized Controlled Trial
>
> PMID: 9506206 [PubMed - indexed for MEDLINE]
> ---------------------------->
> 9)
>
> American Journal Of Reproductive Immunology
> Volume 49 Issue 1 Page 21 - January 2003
>
> Effect of Intravenous Immunoglobulin Treatment on the Th1/Th2
Balance
> in Women with Recurrent Spontaneous Abortions
>
> Olga Graphou, Athanasia Chioti, Ageliki Pantazi, Christina
Tsekoura,
> Virginia Kontopoulou, Eleftheria Georgiadou, Christos Balafoutas,
> Stavros Koussoulakos, Loukas H. Margaritis, and Marighoula Varla> Leftherioti
>
>
> PROBLEM: The way by which intravenous immunoglobulin (IvIg) acts
to
> prevent immunlogically mediated recurrent spontaneous abortions
(RSA)
> has not been clarified. In the present study, a possible effect of
> IvIg on the T helper cell (Th1/Th2) balance was investigated in
> abortions of either alloimmune or autoimmune abnormalities.
>
> METHOD OF STUDY: The study included 21 women treated with IvIg
before
> conception because of a history of RSA characterized by alloimmune
> abnormalities (n = 15) or associated with anti-phospholipid
> antibodies (APA) (n = 6). Peripheral blood samples, collected
before
> and 5 days after the first IvIg infusion, were stimulated, and Th1
> and Th2 cells were detected by flow-cytometric analysis using a
> combination of monoclonal antibodies against T-cell surface
markers
> and intracellular interferon (IFN)- and interleukin (IL)-4. The
> percentage of IFN--producing (Th1) and IL-4-producing (Th2) cells
and
> the Th1/Th2 ratio were compared between pre- and post-infusion
> samples.
>
> RESULTS: A decrease of Th1 percentage in 66.6% of the cases and a
> concurrent Th2 percentage increase (47.61%) resulted in a decrease
in
> the Th1/Th2 ratio in most of the cases (76.1%) (p < 0.01). Similar
> results were found in Group A (Th1/Th2 decreased in 60% of the
cases,
> p < 0.05), while in Group B the effect of IvIg was not clear
(Th1/Th2
> increased in three and decreased in another three cases).
>
> CONCLUSION: Our finding suggests that IvIg administration in women
> with alloimmune RSA enhances Th2 polarization. This is not always
the
> case with APA-associated abortions.
>
> ------------------------>
> 10)
>
> American Journal Of Reproductive Immunology
> Volume 49 Issue 2 Page 84 - February 2003
>
> Intravenous Immunoglobulin Treatment in Women with Recurrent
> Abortions: Increased Cytokine Levels and Reduced Th1/ Th2
Lymphocyte
> Ratio in Peripheral Blood
>
> Hideto Yamada, Mamoru Morikawa, Itsuko Furuta, Emi H. Kato,
Shigeki
> Shimada, Kazuya Iwabuchi, and Hisanori Minakami
>
> PROBLEM: The aim of this study was to investigate changes in
> peripheral blood Th1/Th2 cytokine levels and lymphocyte ratios
after
> massive intravenous immunoglobulin (MIVIg) treatment for women
with
> recurrent spontaneous abortion (RSA) of unexplained etiology.
>
> METHOD OF STUDY: Serum Th1 (IFN-, TNF-) and Th2 cytokine (IL-4, IL> 10) levels were assessed by ELISA methods (n = 9) and peripheral
> blood Th1/Th2 lymphocyte ratios (n = 4) by flow cytometry before
and
> after MIVIg treatments in women with four or more consecutive RSA.
