- Email: [email protected]
Granulocyte colony-stimulating factor for the treatment of recurrent miscarriage
158
Symposium Abstracts / Journal of Reproductive Immunology 90 (2011) 131–163
knowledge of the obstetric history (86%) and gives information about RM (84%). Also an ultrasound during symptoms (88%), directly after a positive pregnancy test (67%) and every two weeks a repeat ultrasound (66%) was preferred by the majority of women with RM. Finally 61% of women would prefer to talk to a medical or psychological professional after their next miscarriage. In general, the majority of the women did not prefer admittance to a hospital ward on the same gestational age as previous miscarriages (65%) nor bereavement therapy (66%). The mean preference for supportive care for women with RM on a one to ten scale was 8.0 ± 2.2. Ethnicity, education level, parity, pregnancy during questionnaire and time passed since last miscarriage proved to be predictors in the preference of different supportive care options, female age did not. Conclusions: In conclusion, our study shows that women with RM want supportive care during their next pregnancy. Women with RM prefer medical supportive care from a gynaecologist or doctor specialized in RM that takes them seriously. Women from ethnic minorities and women who were not pregnant during the questionnaire are the two patient groups that prefer the most supportive care options. Tailor-made supportive care can now be offered to women with RM. Keywords: Recurrent miscarriage; Counselling & psychology; Supportive care
antiphospholipid antibodies” and “recurrent IVF failure”. Included articles were limited to randomized trials and meta-analyses of randomized trials; abstracts were excluded. Results: Two randomized trials were found which evaluated IVIG for treatment of antiphospholipd-associated recurrent miscarriage, two for women with idiopathic or antiphospholipid-associated recurrent miscarriage, six for idiopathic recurrent miscarriage, and one for repeated idiopathic IVF failure and one for women with recurrent early pregnancy loss or recurrent IVF failure. Three metaanalyses were identified for IVIG and recurrent miscarriage. Conclusions: Based on published randomized trials, there appears to be no significant beneficial effect of IVIG, as used in the randomized trials, for treatment of idiopathic recurrent miscarriage. Perhaps a beneficial effect could be found if validated and reproducible tests were available to identify a homogenous subset of women with, otherwise, idiopathic recurrent miscarriage. Aspirin and heparin appear to be superior to IVIG as first line treatment of antiphospholipid antibody-associated recurrent miscarriage, but whether IVIG is beneficial in aspirin/heparin treatment failures remains to be determined. Further randomized trials are needed to assess IVIG in recurrent IVF failure. Keywords: IVIG; Recurrent miscarriage; Antiphospholipid syndrome; Recurrent IVF failure
Reference
doi:10.1016/j.jri.2011.06.051
Musters, A.M., Taminiau-Bloem, E.F., van den Boogaard, E., van der Veen, F., Goddijn, M., 2011. Supportive care for women with unexplained recurrent miscarriage: patients’ perspectives. Hum. Reprod. 26, 873–877.
S50 Granulocyte colony-stimulating factor for the treatment of recurrent miscarriage
doi:10.1016/j.jri.2011.06.050
F. Scarpellini ∗ , M. Sbracia
S49
Hungaria Center for Endocrinology and Reproductive Medicine, Rome, Italy
Intravenous immunoglobulin for treatment of recurrent miscarriage and IVF failure: review of randomized trials M.D. Stephenson Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA Introduction: The use of intravenous immunoglobulin (IVIG) as passive immunotherapy in women with reproductive problems, such as recurrent miscarriage and recurrent IVF failure, has been reported for several decades, however the effectiveness of IVIG has remained inconclusive because of the limited number of randomized trials, their small sample sizes and heterogenous cohorts. IVIG has been evaluated in randomized trials for antiphospholipid antibody-associated recurrent miscarriage, idiopathic recurrent miscarriage and recurrent IVF failure. The objective of this lecture is to present the highest level of evidence for these three devastating reproductive problems. Materials and methods: A literature review was performed in Ovid Medline and PubMed by combining the following medical subject heading terms and keywords “intravenous immunoglobulin”, “recurrent miscarriage”,
