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Study question Does uninterrupted embryo culture with or without the application of a time-lapse monitoring (TLM) selection algorithm lead to higher (cumulative) ongoing pregnancy rates? Summary answer Uninterrupted embryo culture with or without a TLM selection algorithm and interrupted culture with morphological embryo selection all resulted in comparable (cumulative) ongoing pregnancy rates. What is known already The application of TLM for embryo development has been claimed to improve success rates of IVF and ICSI treatments. Systematic reviews, however, show that evidence supporting the routine clinical use of TLM in IVF laboratories is limited and well-designed RCTs are needed to assess its clinical value. The uninterrupted and stable culture conditions in a TLM incubator may cause an increase of the clinical success rate independent from a possible improvement mediated by TLM based embryo selection procedures. Therefore, three study groups were needed to distinguish these two mechanisms. Study design, size, duration In this multicenter, double-blind, superiority RCT, women were prospectively randomized in three groups between 2017-2020: 1) TLE (Time-Lapse Eeva): embryo selection based on the Eeva® Test (a day three TLM algorithm, used adjunctively with morphology) and uninterrupted culture. 2) TLR (Time-Lapse Routine): routine morphological embryo selection and uninterrupted culture. 3) CON (Control): routine morphological embryo selection and interrupted culture. Embryos were cultured in Geri+ incubators. Randomization was stratified for laboratory-site and ovum pickup number. Participants/materials, setting, methods Women scheduled for day three single embryo transfer (SET) during their first, second or third ovum pickup were included. Primary endpoints were: 1) cumulative ongoing pregnancy rate (cOPR) including fresh SET and associated cryo transfers within 12 months of all women; 2) ongoing pregnancy rate (OPR) after fresh SET in a good-prognosis population: women Main results and the role of chance A total of 1731 women were randomly assigned to TLE (577), TLR (579) or CON (575). The 12 month cOPR did not differ significantly between the groups (p = 0.85) with a cOPR of 50.8% (293/577) in TLE, 50.9% (295/579) in TLR and 49.4% (284/575) in CON (TLE vs TLR: OR 0.99, 95% CI 0.79 – 1.25; TLE vs CON: OR 1.06, 95% CI 0.84 – 1.33; CON vs TLR: OR 0.94, 95% CI 0.75 – 1.19). In the good-prognosis population, the OPR after fresh SET was 38.2% (125/327) in TLE, 36.5% (118/323) in TLR and 37.8% (123/325) in CON (p = 0.90). Consistent results were found for pregnancy and live birth rates after fresh embryo transfer and cumulatively within one year. A planned subgroup analysis of three female age groups revealed interaction between age group and treatment on cOPR (p = 0.02). In women of 39 years and older (n = 245), the cOPR was higher in TLE compared to TLR (40.0% vs 23.7%: OR 2.10, 95% CI 1.05-4.21) with no difference between TLE vs CON (40.0% vs 31.5%: OR 1.44, 95% CI 0.76-2.71). Limitations, reasons for caution This study investigated embryo culture in the Geri+ incubator and the Eeva® Test algorithm, which predicts blastocyst formation on day three and was used in combination with morphology for embryo selection, while more TLM systems and algorithms are currently available. Wider implications of the findings Neither embryo selection based on a TLM selection algorithm in combination with morphology (TLE) nor the uninterrupted culture conditions in the Geri+ incubator (TLR) improved (cumulative) ongoing pregnancy and live birth rates after IVF or ICSI. Widespread application for fertility treatments with the promise of improved outcomes should be questioned. Trial registration number NL5314

