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Recurrent spontaneous abortion: a clinical, immunological and genetic study
Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Recurrent spontaneous abortion (RSA) is defined as the loss of three or more consecutive pregnancies before 20 completed gestational weeks. The condition affects 0.5-1% of all women. In the majority of women with RSA, the cause remains unexplained after genetic, endocrine, immunological and anatomical investigations of the couple. However, there is increasing evidence that immunological mechanisms might contribute in the pathogenesis of RSA. Therefore high doses of intravenous immunoglobulin (IVIG), known to modulate immune responses, has been suggested as a treatment of RSA. The aim of this study was to evaluate IVIG in the treatment of RSA, and to elucidate immunological and genetic mechanisms behind this condition. In a prospective, double blind, placebo-controlled IVIG study we investigated 41 women with a history of unexplained RSA. They received 20g IVIG or placebo-saline every 3 weeks on five occasions from 6-7 gestational weeks. The overall success rate was 77% in the IVIG group compared with 79% in the placebo group, indicating that IVIG was not better than placebo and that both groups had better results than the predicted outcome.

We also investigated the presence of blocking effect of maternal serum in a mixed leukocyte culture (MLC). Blood samples were obtained before and after pregnancy in the IVIG/placebo groups. As RSA controls we used 31 RSA women who did not achieve pregnancy during this study and were not enrolled in the IVIG study. As normal controls we used 10 non-pregnant women without a history of spontaneous abortions. Blocking antibodies were present in 20% of women with unexplained RSA and in 30% of the control group. The blocking effect before pregnancy was the same for IVIG-, placebo-, and untreated RSA controls as well as in the normal controls. We found no significant differences in blocking effect before compared with after IVIG or placebo treatment.

We measured lymphocyte subset distributions in blood samples obtained in the first trimester and after pregnancy in 39 RSA women in the IVIG study and compared them with previous results from pregnant and non-pregnant controls. In the first trimester of pregnancy, the RSA women had significantly increased proportions ofB-cells (CD19), T cells subsets including activated HLA-DR expressing T cells (CD3+HLA-DR+), and T killer/effector cells (CD+S6F1+). The proportion of T suppressor/inducer cells (CD4+CD45RA+) was significantly decreased. Thus, in early pregnancy the immune system seems to be activated in RSA patients in contrast to the suppression noted in normal pregnancy. These changes in subpopulations do, however, not correlate to the outcome of pregnancy.

We studied the compatibility of HLA-DRB1 alleles in the couples with unexplained RSA and the frequency of HLA-DRB1 and HLA-G alleles in these couples compared with fertile controls. We did not find significantly increased sharing of HLA-DRB1 alleles between partners. We found no significant differences for HLA-DRB1 and HLA-G allele frequencies in RSA couples compared with fertile controls.

In conclusion, RSA patients have no genetic differences, their immune reaction during pregnancy is altered, their levels of blocking antibodies is of no use to predict pregnancy outcome and intravenously given high dose IVIG does not effect their pregnancy outcome.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2003. , 88 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 772
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-26658Local ID: 11223ISBN: 91-7373-529-9 (print)OAI: oai:DiVA.org:liu-26658DiVA: diva2:247207
Public defence
2003-01-31, Berzeliussalen, Hälsouniversitet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-11Bibliographically approved
List of papers
1. Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study
Open this publication in new window or tab >>Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study
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1999 (English)In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 14, no 3, 838-841 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to evaluate the therapeutic efficacy of intravenous immunoglobulin (IVIG) in the prevention of recurrent spontaneous abortion (RSA). In a double-blind, randomized, placebo-controlled study, 41 women with a history of unexplained recurrent spontaneous abortion were treated with IVIG or saline infusions during pregnancy. The birth of a child was considered a successful outcome. The overall success rate was 77% in the IVIG group compared with 79% in the placebo group. For women with primary RSA the success rates were 82 (IVIG) and 89% (placebo), and for women with secondary RSA the rates were 73 (IVIG) and 70% (placebo). We found no statistically significant difference in treatment results between IVIG and placebo.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25896 (URN)10.1093/humrep/14.3.838 (DOI)10337 (Local ID)10337 (Archive number)10337 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
2. Blocking antibodies in blood from patients with recurrent spontaneous abortion in relation to pregnancy outcome and intravenous immunoglobulin treatment
Open this publication in new window or tab >>Blocking antibodies in blood from patients with recurrent spontaneous abortion in relation to pregnancy outcome and intravenous immunoglobulin treatment
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2001 (English)In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 45, no 4, 226-231 p.Article in journal (Refereed) Published
Abstract [en]