>
> RESULTS: Pre-treatment serum IFN- (0.06 ± 0.09 pg/mL, mean ± SD),
TNF> (0.21 ± 0.45 pg/mL), IL-4 (0.70 ± 1.16 pg/mL), and IL-10 (1.12 ±
> 1.67 pg/mL) increased to 0.17 ± 0.16 pg/mL, 0.77 ± 0.28 pg/mL,
1.82 ±
> 0.89 pg/mL, and 3.44 ± 0.48 pg/mL, respectively, after MIVIg
> treatments (P < 0.05). CD4-positive IFN-/IL-4 lymphocyte ratios
(17.3
> ± 9.1) were reduced to 11.5 ± 7.1 after treatment (P < 0.05).
>
> CONCLUSIONS: Massive intravenous immunoglobulin treatments
increased
> peripheral blood cytokine levels and decreased Th1/Th2 lymphocyte
> ratios; thus, MIVIg treatments modify the peripheral Th1/Th2
balance.
>
> -----------------------------------------------
>
> Articles with full text links:
>
> --------------------------------->
> 11) Immunoglobulin G Infusion Treatment For Women With Recurrent
> Spontaneous Abortions And Elevated CD56+ Natural Killer Cells
>
> http://www.earlypregnancy.org/EPBM/EPBM%20IV/Vol.%20IV,%20Num%
> 202/EPBM1288.htm
>
> 12) The Selective Use of Heparin/Aspirin Therapy, alone or in
> Combination with Intravenous Immunoglobulin G, in the Management
of
> Antiphospholipid Antibody-Positive Women Undergoing In Vitro
> Fertilization
>
> http://www.rialab.com/docum/select.pdf
>
> 13) The Use of Combined Heparin/Apirin and Immunoglobulin G
Therapy
> in the Treatment of In Vitro Fertilization Patients With
Antithyroid
> Antibodies.
>
> http://www.rialab.com/docum/use.pdf
>
> 14). A Rational Basis for the Use of Combined Heparin/Aspirin and
> IVIG Immunotherapy in the Treatment of Recurrent IVF Failure
> Associated with Antiphospholipid Antibodies
>
> http://www.rialab.com/docum/ration.pdf
>
> 15) Intravenous Immunoglobulin for Recurrent Pregnancy Loss (a
> prospective randomized, placebo-controlled clinical trial)
> http://www.inciid.org/article.php?cat=miscarriage&id=19
>
> 16) Intravenous Immunoglobulin (IVIG) Therapy for Immunologic
Abortion
> (Clinical and Applied Immunology Reviews 2 (2002) 187-199, PDF
93K)
>
> http://www.rialab.com/docum/cair_ivig.pdf
>
> --------------------------->
>
>
> 17) Ginekol Pol. 2003 May;74(5):350-5
> [Application of intravenous immunoglobulin therapy (IVIG) in
pregnant
> patients with recurrent spontaneous abortions]
>
> [Article in Polish]
>
> Sipak-Szmigiel O, Ronin-Walknowska E, Miklaszwicz A.
>
> Kliniki Patologii Ciazy i Porodu Pomorskiej Akademii Medycznej,
> Szczecinie.
>
> OBJECTIVE: Clinical outcome of pregnancy in patients with
recurrent
> pregnancy losses treated with IVIG during their current pregnancy.
> MATERIAL AND METHODS: The study group consisted of 10 pregnant
women
> with 3-5 spontaneous abortions. Any genetic, anatomical or
infectious
> abnormalities were excluded as well as antiphospholipid antibody
> syndrome and negative lymphocytotoxic test. The treatment
consisted
> of passive immunotherapy by means of intravenous administration of
> immunoglobulin (IVIG) at a dose of 0.4 g/kg b.w. Therapy was
> commenced at week 5-6 of gestation, infusions were repeated every
3-4
> weeks until 28th week of gestation in 5-, 3- and 1-day protocols.
In
> 2 patients that therapy followed active immunotherapy with
paternal
> lymphocytes. RESULTS: Eight (80%) patients bore healthy babies (3
> preterm); in 2 cases embryos died at 6-7 week of gestation.
> CONCLUSIONS: The results confirm the efficacy of IVIG in pregnant
> patients with recurrent spontaneous abortions in whom likelihood
of
> immunological pattern of pregnancy failures is high.