Introduction: We have investigated the role of G-CSF (CSF3) in the trophoblast and in early pregnancy by a series of clinical and experimental studies, testing its effectiveness in the treatment of recurrent miscarriage (RM) women and in women with recurrent implantation failure. Material and methods: Specimens from 25 spontaneous abortions that occurred in 12 women affected by unexplained RM (women who tested negative for all analysis used to recognize known causes of RM) were used for immunohistochemical analysis of G-CSF and the receptor c-fms. As controls the specimens of 20 first trimester voluntary pregnancy terminations were used. Furthermore, 68 women with unexplained RM, all of them with at least four consecutive abortions and negative for all clinical investigations were selected for this study. Patients were randomly treated with G-CSF, at the subcutaneous dose of 1 mg/Kg/day, starting on the 6th day after ovulation or with placebo. Furthermore 89 women with recurrent implantation failure after IVF cycles were treated with G-CSF or placebo. These women underwent IVF cycle and they were randomly divided into two groups: (1) Treatment group (45 women) treated with subcutaneous G-CSF 1.5 mg/Kg /day
Symposium Abstracts / Journal of Reproductive Immunology 90 (2011) 131–163
(60–100 mg) from the day of transfer to the day of -hCG test, and if it was positive the treatment was continued for other 40 days, and (2) the control group, treated with subcutaneous saline solution infusion in the same way as the study group. Results: The expression of G-CSF was found to be reduced in the cytotrophoblast of RM specimens with respect to controls, especially in five cases where it was very faint. On the other side, the expression of c-fms was found to be increased in the cytotrophoblast of RM specimens compared to controls. In the group treated with G-CSF, 29 out of 35 (82.2%) women delivered a healthy baby whereas in the placebo group only 16 out of 33 (48.5%) women delivered (P < 0.01). Furthermore, the women treated with G-CSF showed significantly higher levels of hCG with respect to controls during the early gestational weeks (P < 0.01). The pregnancy rate in the group treated with G-CSF was of 42.2% (16/45) whereas in the control group 15.9% (7/44), this difference was statistically significant P = 0.0176. The levels of hCG after 14 days, 21 days 28 days and 35 days from embryo transfer were significantly higher in the pregnancies obtained in the group treated with G-CSF than in control group pregnancies (P < 0.001). Conclusions: We have demonstrated the role of G-CSF in regulating trophoblast growth and development in early pregnancy and its effectiveness in the treatment of unexplained RM and recurrent implantation failure. Keywords: G-CSF; Recurrent miscarriage; Recurrent implantation failure; Trophoblast doi:10.1016/j.jri.2011.06.052 S51 564 cycles with G-CSF application in patients with fertility disorders C. Santjohanser a,∗ , C. Franz c , W. Wuerfel a , O. Meri a , K. Fiedler a , G. Krüsmann a , J. Krüsmann a , K. Hirv b , B. Toth c a
Fertility Center (KCM), München, Germany Center for Human Genetics and Laboratory Medicine, Lochamerstr. München, Germany c Ruprecht-Karls University, Endocrinology and Fertility Disorders, Heidelberg, Germany b
Introduction: Despite recent advances concerning pronuclear morphology pattern, sperm characterization and embryo scoring, the implantation process remains altered in a subgroup of infertile couples. The maternal immune system with key players in the endometrium can influence the fate of the developing embryo. Therefore, immune modulating treatment options seem to be promising tools especially in patients with recurrent implantation failure (RIF) or recurrent miscarriages (RM). Although natural killer cell (NK) profiles as well as interleukin concentrations differ between RIF patients and controls, data are missing for helping to identify patients which may benefit from immune modulating therapy. Within our retrospective study, we summarize 5 years experience with G-CSF (CSF3) application in patients with fertility disorders.