PROBLEM: To study whether the occurrence of mixed lymphocyte culture (MLC) blocking antibodies is associated with pregnancy outcome in women with unexplained recurrent spontaneous abortion (RSA) and the in vivo effect of intravenous immunoglobulin (IVIG) treatment on MLC blocking effect.

METHOD OF STUDY: Blood samples from 41 RSA patients were obtained before and after pregnancy, and blocking antibodies were estimated by one-way MLC assay. The patients received IVIG or placebo (saline) during pregnancy. Additionally, pre-pregnancy blood samples from 31 RSA women and 10 controls were obtained.

RESULTS: We found no correlation between blocking antibodies before pregnancy and the pregnancy outcome. The occurrence of blocking antibodies was not affected by pregnancy or IVIG treatment.

CONCLUSIONS: Blocking antibodies have no predictive value for the pregnancy outcome in RSA patients, and their production seems not to be affected by IVIG.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25897 (URN)10.1111/j.8755-8920.2001.450405.x (DOI)10338 (Local ID)10338 (Archive number)10338 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
3. T and B lymphocyte subsets in patients with unexplained recurrent spontaneous abortion: IVIG versus placebo treatment
Open this publication in new window or tab >>T and B lymphocyte subsets in patients with unexplained recurrent spontaneous abortion: IVIG versus placebo treatment
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2002 (English)In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 48, no 5, 312-318 p.Article in journal (Refereed) Published
Abstract [en]

Jablonowska B, Palfi M, Matthiesen L, Selbing A, Kjellberg S, Ernerudh J. T and B Lymphocyte subsets in patients with unexplained recurrent spontaneous abortion: IVIG versus placebo treatment. AJRI 2002; 48:312–318 © Blackwell Munksgaard, 2002

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 T-cell 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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26434 (URN)10.1034/j.1600-0897.2002.01010.x (DOI)10977 (Local ID)10977 (Archive number)10977 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
4. Analyses of human leukocyte antigen (HLA-DRB1 and HLA-G alleles in couples with unexplained recurrent spontaneous abortion: typing by using the Polymerase Chain Reaction method
Open this publication in new window or tab >>Analyses of human leukocyte antigen (HLA-DRB1 and HLA-G alleles in couples with unexplained recurrent spontaneous abortion: typing by using the Polymerase Chain Reaction method
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Increased parental Human Leukocyte Antigen (HLA) sharing has been repmted in couples witb history of unexplained recurrent spontaneous abmtion (RSA). Parental HLA sharing increases the risk of feto-matemal histo-compatibility and potentially affects maternal alia-recognition of the fetus. HLA-G is expressed on trophoblast and is expected to play an important role during placental and fetal development. The aim of the present study was to investigate the compatibility of HLA-DRB1 alleles in the couples with unexplained RSA and to investigate the frequency of HLA-DRB1 alleles and HLA-G alleles in these couples compared with fertile controls.

Methods: The frequency of HLA-DRB1 alleles in 36 couples with unexplained recurrent spontaneous abmtion, and the compatibility of HLA-DRB1 alleles between patient couples were studied using a polymerase chain reaction-sequence specific primers (PCR- SSP) method. The frequency of HLA-G alleles in 35 couples were studied using a polymerase chain reaction - single nuclotide polymorphism (PCR-SNP). As controls we used 40 fertile couples who were typed for HLA-DRB1 and HLA-G alleles.

Results: There were no significant differences for HLA-DRB1 and HLA-G allele frequencies in RSA couples compared with fertile controls. There was no significant HLA-DRB1 allele sharing between the RSA couples and fertile controls.

Conclusions: There is no higher HLA-DRB1 allele sharing in couples with unexplained RSA than in fettile couples. The association on allelic level between RSA and HLA-G gene was not supported by our data.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84516 (URN)
Available from: 2012-10-11 Created: 2012-10-11 Last updated: 2012-10-11Bibliographically approved

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