Assisted Reproduction and Gynaecology Center

Bodle Street, United Kingdom

Assisted Reproduction and Gynaecology Center

Bodle Street, United Kingdom
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Tirado-gonzalez I.,Medicine University Berlin | Freitag N.,Medicine University Berlin | Barrientos G.,Medicine University Berlin | Shaikly V.,University of Essex | And 8 more authors.
Molecular Human Reproduction | Year: 2013

Galectin-1 (gal-1) is expressed at the feto-maternal interface and plays a role in regulating the maternal immune response against placental alloantigens, contributing to pregnancy maintenance. Both decidua and placenta contribute to gal-1 expression and may be important for the maternal immune regulation. The expression of gal-1 within the placenta is considered relevant to cell-adhesion and invasion of trophoblasts, but the role of gal-1 in the immune evasion machinery exhibited by trophoblast cells remains to be elucidated. In this study, we analyzed gal-1 expression in preimplantation human embryos and first-trimester decidua-placenta specimens and serum gal-1 levels to investigate the physiological role played by this lectin during pregnancy. The effect on human leukocyte antigen G (HLA-G) expression in response to stimulation or silencing of gal-1 was also determined in the human invasive, proliferative extravillous cytotrophoblast 65 (HIPEC65) cell line. Compared with normal pregnant women, circulating gal-1 levels were significantly decreased in patients who subsequently suffered a miscarriage. Human embryos undergoing preimplantation development expressed gal-1 on the trophectoderm and inner cell mass. Furthermore, our in vitro experiments showed that exogenous gal-1 positively regulated the membrane-bound HLA-G isoforms (HLA-G1 and G2) in HIPEC65 cells, whereas endogenous gal-1 also induced expression of the soluble isoforms (HLA-G5 and -G6). Our results suggest that gal-1 plays a key role in pregnancy maternal immune regulation by modulating HLA-G expression on trophoblast cells. Circulating gal-1 levels could serve as a predictive factor for pregnancy success in early human gestation. © The Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Shaikly V.,University of Essex | Shaikly V.,Assisted Reproduction and Gynaecology Center | Shakhawat A.,University of Essex | Withey A.,Assisted Reproduction and Gynaecology Center | And 6 more authors.
Reproductive BioMedicine Online | Year: 2010

The non-classical major histocompatibility complex (MHC) class Ib antigens, termed HLA-G and HLA-E, have been associated with fetal maternal tolerance. The role of HLA-G in the preimplantation embryo remains unclear although immunoprotection, adhesion and cell signalling mechanisms have been suggested. Unlike HLA-G, HLA-E protein expression has not been previously studied in preimplantation embryos. Embryos and model trophoblast cell lines JEG-3 and BeWo were labelled with the HLA-G- and HLA-Especific monoclonal antibodies MEMG9 and MEME07. Flow cytometry, confocal microscopy and single particle fluorescence imaging techniques were employed to investigate the spatial and temporal expression of these receptors. Lipid raft analysis and adhesion assays were performed to investigate the role of these receptors in cell membrane domains and in promoting adhesion by cell-to-cell contact. HLA-E and HLA-G were co-localized in the trophectoderm of day 6 blastocysts. Analysis on trophoblast cell lines revealed that 37% of HLA-G and 41% of HLA-E receptors were co-localized as tetramers or higher order homodimer clusters. HLA-G receptors did not appear to play a role in either cell adhesion or immunoreceptor signalling via lipid raft platforms on the cell membrane. A possible role of HLA-G and HLA-E in implantation via immunoregulation or modulation of uterine maternal leukocytes is discussed. © 2010, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


Pundir J.,Assisted Conception Unit | Pundir V.,Conquest | Omanwa K.,Assisted Reproduction and Gynaecology Center | Khalaf Y.,Assisted Conception Unit | El-Toukhy T.,Assisted Conception Unit
Reproductive BioMedicine Online | Year: 2014