159
Material and methods: Between January 2006 and December 2010, 399 patients were included and 564 cycles of G-CSF application were documented. 313 patients received 2 × 13 Mill IU G-CSF per week starting on the day of the embryo transfer until the 12th week of pregnancy, and 86 patients received 1 × 34 Mill IU GCSF per week. Patients underwent assisted reproduction techniques (ART) with the exception of 16.3% (n = 65) with normal conception. Killer-cell immunoglobulin-like receptor (KIR) genes (8 inhibitory, 6 activating and 2 pseudogenes) were analyzed. Statistical analysis was performed with SPSS for Windows (18.0). Results: A total of 19.5% (n = 78) patients suffered recurrent miscarriages (RM) with two or more miscarriages before G-CSF application and 53.6% (n = 214) from recurrent implantation failure (RIF). The mean number of ART cycles was 5.7 ± 3.8 (0–26) (standard deviation, minimum-maximum) with 3.4 cycles at the Pasing, Munich fertility center (2.7 ± 4.3 (0–16) ART cycles with controlled ovarian hyperstimulation, 1.4 ± 1.9 (0–12) with cryopreserved embryos). G-CSF treatment generally took place at the fifth ART cycle. Mean age was 36.8 ± 4.1 (25–48) years. An average of 7.9 ± 5.9 (0–26) oocytes was obtained per patient and 4.4 ± 3.7 (0–17) were fertilized. Most patients received 2.0 ± 0.7 (0–3) embryos. Altogether, 38.8% (n = 155) patients became pregnant and so far, 27.8% (n = 111) delivered (n = 29 ongoing pregnancies). In half of the patients (n = 200) KIR profiling was performed. Fifty patients were missing at least one activating gene (2DS1+2DS5+3DS1), of whom 44/50 did not deliver and 6/50 delivered. When all 3 genes (2DS1+2DS5+3DS1) were missing, 110 patients did not deliver and 40 gave birth to a child. Live birth rate differed significantly between patients missing 3 (2DS1+2DS5+3DS1) and 2 (2DS1+2DS5) genes as compared to patients with at least one missing gene (p = 0.012, p = 0.007). Main side effects included leukocytosis, irrigation at the injection side and slight rise of temperature (<10% of affected patients). Conclusion: G-CSF was mainly offered to patients with severe fertility disorders after a long history of ART cycles. Pregnancy and baby take home rate were therefore high within this context. It seems that patients with missing 2DS1+2DS5+3DS1 might benefit from G-CSF treatment. So far, side effects seem to be rare, although larger study populations are needed. doi:10.1016/j.jri.2011.06.053 S52 Recommendations for recurrent comparison of 5 different guidelines
miscarriage—
M. Goddijn Center for Reproductive Medicine, Academic Medical Center, Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, Denmark Good clinical practice starts with a clear definition of the clinical problem. Currently, no consensus exists on the definition of recurrent miscarriage. Several national and international guidelines have been published on this
Symposium Abstracts / Journal of Reproductive Immunology 90 (2011) 131–163
knowledge of the obstetric history (86%) and gives information about RM (84%). Also an ultrasound during symptoms (88%), directly after a positive pregnancy test (67%) and every two weeks a repeat ultrasound (66%) was preferred by the majority of women with RM. Finally 61% of women would prefer to talk to a medical or psychological professional after their next miscarriage. In general, the majority of the women did not prefer admittance to a hospital ward on the same gestational age as previous miscarriages (65%) nor bereavement therapy (66%). The mean preference for supportive care for women with RM on a one to ten scale was 8.0 ± 2.2. Ethnicity, education level, parity, pregnancy during questionnaire and time passed since last miscarriage proved to be predictors in the preference of different supportive care options, female age did not. Conclusions: In conclusion, our study shows that women with RM want supportive care during their next pregnancy. Women with RM prefer medical supportive care from a gynaecologist or doctor specialized in RM that takes them seriously. Women from ethnic minorities and women who were not pregnant during the questionnaire are the two patient groups that prefer the most supportive care options. Tailor-made supportive care can now be offered to women with RM. Keywords: Recurrent miscarriage; Counselling & psychology; Supportive care
antiphospholipid antibodies” and “recurrent IVF failure”. Included articles were limited to randomized trials and meta-analyses of randomized trials; abstracts were excluded. Results: Two randomized trials were found which evaluated IVIG for treatment of antiphospholipd-associated recurrent miscarriage, two for women with idiopathic or antiphospholipid-associated recurrent miscarriage, six for idiopathic recurrent miscarriage, and one for repeated idiopathic IVF failure and one for women with recurrent early pregnancy loss or recurrent IVF failure. Three metaanalyses were identified for IVIG and recurrent miscarriage. Conclusions: Based on published randomized trials, there appears to be no significant beneficial effect of IVIG, as used in the randomized trials, for treatment of idiopathic recurrent miscarriage. Perhaps a beneficial effect could be found if validated and reproducible tests were available to identify a homogenous subset of women with, otherwise, idiopathic recurrent miscarriage. Aspirin and heparin appear to be superior to IVIG as first line treatment of antiphospholipid antibody-associated recurrent miscarriage, but whether IVIG is beneficial in aspirin/heparin treatment failures remains to be determined. Further randomized trials are needed to assess IVIG in recurrent IVF failure. Keywords: IVIG; Recurrent miscarriage; Antiphospholipid syndrome; Recurrent IVF failure
Reference
doi:10.1016/j.jri.2011.06.051
Musters, A.M., Taminiau-Bloem, E.F., van den Boogaard, E., van der Veen, F., Goddijn, M., 2011. Supportive care for women with unexplained recurrent miscarriage: patients’ perspectives. Hum. Reprod. 26, 873–877.