IntroductionPreterm birth is one of the main problems in obstetrics, and the most important cause of neonatal mortality, morbidity and neurodevelopmental impairment. Multiple gestation is an important risk factor for preterm birth, with up to 50% delivering before 37 weeks. Progesterone has a role in maintaining pregnancy and is frequently prescribed to prevent (recurrent) preterm birth and improve pregnancy outcomes in high-risk patients. However, little is known about its long-term effects in multiple gestations. The objective of this follow-up study is to assess long-term benefits and harms of prenatal exposure to progesterone treatment in multiple gestations on child development.Methods and analysisThis is a follow-up study of a multicentre, double-blind, placebo-controlled randomised trial (AMPHIA trial, ISRCTN40512715). Between 2006 and 2009 women with a multiple gestation were randomised at 16–20 weeks of gestation to weekly injections 250 mg 17α-hydroxyprogesterone caproate or placebo, until 36 weeks of gestation or delivery. The current long-term follow-up will assess all children (n=1355) born to mothers who participated in the AMPHIA trial, at 11–14 years of age, with internationally validated questionnaires, completed by themselves, their parents and their teachers.Main outcomes are child cognition and behaviourAdditional outcomes are death (perinatal and up to age 14), gender identity, educational performance and health-related problems. We will use intention-to-treat analyses comparing experimental and placebo group. To adjust for the correlation between twins, general linear mixed-effects models will be used.Ethics and disseminationAmsterdam UMC MEC provided a waiver for the Medical Research Involving Human Subjects Act (W20_234#20.268). Results will be disseminated through peer-reviewed journals and summaries shared with stakeholders, patients and participants. This protocol is published before analysis of the results.Trial registration numberNL8933.

Objective To compare recurrence of a cyst or abscess of the Bartholin gland after surgical treatment using a Word catheter or marsupialisation. Design Multicentre, open-label, randomised controlled trial. Setting Eighteen hospitals in the Netherlands and one hospital in England. Population Women with a symptomatic cyst or abscess of the Bartholin gland. Methods Women were randomised to treatment with Word catheter or marsupialisation. Main outcome measures The primary outcome was recurrence of the cyst or abscess within 1 year of treatment. The secondary outcomes included pain during and after treatment (measured on a 10-point scale), use of analgesics, and time from diagnosis to treatment. Analysis was by intention-to-treat. To assess whether marsupialisation would reduce the recurrence rate by 5% (from 20 to 15%) we needed to include 160 women (alpha error 0.05, beta error 0.2). Results One hundred and sixty-one women were randomly allocated to treatment by Word catheter (n = 82) or marsupialisation (n = 79) between August 2010 and May 2014. Baseline characteristics were comparable. Recurrence occurred in 10 women (12%) allocated to Word catheter versus eight women (10%) allocated to marsupialisation: relative risk (RR) 1.1, 95% confidence interval (CI) 0.64–1.91; P = 0.70. Pain scores after treatment were also comparable. In the first 24 hours after treatment, 33% used analgesics in the Word catheter group versus 74% in the marsupialisation group (P

Background Double-layer compared to single-layer closure of the uterus after a caesarean section (CS) leads to a thicker myometrial layer at the site of the CS scar, also called residual myometrium thickness (RMT). It possibly decreases the development of a niche, which is an interruption of the myometrium at the site of the uterine scar. Thin RMT and a niche are associated with gynaecological symptoms, obstetric complications in a subsequent pregnancy and delivery and possibly with subfertility. Methods Women undergoing a first CS regardless of the gestational age will be asked to participate in this multicentre, double blinded randomised controlled trial (RCT). They will be randomised to single-layer closure or double-layer closure of the uterine incision. Single-layer closure (control group) is performed with a continuous running, unlocked suture, with or without endometrial saving technique. Double-layer closure (intervention group) is performed with the first layer in a continuous unlocked suture including the endometrial layer and the second layer is also continuous unlocked and imbricates the first. The primary outcome is the reported number of days with postmenstrual spotting during one menstrual cycle nine months after CS. Secondary outcomes include surgical data, ultrasound evaluation at three months, menstrual pattern, dysmenorrhea, quality of life, and sexual function at nine months. Structured transvaginal ultrasound (TVUS) evaluation is performed to assess the uterine scar and if necessary saline infusion sonohysterography (SIS) or gel instillation sonohysterography (GIS) will be added to the examination. Women and ultrasound examiners will be blinded for allocation. Reproductive outcomes at three years follow-up including fertility, mode of delivery and complications in subsequent deliveries will be studied as well. Analyses will be performed by intention to treat. 2290 women have to be randomised to show a reduction of 15% in the mean number of spotting days. Additionally, a cost-effectiveness analysis will be performed from a societal perspective. Discussion This RCT will provide insight in the outcomes of single- compared to double-layer closure technique after CS, including postmenstrual spotting and subfertility in relation to niche development measured by ultrasound. Trial registration Dutch Trial Register (NTR5480). Registered 29 October 2015. Electronic supplementary material The online version of this article (10.1186/s12884-019-2221-y) contains supplementary material, which is available to authorized users.