This systematic review and meta-analysis investigated the use of routine hysteroscopy prior to starting the first IVF cycle on treatment outcome in asymptomatic women. Searches were conducted on MEDLINE, EMBASE, Cochrane Library, National Research Register and ISI Conference Proceedings. The main outcome measures were clinical pregnancy and live birth rates achieved in the index IVF cycle. One randomized and five non-randomized controlled studies including a total of 3179 participants were included comparing hysteroscopy with no intervention in the cycle preceding the first IVF cycle. There was a significantly higher clinical pregnancy rate (relative risk, RR, 1.44, 95% CI 1.08-1.92, P = 0.01) and LBR (RR 1.30, 95% CI 1.00-1.67, P = 0.05) in the subsequent IVF cycle in the hysteroscopy group. The number needed to treat after hysteroscopy to achieve one additional clinical pregnancy was 10 (95% CI 7-14) and live birth was 11 (95% CI 7-16). Hysteroscopy in asymptomatic woman prior to their first IVF cycle could improve treatment outcome when performed just before commencing the IVF cycle. Robust and high-quality randomized trials to confirm this finding are warranted. Currently, there is evidence that performing hysteroscopy (camera examination of the womb cavity) before starting IVF treatment could increase the chance of pregnancy in the subsequent IVF cycle in women who had one or more failed IVF cycles. However, recommendations regarding the efficacy of routine use of hysteroscopy prior to starting the first IVF treatment cycle are lacking. We reviewed systematically the trials related to the impact of hysteroscopy prior to starting the first IVF cycle on treatment outcomes of pregnancy rate and live birth rate in asymptomatic women. Literature searches were conducted in all major database and all randomized and non-randomized controlled trials were included in our study (up to March 2013). The main outcome measures were the clinical pregnancy rate and live birth rate. The secondary outcome measure was the procedure related complication rate. A total of 3179 women, of which 1277 had hysteroscopy and 1902 did not have a hysteroscopy prior to first IVF treatment, were included in six controlled studies. Hysteroscopy in asymptomatic woman prior to their first IVF cycle was found to be associated with improved chance of achieving a pregnancy and live birth when performed just before commencing the IVF cycle. The procedure was safe. Larger studies are still required to confirm our findings. © 2013, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


PubMed | Assisted Reproduction and Gynaecology Center, Conquest and Assisted Conception Unit
Type: Journal Article | Journal: Reproductive biomedicine online | Year: 2014

This systematic review and meta-analysis investigated the use of routine hysteroscopy prior to starting the first IVF cycle on treatment outcome in asymptomatic women. Searches were conducted on MEDLINE, EMBASE, Cochrane Library, National Research Register and ISI Conference Proceedings. The main outcome measures were clinical pregnancy and live birth rates achieved in the index IVF cycle. One randomized and five non-randomized controlled studies including a total of 3179 participants were included comparing hysteroscopy with no intervention in the cycle preceding the first IVF cycle. There was a significantly higher clinical pregnancy rate (relative risk, RR, 1.44, 95% CI 1.08-1.92, P=0.01) and LBR (RR 1.30, 95% CI 1.00-1.67, P=0.05) in the subsequent IVF cycle in the hysteroscopy group. The number needed to treat after hysteroscopy to achieve one additional clinical pregnancy was 10 (95% CI 7-14) and live birth was 11 (95% CI 7-16). Hysteroscopy in asymptomatic woman prior to their first IVF cycle could improve treatment outcome when performed just before commencing the IVF cycle. Robust and high-quality randomized trials to confirm this finding are warranted. Currently, there is evidence that performing hysteroscopy (camera examination of the womb cavity) before starting IVF treatment could increase the chance of pregnancy in the subsequent IVF cycle in women who had one or more failed IVF cycles. However, recommendations regarding the efficacy of routine use of hysteroscopy prior to starting the first IVF treatment cycle are lacking. We reviewed systematically the trials related to the impact of hysteroscopy prior to starting the first IVF cycle on treatment outcomes of pregnancy rate and live birth rate in asymptomatic women. Literature searches were conducted in all major database and all randomized and non-randomized controlled trials were included in our study (up to March 2013). The main outcome measures were the clinical pregnancy rate and live birth rate. The secondary outcome measure was the procedure related complication rate. A total of 3179 women, of which 1277 had hysteroscopy and 1902 did not have a hysteroscopy prior to first IVF treatment, were included in six controlled studies. Hysteroscopy in asymptomatic woman prior to their first IVF cycle was found to be associated with improved chance of achieving a pregnancy and live birth when performed just before commencing the IVF cycle. The procedure was safe. Larger studies are still required to confirm our findings.


