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Oppegaard K.S.,Helse Finnmark | Qvigstad E.,University of Oslo | Fiala C.,GynMed Clinic | Fiala C.,Karolinska University Hospital | And 3 more authors.
The Lancet | Year: 2015

Background Medical abortion with mifepristone and prostaglandins is well established. We compared clinical assessment with self-assessment of abortion outcome. Methods This randomised, controlled, non-inferiority trial was done in four clinics in Austria, Finland, Norway, and Sweden, between Aug 16, 2011, and Jan 31, 2013. Women aged 18 years and older who had requested medical termination of a pregnancy up to 63 days of gestation were eligible. Computer-generated block randomisation (block size ten) assigned women in a 1:1 ratio to attend routine clinical follow-up or to self-assess outcome at home with a semiquantitative urine human chorionic gonadotropin (hCG) test 1-3 weeks after abortion. The primary outcome was the percentage of women with complete abortion not requiring further medical or surgical intervention within 3 months. Analysis was per protocol and by intention to treat. The non-inferiority margin was five percentage points. This trial is registered with ClinicalTrials.gov, number NCT01487213. Findings 924 women were assigned routine follow-up (n=466) or self-assessment (n=458) and included in the intention-to-treat analysis. 901 were included in the per-protocol analysis (n=446 and n=455, respectively). Complete abortion was reported in 432 (95%) of 455 in the routine follow-up group and 419 (94%) of 446 women in the self-assessment group (crude difference -1·0, 95% CI -4·0 to 2·0). 20 (4%) women in the routine follow-up group and 17 (4%) in the self-assessment group required surgery. No women in the routine follow-up group versus three in the self-assessment group had undetected continuing pregnancies. Eight (1·8%) and one (0·2%) women, respectively, had infections (p=0·038). Interpretation Self-assessment was non-inferior to routine follow-up and could save resources. Funding Nordic Federation of Obstetrics and Gynaecology, European Society of Contraception, Helsinki University Central Hospital, Helse Finnmark, Swedish Research Council, and Stockholm County Council and Karolinska University Hospital. © 2015 Elsevier Ltd.


Bahamondes L.,University of Campinas | Mansour D.,Newcastle Hospitals | Fiala C.,Gynmed Clinic | Fiala C.,Karolinska University Hospital | And 2 more authors.
Journal of Family Planning and Reproductive Health Care | Year: 2014

Few studies in the scientific literature provide clear direction on the prevention or management of pain associated with intrauterine contraceptive (IUC) placement. Those that have been published have studied small numbers of women and fail to provide definitive conclusions. There are also no guidelines available detailing recognised standard approaches to this problem. The consensus recommendations in this review focus primarily on non-pharmacological and often non-evidence-based interventions. This review includes general considerations, practical recommendations for both routine and more difficult cases and guidance on the optimal choice of instruments. General considerations, including pre-insertion counselling, the setting for the procedure, the confidence and technique of the provider and the interplay between the provider and assistant, can influence women's level of anxiety and, in turn, influence their perception of pain and their overall experience. Further studies are required to refine the optimal strategy for managing pain associated with IUC insertion.


Biadasiewicz K.,Medical University of Vienna | Sonderegger S.,Prince Henrys Institute of Medical Research | Haslinger P.,Medical University of Vienna | Haider S.,Medical University of Vienna | And 4 more authors.
Endocrinology | Year: 2011

The basic helix-span-helix transcription factor activating protein (AP)-2α is critically involved in cell-specific hormone expression of syncytializing human trophoblasts. Its role in invasive trophoblast differentiation, however, remains largely elusive. Using RT-PCR, Western blotting, and immunofluorescence of first-trimester placentae,wehereshowthat AP-2α is expressed in extravillous trophoblasts (EVTs) both in situ and in vitro as well as in invasive trophoblast cell lines. Its protein expression was increased upon supplementation of epidermal growth factor (EGF) both in primary EVTs and trophoblastic SGHPL-5 cells. Gene silencing of AP-2α using small hairpin microRNA (shRNAmir) did not affect basal invasion of SGHPL-5 cells through Matrigel-coated filters but reduced EGF-stimulated invasion. Similarly, treatment of primary EVTs with AP-2α small interfering RNA decreased EGF-dependent invasion. Proliferation of SGHPL-5 cells and primary EVTs, measured by cumulative cell numbers and 5-bromo-2′-deoxyuridine labeling, respectively, were not affected on loss of AP-2α. EGF-dependent induction of matrix metalloproteinase (MMP)-2, proand active form of urokinase plasminogen activator, and chorionic gonadotropin (CG)-β was noticed in shRNAmir-control cells, whereas these genes were suppressed in EGF-treated shRNAmir-AP-2α cells. Similarly, EGF-stimulated MMP-2 and CGβ protein expression was reduced in AP-2α small interfering RNA-treated primary EVTs. Knockdown of AP-2α also decreased luciferase activity of the CGβ5 promoter in SGHPL-5 cells, which was compensated upon transient overexpression of AP-2α cDNA. In conclusion, we show that AP-2α expression positively affects human trophoblast invasion under EGF-stimulated conditions, likely by inducing critical invasion-promoting genes such MMP-2, urokinase plasminogen activator, and CG. Copyright © 2011 by The Endocrine Society.