Introduction. Recent studies have shown that CADM1/MAL-methylation testing detects high-grade CIN lesions with a high short-term progression risk for cervical cancer. Women treated for CIN2/3 are at risk of post-treatment disease, representing either persistent (incompletely treated) or incident (early onset) lesions. Here, we evaluated CADM1/MAL-methylation analysis as potential tool for detecting recurrent high-grade CIN lesions (rCIN2/3). Methods and materials. A multicenter prospective clinical cohort study was conducted among 364 women treated for CIN2/3. Cervical scrapes were taken prior to treatment, and six and 12 months post-treatment and tested for cytology, hrHPV (plus genotype) and CADM1/MAL-methylation. When at six months either of these tests was positive, a colposcopy-directed biopsy was obtained. At 12 months, all women underwent an exit-colposcopy with biopsy. In case of rCIN2/3, re-treatment was done. Results. We found 28 rCIN2 (7.7%) and 14 rCIN3 (3.8%), resulting in a total recurrence rate of 11.5%. All 14 women with rCIN3 and 15/28 (54%) with rCIN2 showed hrHPV type-persistence. Of these, 9/14 ( 64%) rCIN3 and 8/15 (53%) rCIN2 were CADM1/MAL-methylation positive. All incident rCIN2, characterized by hrHPV genotype-switch, were CADM1/MAL-methylation negative. All three carcinomas found after re-treatment were CADM1/MAL-methylation positive. CADM1/MAL-methylation positivity at both baseline and follow-up significantly increased the risk of >= rCIN3 (from 0.7% to 18.4%), and >= rCIN2 (from 82% to 36.8%), compared to a consistently CADM1/MAL-methylation negative result (p-value

Objective To evaluate the effectiveness of an eHealth intervention on recovery and return to work, after gynaecological surgery. Design Randomised multicentre trial that ran from March 2010 until September 2011. Setting Secondary care in seven general and university hospitals in the Netherlands. Population A cohort of 215 women (aged 18–65 years) who had a hysterectomy and/or laparoscopic adnexal surgery for a benign indication. Methods The women were randomly assigned to the intervention group (n = 110) or the control group (n = 105). The intervention group received an eHealth programme that provided personalised tailor-made pre- and postoperative instructions on the resumption of daily activities, including work, and tools to improve self-empowerment and to identify recovery problems. The control group was provided with access to a control website. Main outcome measures The primary outcome was the duration of sick leave until a full sustainable return to work. Secondary outcome measures were quality of life, general recovery, and pain intensity. Results In intention-to-treat analysis the eHealth intervention was effective on time to return to work (hazard ratio 1.43; 95% confidence interval 1.003–2.040; P = 0.048). The median duration of sick leave until a full sustainable return to work was 39 days (interquartile range 20–67 days) in the intervention group and 48 days (interquartile range 21–69 days) in the control group. After 26 weeks pain intensity was lower (visual analogue scale, cumulative odds ratio 1.84; 95% confidence interval 1.04–3.25; P = 0.035) and quality of life was higher (Rand-36 health survey, between-group difference 30, 95% confidence interval 4–57; P = 0.024) in the intervention group, compared with the control group. Conclusions The use of the eHealth intervention by women after gynaecological surgery results in a faster return to work, with a higher quality of life and less pain.

Objective To study the effect of hrHPV-testing on the detection of CIN2/3+ in women referred to a gynecology outpatient clinic, and to assess a useful risk profile in relation to the referral reason to identify who should be tested for cervical pathology. Methods This study was designed as an observational cohort study. In the first six months of 2007, we categorized the referral reason of 1149 consecutive women who visited our gynecology outpatient clinic and assessed the risk for CIN2/3+ as found by cytology or co-testing with a hrHPV-test and cytology. Results Three different categories of referral reasons were identified; women with presumed cervix pathology, women with presumed endometrial pathology and women with other referral indications. The cumulative 18-month CIN2+ and CIN3+ risks were highest in the group with presumed cervical disease (adjusted risks 11.1% and 5.4% respectively) and lowest in the miscellaneous group with no suspicion of cervical and/or endometrial pathology (adjusted risks 4.1% and 1.8% respectively). HrHPV-testing detected significantly more CIN2/3+ lesions than cytology (relative detection rate: 1.42 (95%CI 1.05–1.92) and 1.38 (95%CI 0.95–2.05) respectively). Conclusions The high (>2%) cumulative 18-month CIN2/3+ risk in patients with presumed cervical and/or endometrial pathology warrants routine cervical testing. In these women a hrHPV-test should be added to cytology because this identifies a significant number of additional women with a substantial risk of CIN2/3+ lesions who would not be identified with cytology alone. Women referred for other reasons should not have cervical testing beforehand, because of their low risk of CIN2/3+.