Winger E.E.,Laboratory for Reproductive Medicine and Immunology | Reed J.L.,Laboratory for Reproductive Medicine and Immunology | Ashoush S.,Assisted Reproduction and Gynaecology Center | El-Toukhy T.,Assisted Reproduction and Gynaecology Center | And 2 more authors.
American Journal of Reproductive Immunology | Year: 2011

Problem In this retrospective observational study, we investigate whether the degree of preconception cytokine elevation predicts the risk of IVF failure. Method of Study Seventy-six women undergoing fresh IVF/ICSI cycles (≤41years, good responders with ≥5 embryos on day 3, each with ≥5 cells with a normal endometrium) and preconception tumor necrosis factor (TNF)-α/IL-10 cytokine elevation [PMA/ionomycin stimulated CD3+CD8-; TNF-α/IL-10 ratio above 30.6 (normal range 13.2-30.6)] were retrospectively evaluated. This high cytokine population was divided into two subgroups. Group I included 39 women with severe preconception and pre-treatment TNF-α/IL-10 cytokine elevation >39.0 (mean 47.5±7.5 pre-treatment, mean 31.5±9.4 post-treatment) treated with preconception Adalimumab (Humira®) and intravenous immunoglobulin (IVIG). Group II included 37 women with a moderate TNF-α/IL-10 ratio >30.6 and ≤39.0 (mean 35.2±2.2 pre-treatment, mean 28.8±8.5 post-treatment) treated with preconception Adalimumab and IVIG. Groups I and II were comparable in relation to baseline IVF characteristics and patient history. Results The implantation rate (number of gestational sacs per embryo transfer, with an average of two embryos transferred per cycle) was 43% (36/83) for Group I and 56% (44/78) for Group II. The clinical pregnancy rate (fetal heart activity per IVF cycle started) was 67% (26/39) for Group I and 73% (27/37) for Group II. The delivery rate was 56% (22/39) for Group I and 68% (25/37) for Group II. The live birthrate per embryo transferred was 36% (30/83) for Group I and 45% (35/78) for Group II. Comparing Groups I and II, there was non-significant increase in implantation rate, clinical pregnancy rate, delivery rate, and live birthrate per embryo transferred (P=0.1, 0.6, 0.4, and 0.3, respectively). However, when the subgroup with the least optimal cytokine conditions (Group I with inadequate cytokine suppression) was compared to the subgroup with the most optimal cytokine conditions (Group II with adequate cytokine suppression), the increase in implantation rate reached statistical significance [41% (19/46) to 64% (29/45); P=0.04]. The reduction in TNF-α/IL-10 ratio following immunotherapy was highly significant (P<0.0001). Conclusion The degree of preconception TNF/IL-10 elevation may correlate with an increased risk of IVF failure. Elevated TNF-α/IL-10 ratios can be corrected with therapy. It may be possible to improve IVF success rates by modulating high cytokine levels. Although our pilot database is small, the trends in the data are consistent and compelling. Larger studies are needed for confirmation. © 2011 John Wiley and Sons A/S.


Winger E.E.,Laboratory for Reproductive Medicine and Immunology | Reed J.L.,Laboratory for Reproductive Medicine and Immunology | Ashoush S.,Assisted Reproduction and Gynaecology Center | El-Toukhy T.,Assisted Reproduction and Gynaecology Center | And 2 more authors.
American Journal of Reproductive Immunology | Year: 2011