>
> PMID: 12931461 [PubMed - indexed for MEDLINE]
> --------------------> 18) Am J Reprod Immunol. 2003 Feb;49(2):84-9.
>
> Intravenous immunoglobulin treatment in women with recurrent
> abortions: increased cytokine levels and reduced Th1/Th2
lymphocyte
> ratio in peripheral blood.
>
> Yamada H, Morikawa M, Furuta I, Kato EH, Shimada S, Iwabuchi K,
> Minakami H.
>
> Department of Obstetrics and Gynecology, Hokkaido University
Graduate
> School of Medicine, Sapporo, Japan. yhideto@m...
>
> PROBLEM: The aim of this study was to investigate changes in
> peripheral blood Th1/Th2 cytokine levels and lymphocyte ratios
after
> massive intravenous immunoglobulin (MIVIg) treatment for women
with
> recurrent spontaneous abortion (RSA) of unexplained etiology.
METHOD
> OF STUDY: Serum Th1 (IFN-gamma, TNF-alpha) and Th2 cytokine (IL-4,
IL> 10) levels were assessed by ELISA methods (n = 9) and peripheral
> blood Th1/Th2 lymphocyte ratios (n = 4) by flow cytometry before
and
> after MIVIg treatments in women with four or more consecutive RSA.
> RESULTS: Pre-treatment serum IFN-gamma (0.06 +/- 0.09 pg/mL, mean
+/> SD), TNF-alpha (0.21 +/- 0.45 pg/mL), IL-4 (0.70 +/- 1.16 pg/mL),
and
> IL-10 (1.12 +/- 1.67 pg/mL) increased to 0.17 +/- 0.16 pg/mL, 0.77
+/> 0.28 pg/mL, 1.82 +/- 0.89 pg/mL, and 3.44 +/- 0.48 pg/mL,
> respectively, after MIVIg treatments (P < 0.05). CD4-positive IFN> gamma/IL-4 lymphocyte ratios (17.3 +/- 9.1) were reduced to 11.5
+/> 7.1 after treatment (P < 0.05). CONCLUSIONS: Massive intravenous
> immunoglobulin treatments increased peripheral blood cytokine
levels
> and decreased Th1/Th2 lymphocyte ratios; thus, MIVIg treatments
> modify the peripheral Th1/Th2 balance.
>
> PMID: 12765346 [PubMed - indexed for MEDLINE]
> ------------------> 19) Am J Reprod Immunol. 2003 Jan;49(1):21-9.
>
>
>
>
> Effect of intravenous immunoglobulin treatment on the Th1/Th2
balance
> in women with recurrent spontaneous abortions.
>
> Graphou O, Chioti A, Pantazi A, Tsukoura C, Kontopoulou V,
Guorgiadou
> E, Balafoutas C, Koussoulakos S, Margaritis LH, Varla-Leftherioti
M.
>
> Department of Biology, Section of Cell Biology and Biophysics,
> National & Kapodistrian University of Athens, Athens, Greece.
>
> PROBLEM: The way by which intravenous immunoglobulin (IvIg) acts
to
> prevent immunlogically mediated recurrent spontaneous abortions
(RSA)
> has not been clarified. In the present study, a possible effect of
> IvIg on the T helper cell (Th1/Th2) balance was investigated in
> abortions of either alloimmune or autoimmune abnormalities. METHOD
OF
> STUDY: The study included 21 women treated with IvIg before
> conception because of a history of RSA characterized by alloimmune
> abnormalities (n = 15) or associated with anti-phospholipid
> antibodies (APA) (n = 6). Peripheral blood samples, collected
before
> and 5 days after the first IvIg infusion, were stimulated, and Th1
> and Th2 cells were detected by flow-cytometric analysis using a
> combination of monoclonal antibodies against T-cell surface
markers
> and intracellular interferon (IFN)-gamma and interleukin (IL)-4.