S50 Granulocyte colony-stimulating factor for the treatment of recurrent miscarriage
doi:10.1016/j.jri.2011.06.050
F. Scarpellini ∗ , M. Sbracia
S49
Hungaria Center for Endocrinology and Reproductive Medicine, Rome, Italy
Intravenous immunoglobulin for treatment of recurrent miscarriage and IVF failure: review of randomized trials M.D. Stephenson Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA Introduction: The use of intravenous immunoglobulin (IVIG) as passive immunotherapy in women with reproductive problems, such as recurrent miscarriage and recurrent IVF failure, has been reported for several decades, however the effectiveness of IVIG has remained inconclusive because of the limited number of randomized trials, their small sample sizes and heterogenous cohorts. IVIG has been evaluated in randomized trials for antiphospholipid antibody-associated recurrent miscarriage, idiopathic recurrent miscarriage and recurrent IVF failure. The objective of this lecture is to present the highest level of evidence for these three devastating reproductive problems. Materials and methods: A literature review was performed in Ovid Medline and PubMed by combining the following medical subject heading terms and keywords “intravenous immunoglobulin”, “recurrent miscarriage”,
Introduction: We have investigated the role of G-CSF (CSF3) in the trophoblast and in early pregnancy by a series of clinical and experimental studies, testing its effectiveness in the treatment of recurrent miscarriage (RM) women and in women with recurrent implantation failure. Material and methods: Specimens from 25 spontaneous abortions that occurred in 12 women affected by unexplained RM (women who tested negative for all analysis used to recognize known causes of RM) were used for immunohistochemical analysis of G-CSF and the receptor c-fms. As controls the specimens of 20 first trimester voluntary pregnancy terminations were used. Furthermore, 68 women with unexplained RM, all of them with at least four consecutive abortions and negative for all clinical investigations were selected for this study. Patients were randomly treated with G-CSF, at the subcutaneous dose of 1 mg/Kg/day, starting on the 6th day after ovulation or with placebo. Furthermore 89 women with recurrent implantation failure after IVF cycles were treated with G-CSF or placebo. These women underwent IVF cycle and they were randomly divided into two groups: (1) Treatment group (45 women) treated with subcutaneous G-CSF 1.5 mg/Kg /day
Symposium Abstracts / Journal of Reproductive Immunology 90 (2011) 131–163
(60–100 mg) from the day of transfer to the day of -hCG test, and if it was positive the treatment was continued for other 40 days, and (2) the control group, treated with subcutaneous saline solution infusion in the same way as the study group. Results: The expression of G-CSF was found to be reduced in the cytotrophoblast of RM specimens with respect to controls, especially in five cases where it was very faint. On the other side, the expression of c-fms was found to be increased in the cytotrophoblast of RM specimens compared to controls. In the group treated with G-CSF, 29 out of 35 (82.2%) women delivered a healthy baby whereas in the placebo group only 16 out of 33 (48.5%) women delivered (P < 0.01). Furthermore, the women treated with G-CSF showed significantly higher levels of hCG with respect to controls during the early gestational weeks (P < 0.01). The pregnancy rate in the group treated with G-CSF was of 42.2% (16/45) whereas in the control group 15.9% (7/44), this difference was statistically significant P = 0.0176. The levels of hCG after 14 days, 21 days 28 days and 35 days from embryo transfer were significantly higher in the pregnancies obtained in the group treated with G-CSF than in control group pregnancies (P < 0.001). Conclusions: We have demonstrated the role of G-CSF in regulating trophoblast growth and development in early pregnancy and its effectiveness in the treatment of unexplained RM and recurrent implantation failure. Keywords: G-CSF; Recurrent miscarriage; Recurrent implantation failure; Trophoblast doi:10.1016/j.jri.2011.06.052 S51 564 cycles with G-CSF application in patients with fertility disorders C. Santjohanser a,∗ , C. Franz c , W. Wuerfel a , O. Meri a , K. Fiedler a , G. Krüsmann a , J. Krüsmann a , K. Hirv b , B. Toth c a