Problem We sought to answer two questions: First, is there a group of patients who benefit from intravenous immunoglobulin (IVIG) in IVF? Second can this group of patients be identified by preconception blood testing? Method of study A total of 202 IVF cycles in subfertile women were divided into four groups. Group I: 62 cycles with preconception Th1:Th2 ratio and/or % CD56 + cell elevation using IVIG; Group II: 27 cycles with similar Th1:Th2 and/or % CD56 + cell elevation not using IVIG; Group III: 71 cycles with normal Th1:Th2 and/or % CD56 + cell levels using IVIG; Group IV: 42 cycles with normal Th1:Th2 and % CD56 + levels not using IVIG. These groups were similar with regard to patient age, diagnosis, and past failure history. Results The implantation rate (number of gestational sacs per embryo transferred, with an average of two embryos transferred per cycle) was 45% (55/123), 22% (12/54), 54% (75/139), and 48% (40/84) for Groups I-IV, respectively. The clinical pregnancy rate (fetal heart activity per IVF cycle started) was 61% (38/62), 26% (7/27), 69% (49/71), and 71% (30/42), respectively. The live birth rate was 58% (36/62), 22% (6/27), 61% (43/71), and 71% (30/42), respectively, and the live birth per embryo transferred was 40% (49/123), 13% (7/24), 43% (60/139), and 48% (40/84), respectively. There was a significant improvement in implantation, clinical pregnancy, live birth rate and live birth rate per embryo transferred for Group I versus Group II (P=0.0032, 0.0021, 0.0017, and 0.0002, respectively) and for Group II versus Group IV (P=0.0021, 0.0002, <0.0001 and <0.0001, respectively). There was no significant difference in success rates between Groups I and III (P=0.085, 0.23, 0.45, 0.34, respectively) and between Groups III and IV (P=0.22, 0.48, 0.17, 0.31, respectively). Conclusion In subfertile women with preconception Th1:Th2 and/or % CD56 + cell elevation, IVF success rates are low without IVIG therapy but significantly improve with IVIG therapy. In patients with normal Th1:Th2 and normal CD56 + cell levels, IVF success rates were not further improved with IVIG therapy. IVIG may be a useful treatment option for patients with previous IVF failure and preconception Th1:Th2 and/or NK elevation. Preconception immune testing may be a critical tool for determining which patients will benefit from IVIG therapy. Prospective controlled studies (preferably double-blind, stratified, and randomized) are needed for confirmation. © 2011 John Wiley & Sons A/S.


Winger E.E.,Laboratory for Reproductive Medicine and Immunology | Reed J.L.,Laboratory for Reproductive Medicine and Immunology | Ashoush S.,Assisted Reproduction and Gynaecology Center | El-Toukhy T.,Assisted Reproduction and Gynaecology Center | Taranissi M.,Assisted Reproduction and Gynaecology Center
American Journal of Reproductive Immunology | Year: 2012

Background: Human embryos develop at varying rates in culture, with only a fraction of the eggs retrieved developing to 'transfer quality' embryos. We investigated whether the ratios between the number of eggs retrieved or the number of pro-nucleate embryos formed and the number of Day 3 embryos with ≥5 cells [oocyte 'die-off ratios' (DOR)] were correlated with the chance of IVF success, independent of other factors such as embryo grade score and patient's age. We also investigated what factors may be correlated with this ratio. Methods: 608 IVF fresh cycles in subfertile women were retrospectively evaluated. For each cycle, an oocyte DOR number was calculated as follows: Number of eggs retrieved divided by the number of Day 3 embryos with ≥5 cells. This number was correlated with the subsequent success rates for the index cycles. A 'post-fertilization' or 'embryo' die-off ratio (EDOR; the number of pro-nucleate embryos/the number of day 3 embryos ≥5 cells) was also calculated. Results: The oocyte DOR showed a reverse linear correlation with IVF live birth rate. Live birth rate = (-5.75; DOR) +71.6 (with DOR > 1; P ≤ 0.005; R = -0.87). In addition, the oocyte DOR continued to show an inverse correlation with success rates even when embryo quality and patient's age were held constant. The post-fertilization or EDOR also continued to show a statistically significant negative correlation with live birth rate (R = -0.91; P ≤ 0.01). The preconception TNF-α:IL-10 ratio, an immmunologic marker (drawn 3.3 ± 2.6 months preconception), was more strongly correlated with high oocyte DOR than either age or number of eggs retrieved (P = 0.04, 0.14, 0.72, respectively). When anti-TNF-α therapy (Humira) was given preconception, the oocyte DOR's negative effect on live birth rate was nearly eliminated (correlation coefficient between oocyte DOR and live birth rate: cycles using no Humira, R = -0.90, P ≤ 0.006; cycles using Humira, R = 0.25, P ≤ 0.55). Conclusions: In subfertile women undergoing IVF, the oocyte DOR may help predict IVF success rates. This factor may offer an additional tool to help improve implantation rate, clinical pregnancy rate, live birth rate, and live birth rate per embryo transferred for an upcoming IVF cycle. Although many mechanisms may contribute to the oocyte DOR's negative effect on IVF success rates, its correlation with elevated preconception TNF-α:IL-10 ratio and correction with Humira suggests a strong immunologic component that may be treatable. © 2012 John Wiley & Sons A/S.

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