The
> percentage of IFN-gamma-producing (Th1) and IL-4-producing (Th2)
> cells and the Th1/Th2 ratio were compared between pre- and post> infusion samples. RESULTS: A decrease of Th1 percentage in 66.6%
of
> the cases and a concurrent Th2 percentage increase (47.61%)
resulted
> in a decrease in the Th1/Th2 ratio in most of the cases (76.1%) (p
<
> 0.01). Similar results were found in Group A (Th1/Th2 decreased in
> 60% of the cases, p < 0.05), while in Group B the effect of IvIg
was
> not clear (Th1/Th2 increased in three and decreased in another
three
> cases). CONCLUSION: Our finding suggests that IvIg administration
in
> women with alloimmune RSA enhances Th2 polarization. This is not
> always the case with APA-associated abortions.
>
> PMID: 12733591 [PubMed - indexed for MEDLINE]
> ------------------------> 20) Am J Reprod Immunol. 2002 Nov;48(5):312-8.
> T and B lymphocyte subsets in patients with unexplained recurrent
> spontaneous abortion: IVIG versus placebo treatment.
>
> Jablonowska B, Palfi M, Matthiesen L, Selbing A, Kjellberg S,
> Ernerudh J.
>
> Division of Obstetrics and Gynecology, Department of Health and
> Environment, University Hospital, Linkoping, Sweden.
> barbara.jablonowska@l...
>
> PROBLEM: To investigate circulating lymphocyte subsets in women
with
> recurrent spontaneous abortion (RSA) in relation to pregnancy
outcome
> and to treatment with intravenous immunoglobulin (IVIG). METHOD OF
> STUDY: Forty-one women with a history of unexplained RSA were
> examined during first trimester of pregnancy before IVIG or
placebo
> treatment and after pregnancy. The results were compared with five
> healthy, non-pregnant women and five women in the first trimester
of
> normal pregnancy. Circulating lymphocyte subsets with focus on Tcell
> subpopulations were determined by flow cytometry. RESULTS: The
> proportions of human leukocyte antigen (HLA)-DR positive T cells
> (CD3+ HLA-DR+), T-killer/effector cells (CD8+ S6F1+) and B cells
> (CD19+) were increased, whereas the proportion of T> suppressor/inducer cells (CD4+ CD45RA+) was decreased during first
> trimester pregnancy of RSA women compared with pregnant normal
> controls. T and B lymphocyte subsets did not correlate with
pregnancy
> outcome on either IVIG or placebo group. CONCLUSIONS: In RSA
> patients, the immune system seems to be activated in contrast to
the
> suppression noted in normal pregnancy.
> ----------------------------------> 21) Eur J Obstet Gynecol Reprod Biol. 2003 Jul 1;109(1):21-6.
>
> Live birth rate varies with gestational history and etiology in
women
> experiencing recurrent spontaneous abortion.
>
> Morikawa M, Yamada H, Kato EH, Shimada S, Sakuragi N, Fujimoto S,
> Minakami H.
>
> Department of Obstetrics and Gynecology, Hokkaido University
Graduate
> School of Medicine, Kita-ku N15 W7, Sapporo 060 8638, Japan.
>
> OBJECTIVES: The aims of this study were to assess pregnancy
outcome
> in relation to etiologic factors of recurrent spontaneous abortion
> (RSA). STUDY DESIGN: The pregnancies from consecutive 216 RSA
women
> were assessed for live birth rates (LBR) according to etiology.
The
> LBR in 110 pregnancies from RSA women with unexplained etiology
was
> investigated according to various therapies. An attempt to
karyotype
> the abortuses was made. RESULTS: Excluding pregnancies ending in
> abortion with abnormal karyotype, the LBR in primary recurrent
> spontaneous aborters (68.8%) who experienced three or more
abortions
> was significantly lower than that in primary repeated aborters
> (82.4%) who experienced two abortions. The LBR ranged from 50 to
100%
> according to the etiology. In RSA women with unexplained etiology,
> the LBR in those undergoing massive intravenous immunoglobulin
> (MIVIg) therapy (100%) was significantly higher than those with
low
> dose aspirin (57.1%) and luteal support therapy (67.3%).