Haider S.,Medical University of Vienna | Meinhardt G.,Medical University of Vienna | Velicky P.,Medical University of Vienna | Otti G.R.,Medical University of Vienna | And 4 more authors.
Endocrinology | Year: 2014

Failures in human extravillous trophoblast (EVT) development could be involved in the pathogenesis of pregnancy diseases. However, the underlying mechanisms have been poorly characterized. Here, we provide evidence that Notch signaling could represent a key regulatory pathway controlling trophoblast proliferation, motility, and differentiation. Immunofluorescence of first-trimester placental tissues revealed expression of Notch receptors (Notch2 and Notch3) and membrane-Anchored ligands (delta-like ligand [DLL] 1 and -4 and Jagged [JAG] 1 and -2) in villous cytotrophoblasts (vCTBs), cell column trophoblasts (CCTs), and EVTs. Notch4 and Notch1 were exclusively expressed in vCTBs and in CCTs, respectively. Both proteins decreased in Western blot analyses of first-trimester, primary cytotrophoblasts (CTBs) differentiating on fibronectin. Luciferase reporter analyses suggested basal, canonical Notch activity in SGHPL-5 cells and primary cells that was increased upon seeding on DLL4-coated dishes and diminished in the presence of the Notch/-secretase inhibitors N-[N-(3,5-difluorophenacetyl-L-Alanyl)]-S-phenylglycine t-butyl ester (DAPT) or L-685,458. Bromodeoxyuridine labeling, cyclin D1 mRNA expression, and cell counting indicated that chemical inhibition of Notch signaling elevated proliferation in the different primary trophoblast model systems. Notch inhibition also increased motility of SGHPL-5 cells through uncoated and fibronectin-coated Transwells, motility of primary CTBs, as well as migration in villous explant cultures on collagen I. Accordingly, small interfering RNA-mediated gene silencing of Notch1 also elevated SGHPL-5 cell migration. In contrast, motility of primary cultures and SGHPL-5 cells was diminished in the presence of DLL4. Moreover, DAPT increased markers of differentiated EVT, ie, human leukocyte antigen G1, integrin 5, and T-cell factor 4, whereas DLL4 provoked the opposite. In summary, the data suggest that canonical Notch signaling impairs motility and differentiation of first-trimester CTBs. Copyright © 2014 by The Endocrine Society.


Gemzell-Danielsson K.,Karolinska University Hospital | Mansour D.,New Croft Center | Fiala C.,Gynmed Clinic | Fiala C.,Karolinska University Hospital | And 2 more authors.
Human Reproduction Update | Year: 2013

Background: Most intrauterine contraception (IUC) placements do not require pain relief. However, small proportions of nulliparous (~17%) and parous (~11%) women experience substantial pain that needs to be proactively managed. This review critically evaluates the evidence for pain management strategies, formulates evidence-based recommendations and identifies data gaps and areas for further research. Methods: A PubMed literature search was undertaken. Relevant articles on management of pain associated with IUC insertion, published in English between 1980 and November 2012, were identified using the following search terms: 'intrauterine contraception', 'insertion' and 'pain'. RCTs were included; further relevant articles were also identified and included as appropriate. Results: Seventeen studies were identified and included: 12 RCTs and one non-randomized study of pre-insertion oral analgesia, cervical priming and local anaesthesia; one systematic review and one RCT on post-insertion analgesia and two non-randomized studies on non-pharmacological interventions. There was no conclusive evidence that any prophylactic pharmacological intervention reduces pain associated with IUC insertion.However, most of the regimens studiedwere adopted from hysteroscopy or abortion and effectiveness in specific subsets ofwomenhas not been studied adequately.Asystematic review found non-steroidal anti-inflammatory agents (NSAID) to be effective in reactively treating postinsertion pain, but no benefit was found with prophylactic use. Conclusions: No prophylactic pharmacological intervention has been adequately evaluated to support routine use for pain reduction during or after IUC insertion.Women's anxiety about the procedure may contribute to higher levels of perceived pain, which highlights the importance of counselling, and creating a trustworthy, unhurried and professional atmosphere in which the experience of the provider also has a major role; a situation frequently referred to as 'verbal anaesthesia'.