Fertility Center (KCM), München, Germany Center for Human Genetics and Laboratory Medicine, Lochamerstr. München, Germany c Ruprecht-Karls University, Endocrinology and Fertility Disorders, Heidelberg, Germany b
Introduction: Despite recent advances concerning pronuclear morphology pattern, sperm characterization and embryo scoring, the implantation process remains altered in a subgroup of infertile couples. The maternal immune system with key players in the endometrium can influence the fate of the developing embryo. Therefore, immune modulating treatment options seem to be promising tools especially in patients with recurrent implantation failure (RIF) or recurrent miscarriages (RM). Although natural killer cell (NK) profiles as well as interleukin concentrations differ between RIF patients and controls, data are missing for helping to identify patients which may benefit from immune modulating therapy. Within our retrospective study, we summarize 5 years experience with G-CSF (CSF3) application in patients with fertility disorders.
159
Material and methods: Between January 2006 and December 2010, 399 patients were included and 564 cycles of G-CSF application were documented. 313 patients received 2 × 13 Mill IU G-CSF per week starting on the day of the embryo transfer until the 12th week of pregnancy, and 86 patients received 1 × 34 Mill IU GCSF per week. Patients underwent assisted reproduction techniques (ART) with the exception of 16.3% (n = 65) with normal conception. Killer-cell immunoglobulin-like receptor (KIR) genes (8 inhibitory, 6 activating and 2 pseudogenes) were analyzed. Statistical analysis was performed with SPSS for Windows (18.0). Results: A total of 19.5% (n = 78) patients suffered recurrent miscarriages (RM) with two or more miscarriages before G-CSF application and 53.6% (n = 214) from recurrent implantation failure (RIF). The mean number of ART cycles was 5.7 ± 3.8 (0–26) (standard deviation, minimum-maximum) with 3.4 cycles at the Pasing, Munich fertility center (2.7 ± 4.3 (0–16) ART cycles with controlled ovarian hyperstimulation, 1.4 ± 1.9 (0–12) with cryopreserved embryos). G-CSF treatment generally took place at the fifth ART cycle. Mean age was 36.8 ± 4.1 (25–48) years. An average of 7.9 ± 5.9 (0–26) oocytes was obtained per patient and 4.4 ± 3.7 (0–17) were fertilized. Most patients received 2.0 ± 0.7 (0–3) embryos. Altogether, 38.8% (n = 155) patients became pregnant and so far, 27.8% (n = 111) delivered (n = 29 ongoing pregnancies). In half of the patients (n = 200) KIR profiling was performed. Fifty patients were missing at least one activating gene (2DS1+2DS5+3DS1), of whom 44/50 did not deliver and 6/50 delivered. When all 3 genes (2DS1+2DS5+3DS1) were missing, 110 patients did not deliver and 40 gave birth to a child. Live birth rate differed significantly between patients missing 3 (2DS1+2DS5+3DS1) and 2 (2DS1+2DS5) genes as compared to patients with at least one missing gene (p = 0.012, p = 0.007). Main side effects included leukocytosis, irrigation at the injection side and slight rise of temperature (<10% of affected patients). Conclusion: G-CSF was mainly offered to patients with severe fertility disorders after a long history of ART cycles. Pregnancy and baby take home rate were therefore high within this context. It seems that patients with missing 2DS1+2DS5+3DS1 might benefit from G-CSF treatment. So far, side effects seem to be rare, although larger study populations are needed. doi:10.1016/j.jri.2011.06.053 S52 Recommendations for recurrent comparison of 5 different guidelines
miscarriage—
M. Goddijn Center for Reproductive Medicine, Academic Medical Center, Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, Denmark Good clinical practice starts with a clear definition of the clinical problem. Currently, no consensus exists on the definition of recurrent miscarriage. Several national and international guidelines have been published on this