CONCLUSIONS:
> Excluding pregnancies ending in abortion with abnormal karyotype,
we
> found that LBR varied with abortion history and etiologic factors
of
> RSA.
>
> PMID: 12818438 [PubMed - indexed for MEDLINE]
> ------------------> 22) Early Pregnancy. 2000 Apr;4(2):90-8.
>
>
>
>
> Increased pregnancy rates after IVF/ET with intravenous
> immunoglobulin treatment in women with elevated circulating C56+
> cells.
>
> Coulam CB, Goodman C.
>
> The Center for Human Reproduction, 750 N. Orleans St., Chicago, IL
> 60610, USA.
>
> Intravenous (IV) immunoglobulin (Ig) has been previously shown to
> increase pregnancy rates after previously failed in vitro
> fertilization (IVF) embryo (ET) attempts in women who are
efficient
> embryo producers (fertilize at least 50% of oocytes retrieved and
> generate at least 3 embryos/cycle). Women experiencing
implantation
> failure have a higher frequency of elevated percentage of
circulating
> CD56+ (natural killer) cells (>12%) than fertile women (3-12%). To
> evaluate the effects of IVIg on pregnancy rates in women with
> elevated percentage of circulating CD56+ cells, 32 women who had
> previously failed IVF/ET (>12 embryos transferred without
pregnancy)
> were studied. Pregnancy and live birth rates with and without IVIg
> were compared in the same woman. All 32 women had previously
failed
> to conceive after at least 12 ET, were efficient embryo producers
and
> had persistently elevated plasma concentrations of CD56+ cells.
Each
> woman received IVIg 500mg/kg prior to ET. If serum hCG
concentrations
> were positive for pregnancy, IVIg was continued at 500mg/kg/mo
until
> 28 weeks gestation. Pregnancy rates with and without IVIg were 56%
> and 9% (P<0.0001). The rate of live birth was 38% with IVIg and 0%
> without IVIg (P<0.0001). IVIg enhances pregnancy and live birth
rates
> in women with elevated circulating CD56+ cells who have a history
of
> implantation failure. Despite technologic advances leading to
> enhancement of fertilization rates after in vitro fertilization
(IVF)
> (1, 2) implantation rates after embryo transfer (ET) have not
> increased significantly (3) over the last 20 years (4).
Implantation
> rates after IVF/ET are influenced by the quality of the embryos
and
> receptivity of the endometrium (3-9). Endometrial receptivity
> involves both hormonal (10-13) and immunologic (14-29) factors.
Among
> the immunologic factors that play a crucial role in successful
> implantation are natural killer (NK) cells (14-18). NK cells
present
> within the decidua that express CD56(but lack CD 16) have been
> associated with successful implantation (14-18). A deficiency of
> decidual CD56+ CD16- cells (18) and an increase in circulating
CD56+
> cells (25, 26) have been observed in women experiencing
implantation
> failure. Women experiencing implantation failure after IVF and
> multiple ET have been successfully treated with intravenous (IV)
> immunoglobulin (Ig) (27). IVIg reduces activation of NK cells and
NK
> killing activity both in vitro (29) and in vivo (30-31). This
> reduction in activation of NK cells is essential for normal
> implantation to occur (14). To further define the role of IVIg for
> treatment of implantation failure, pregnancy and live birth rates
> were compared before and after IVIg treatment in women undergoing
> IVF/ET who had elevated levels of circulating CD56+ cells.
>
> PMID: 11723539 [PubMed - indexed for MEDLINE]
> -----------------------> 23) : Am J Reprod Immunol. 2000 Aug;44(2):121-4.
>
>
>
>
> Clinical experience with IVIg Rx in patients with prior failed IVF
> pregnancies: report of 30 consecutive patients.
>
> Scher J, Salazar C.
>
> b.scher@w...