Meinhardt G.,Reproductive Biology Unit | Haider S.,Reproductive Biology Unit | Haslinger P.,Reproductive Biology Unit | Proestling K.,Medical University of Vienna | And 3 more authors.
Endocrinology | Year: 2014

Formation of migratory extravillous trophoblasts (EVTs) is critical for human placentation and hence embryonic development. However, key regulatory growth factors, hormones, and nuclear proteins controlling the particular differentiation process remain poorly understood. Here, the role of the Wingless (Wnt)-dependent transcription factor T-cell factor-4 (TCF-4) in proliferation and motility was investigated using different trophoblast cell models. Immunofluorescence of firsttrimester placental tissues revealed induction of TCF-4 and nuclear recruitment of its coactivator -βcatenin in nonproliferating EVTs, whereas membrane-associated -βcatenin decreased upon differentiation. In addition, EVTs expressed the TCF-4/β-catenin coactivator Pygopus 2 as well asrepressors of the Groucho/transducin-like enhancer of split family. Western blotting revealed Pygopus 2 expression and up-regulation of integrin 1 and nuclear TCF-4 in purified first-trimester cytotrophoblasts (CTBs) differentiating on fibronectin. Concomitantly, elevated TCF-4 mRNA, quantitated by real-time PCR, and increased TCF-dependent luciferase reporter activity were noticed in EVTs of villous explant cultures and differentiated primary CTBs. Gene silencing using specific small interfering RNA decreased TCF-4 transcript and protein levels, TCF-dependent reporter activity as well as basal and Wnt3a-stimulated migration of trophoblastic SGHPL-5 cells and primary CTBs through fibronectin-coated transwells. In contrast, proliferation of SGHPL-5 cells and primary cells, measured by cumulative cell numbers and 5-bromo-2'-deoxy-uridine labeling, respectively, was not affected. Moreover, siRNA-mediated down-regulation of TCF-4 in primary CTBs diminished markers of the differentiated EVT, such as integrin α1 and α5, Snail1, and Notch2. In summary, the data suggest that Wnt/TCF-4-dependent signaling could play a role in EVT differentiation promoting motility and expression of promigratory genes. © 2014 by the Endocrine Society.


Sonderegger S.,Medical University of Vienna | Haslinger P.,Medical University of Vienna | Sabri A.,Medical University of Vienna | Leisser C.,Medical University of Vienna | And 3 more authors.
Endocrinology | Year: 2010

Invasion of human trophoblasts is promoted through activation of wingless (Wnt) signaling, suggesting a role of the pathway in placental development and morphogenesis. However, details on the process such as involvement of canonical and/or noncanonical Wnt signaling cascades as well as their target genes are largely unknown. Hence, signal transduction via canonical Wnt signaling or phosphatidylinositide 3-kinase (PI3K)/AKT and their cross talk as well as trophoblast-specific protease expression were investigated in trophoblastic SGHPL-5 cells and primary extravillous trophoblasts purified from first-trimester placentas. Western blot analyses revealed that the recombinant Wnt ligand Wnt-3A increased phosphorylation of AKT and the downstream kinase glycogen synthase kinase (GSK)-3β as well as accumulation of activated, nuclear β-catenin. In accordance, luciferase expression of a canonical Wnt/TCF reporter and cell migration in first-trimester villous explant cultures and of SGHPL-5 cells were stimulated. Chemical inhibition of PI3K abolished Wnt-dependent phosphorylation of AKT and GSK-3β and trophoblast motility but did not affect appearance of activated β-catenin or Wnt/TCF reporter activity. In contrast, inhibition of the canonical pathway through soluble Dickkopf-1 did not influence AKT and GSK-3β phosphorylation but reduced Wnt reporter activity, accumulation of active β-catenin, and cell migration. Both inhibitors decreased Wnt-3A-induced secretion of pro- and active matrix metalloproteinase-2 from SGHPL-5 cells and pure EVT. The data suggest that Wnt-3A may activate canonical Wnt signaling and PI3K/AKT through distinct receptors. The two signaling cascades act independently in trophoblasts; however, both pathways promote Wnt-dependent migration and the release of matrix metalloproteinase-2, which has been identified as novel Wnt target in invasive trophoblasts. Copyright © 2010 by The Endocrine Society.