>
> PROBLEM: This study reviews one practitioner's experience with
> intravenous immunoglobulin (IVIg) therapy in the in-vitro
> fertilization (IVF) cycles of 30 patients with previous IVF
failures.
> METHOD OF STUDY: Thirty patients had undergone 82 prior assisted
> reproductive technology (ART) cycles (mean 3.9 +/- 2 failed ART
> cycles, median 3.0, range 1-8) yielding one term birth, one loss
at
> 22.5 weeks, and five chemical pregnancies. These patients
underwent
> comprehensive clinical and laboratory evaluation, including
> immunologic workup, and were accepted for IVIg therapy in their
next
> IVF cycle. RESULTS: A total of 40 cycles were treated. Twenty-four
> (60%) of the IVIg-treated IVF cycles showed a positive human
> chorionic gonadotropin test. Comparing the IVIg cycles to the
> untreated ART cycles, there were no differences in the number of
> embryos transferred, fertilized embryos, or eggs. Eighty-six
percent
> of the cases with confirmed implantation delivered; there was one
> chemical pregnancy, one 20-week spontaneous fetal death, and one
> trisomy. Five (24%) of the 21 pregnant patients delivered at 30-36
> weeks. The remaining 13 delivered at term. Only three (11%) had no
> positive immune test. CONCLUSION: In what may be a selected
> population of IVF patients (with high incidence of abnormal immune
> testing), early IVIg therapy may be associated with the improved
> success of IVF, and the high rate of live birth.
>
> PMID: 10994640 [PubMed - indexed for MEDLINE]
> ****************
>
> 23) Ginekol Pol. 2003 Oct;74(10):1107-11.
>
> [Immunotherapy as an effective treatment of recurrent spontaneous
> abortion--own experience]
>
> [Article in Polish]
>
> Jerzak M, Rechberger T, Baranowski W, Semczuk M.
>
> Kliniki Poloznictwa i Patologii Ciazy AM w Lublinie.
>
> OBJECTIVES: Recent data emphasize relationship between
> antiphospholipid antibodies (APA) and increased natural killer
cell
> activity in women with recurrent spontaneous abortion (RSA).
> Therefore, it has been proposed that final common mechanism
involved
> in the pathogenesis of RSA is associated with auto- and
alloimmunity.
> DESIGN: The aim of this study was to present our data concerning
> diagnosis and treatment of women with RSA. MATERIALS AND METHODS:
> Sixty nonpregnant women with the history of RSA were studied,
among
> them 41 were screened at the beginning of their next pregnancy. We
> investigated the existence of inherited (deficiencies of protein
C,
> protein S, antithrombin III, a resistance to the activated protein
C> including Leiden V mutation) or acquired thrombophilia (APA> anticardiolipin antibodies, antiphosphatidylserine antibodies,
lupus
> anticoagulant). Natural killer cell activity was measured using
flow
> cytometry. In addition, the following lymphocytes surface
antigens:
> CD3, CD4, CD8, CD16, CD56 were studied using flow cytometry. We
also
> studied the existence of autoimmunity: antinuclear antibodies
(ANA),
> antithyroid antibodies (ATA). According to presence of auto- or
> alloimmunity, we introduce immunotherapy: intravenous
immunoglobulin,
> alloimmunization, heparin/aspirin, aspirin alone, steroids or
combine
> therapy. RESULTS: We determined the existence of thrombophilia in
17
> women, ANA in 5 women, ATA in 5 women, increased number of NK
cells
> in 16 women and increased NK cell activity in 14 women. Forty-one
> women were pregnant and followed up during pregnancy, among them
> 33/41 delivered normal healthy baby, 7/41 experienced the next
> abortion and 1/41 had ectopic pregnancy. Therefore, overall
success
> of immunotherapy was 80.5%. CONCLUSIONS: Immunotherapy seems to be
> effective treatment for women with the history of RSA and combined
> immune abnormalities. Regulation of immune system activity may
> underlie possible effect of such therapy.
>
> PMID: 14669403 [PubMed]
>
> ****************
>
> 24) Am J Reprod Immunol. 2003 Sep;50(3):232-7.
>
> GM-CSF and pregnancy: evidence of significantly reduced blood
> concentrations in unexplained recurrent abortion efficiently
reverted
> by intravenous immunoglobulin treatment.
>
> Perricone R, De Carolis C, Giacomelli R, Guarino MD, De Sanctis G,
> Fontana L.
>
> Department of Internal Medicine, University of Rome Tor Vergata,
> Rome, Italy. roberto.perricone@u...
>
> PROBLEM: Certain Th-2 cytokines and granulocyte-macrophage colony> stimulating factor (GM-CSF) are propitious for the success of
> pregnancy and recurrent spontaneous abortion (RSA) is often
> characterized by a failure of Th-2 type responses. These
> considerations as well as the use of intravenous immunoglobulin
> (IVIg) in RSA induced us to evaluate the levels of GM-CSF in
normal
> pregnancies, in pregnant women affected with unexplained RSA and
the
> effects of IVIg treatment. METHOD OF STUDY: Peripheral blood free
GM> CSF was measured by means of a sandwich enzyme immunoassay in 39
> healthy women (13 non-pregnant, 26 pregnant) and in 53 RSA
patients
> (11 non-pregnant, 42 pregnant). In 14 pregnant RSA patients GM-CSF
> was studied also after the very first IVIg infusion (0.5 g/kg body
> weight). RESULTS: In healthy women we found a significant increase
of
> GM-CSF during pregnancy, in pregnant RSA patients such an increase
> was not detected. After IVIg, GM-CSF concentrations were almost
> doubled. CONCLUSIONS: GM-CSF is found increased in normal
pregnancy
> and is very low during pregnancy in RSA. IVIg infusions are
capable
> of increasing GM-CSF in pregnant recurrent aborters.
>
> PMID: 14629028 [PubMed]
>
> ***************
>
> 25) Akush Ginekol (Sofiia). 2004;43(2):3-10.
>
>
> [Effect of intravenous gamma-globulin therapy on lymphocyte
> population in pregnant women with antiphospholipid antibodies]
>
> [Article in Bulgarian]
>
> Konova E, Ivanova I, Petrova P, Popov I, Andreeva Kh, Lukanov Ts,
> Gecheva S.
>
> The aim of the study was to establish the distribution of the
> lymphocyte populations in peripheral blood in pregnant women with
> antiphospholipid antibodies (aPL) and a history of recurrent
> pregnancy loss as well as to make a study on the influence of the
> intravenous IgG-treatment (IVIg) on the levels of antibodies and
> peripheral lymphocytes. MATERIALS AND METHODS: 14 pregnant women
were
> investigated. The latter had two or more recurrent abortions and
> positive aPL--anticardiolipin (aCL) and/or anti-beta 2Glycoprotein I
> (anti-beta 2-GPI). The lymphocyte populations were examined, using
a
> flowcytometric method in peripheral blood before 6-7th gestational
> week and on the 10-14 day after the second IVIg infusion. 10
pregnant
> women wer used as controls who had no aPL antibodies and no
pregnancy
> loss. RESULTS: 13 out of 14 pregnancies were successful Lymphocyte
> populations of the examined patients before the first infusion
> compared to the controls showed statistically significant
differences
> for: T-lymphocyted Th(reduced) and CD3-CD56 + NK (increased)
> Significant increase after therapy was noticed for the levels of T> lymphocytes, and Th while the NK-cell populations were
significantly
> reduced. CONCLUSIONS: aPL-positive pregnancies most probably were
> associated with elevated and activated peripheral NK-cell
> subpopulations. The low doses of IVIg successfully reduce the
levels
> of aPL, as well as peripheral CD3-CD56 + NK cells.
>
> Publication Types:
> Clinical Trial
>
> PMID: 15185522 [PubMed - indexed for MEDLINE]
> ************************