Prutsch N.,Medical University of Vienna | Fock V.,Medical University of Vienna | Haslinger P.,Medical University of Vienna | Haider S.,Medical University of Vienna | And 3 more authors.
Placenta | Year: 2012

The pleiotropic cytokine interleukin-1β (IL-1β) can promote physiological cell migration, as well as cancer cell invasion and metastasis. Its role in human trophoblast invasion, however, has not been satisfactorily answered since direct, indirect as well as no effects on trophoblast motility have been published. Therefore, the role of IL-1β has been re-evaluated by exclusively using human primary trophoblast model systems. Immunofluorescence of first trimester placentae indicated IL-1 receptor 1 (IL-1R1) protein expression in first trimester villous cytotrophoblasts (vCTB) and extravillous trophoblasts (EVT). The latter expressed higher mRNA levels of the receptor as shown by comparative gene chip data of vCTB and EVT. Similarly, Western blot analyses and immunofluorescence revealed a time- and differentiation-dependent increase of IL-1R1 in primary EVT seeded on fibronectin. IL-1β dose-dependently elevated migration of isolated first trimester EVT through fibronectin-coated transwells, which was inhibited in the presence of IL-1R antagonist (IL-1Ra), whereas proliferation of these cells was not affected. Similarly, the interleukin did not alter proliferation of vCTB and cell column trophoblasts in floating villi of early pregnancy, but promoted migration in villous explant cultures seeded on collagen I. Western blot analyses of supernatants of primary EVT and first trimester villous explant cultures revealed IL-1β induced secretion of urokinase plasminogen activator (uPA), plasminogen activator inhibitor (PAI)-1 and PAI-2, which was diminished upon combined IL-1β/IL-1Ra treatment. In conclusion, these data suggest that IL-1β directly promotes trophoblast motility of first trimester EVT involving the uPA/PAI system. Crown Copyright © 2012 Published by Elsevier Ltd. All rights reserved.


Kopp Kallner H.,Karolinska University Hospital | Fiala C.,Gynmed Clinic | Stephansson O.,Karolinska University Hospital | Gemzell-Danielsson K.,Karolinska University Hospital
Human Reproduction | Year: 2010

BACKGROUND: Home use of misoprostol for termination of pregnancy is still controversial in many countries. Acceptability of home use of misoprostol has been investigated in pregnancies below 49 days gestation. In this study, we aimed to assess efficacy, feasibility and acceptability of home use of vaginal misoprostol for medical termination of pregnancy at 50-63 days compared with gestation of below 50 days among women who chose to administer misoprostol at home.METHODSIn this prospective study, mifepristone 200 mg was given in hospital under nursing supervision in the university hospital outpatient family planning clinic. Women self-administered misoprostol 800 g vaginally 36-48 h later at home. Follow-up was 2 weeks later. Women with gestation of 50-63 days on the day of mifepristone administration were compared with women with gestation of below 50 days. Efficacy and feasibility were assessed by review of patient records and questionnaires. Acceptability was assessed using questionnaires where women reported on future choice of abortion method were they to have another abortion.RESULTSAmong the 2992 women who had a medical abortion during the study period, 395 women chose to administer misoprostol at home and were included in the study. A total of 203 women were below 50 days gestation and 192 were between 50 and 63 days gestation. Efficacy was 97.5 and did not differ between the groups. Surgical intervention was needed in 10 patients, of whom four were in the lower gestational band (P = 0.36). No serious adverse events or blood transfusions were reported. Preference for home administration of misoprostol, were they to have another induced abortion in the future, was high, 92.3 and 86.6 respectively, and did not differ between the groups (P = 0.097). Need for extra analgesia significantly influenced women's experiences in both gestational groups.CONCLUSIONSMedical abortion with mifepristone followed by home administration of vaginal misoprostol is safe and highly acceptable also to women with gestational length of 50-63 days as compared with shorter gestations. Efficacy, acceptability and preference for future place of administration of misoprostol, were women to have another abortion, did not differ between women with gestation below 50 days or between 50 and 63 days. © 2010 The Author.


Kopp Kallner H.,Karolinska University Hospital | Fiala C.,Gynmed Clinic | Gemzell-Danielsson K.,Karolinska University Hospital
Contraception | Year: 2012

Background: Knowledge on factors affecting acceptability of medical abortion with mifepristone followed by home administration of misoprostol is scarce. The objective of this study was therefore to assess factors affecting acceptability and experience of home use of misoprostol for medical abortion up to 63 days' gestation. Study Design: Prospective observational study with acceptability assessed through questionnaires. Factors affecting acceptability were analyzed using multivariate logistic regression. Results: A total of 395 women were included. Independent factors for acceptability were having a partner/friend present and having a positive low-sensitivity urine hCG at follow-up, although most of these patients had successful abortions. Age, gestational length and requirement of extra pain medication did not affect acceptability. Conclusion: Home administration of misoprostol is highly acceptable. Increasing the number of complete abortions should be a focus of future research. Women should be encouraged to have a partner/friend present during home administration of misoprostol. © 2012 Elsevier Inc. All rights reserved.

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