To investigate the effect of postmenopausal oral and transdermal hormone therapy on plasma levels of C-reactive protein (CRP), we performed a randomised, double-blind, double-dummy, placebo-controlled, 15-month study. One hundred and fifty-two healthy hysterectomised postmenopausal women received daily either placebo (n = 49), or transdermal 17beta-oestradiol (E(2)) 50 micro g (tE(2) group, n = 33), or oral E(2) 1 mg (oE(2) group, n = 37), or oral E(2) 1 mg combined with gestodene 25 micro g (oE(2) + G group, n = 33) for thirteen 28-day treatment cycles, followed by four cycles placebo for each group. Data were collected at baseline and in cycles 4, 13 and 17. In cycle 13, CRP was significantly increased in the oE(2) group compared to placebo (P = 0.004). The median percentage change from baseline versus placebo was +75% (P0.001). In cycle 17, significantly lower values were observed in the oE(2) group compared to cycle 13 and to the placebo group (-49%, P0.001). There were no significant changes versus placebo in the other groups. In conclusion, oral E(2) significantly increased CRP levels. This change was larger than the increase found during oral E(2) + G. Transdermal E(2) did not affect CRP levels.

Hormone replacement therapy (HRT) increases the risk of cardiovascular morbidity in postmenopausal women under certain circumstances. Part of this effect may be the result of the influence of HRT on blood platelets. We studied the effect of short-term oral hormone replacement therapy (unopposed oestradiol or sequentially combined oestradiol and trimegestone or dydrogesterone) on platelet activation parameters in healthy postmenopausal women.We designed a prospective, randomised, placebo-controlled 12-week study. Sixty healthy, normotensive, nonhysterectomised, postmenopausal women received daily micronised oestradiol (E2) 2 mg (n = 16), or 2 mg E2 daily sequentially combined with either trimegestone 0.5 mg daily (n = 14) or dydrogesterone 10 mg daily (n = 14), or placebo (n = 16). Data on platelet activation were collected at baseline and after 12 weeks of treatment using flow cytometry.Twelve weeks of treatment with combined HRT was associated with an increase in platelet activation parameters P-selectin and glycoprotein 53 (by 17% and 14%, respectively, P = 0.04 vs. the placebo group for both comparisons), suggesting alpha granule and lysosome degranulation. E2 replacement therapy was associated with an increase in P-selectin labelling by 22% (P = 0.04 vs. the placebo group).Short-term treatment with oestradiol or combined HRT increases the amount of circulating activated platelets as measured by flow cytometry. This could be a mechanism by which short-term HRT might increase the risk of thrombosis.

Post MS, Hendriks DF, van der Mooren MJ, van Baal WM, Leurs JR, Emeis JJ, Kenemans P, Stehouwer CDA (VU university medical center, Amsterdam, The Netherlands; University of Antwerp, Wilrijk, Belgium; and Gaubius Laboratory, TNO-PG, Leiden, The Netherlands). Oral oestradiol/trimegestone replacement reduces procarboxypeptidase U (TAFI): a randomized, placebo-controlled, 12-week study in early postmenopausal women. J Intern Med 2002; 251: 245–251. Objective. To investigate the effects of short-term postmenopausal oral hormone administration on plasma levels of procarboxypeptidase U (proCPU, thrombin-activatable fibrinolysis inhibitor, EC 3.4.17.20), an inhibitor of fibrinolysis, in healthy early postmenopausal women. Design. A prospective, randomized, placebo-controlled study. Setting. Outpatient clinic of the Department of Obstetrics and Gynaecology. Subjects. Seventy-seven healthy early postmenopausal women were screened of whom 65 were randomized. Analyses were based on 60 participants. Interventions. The women received oral micronized oestradiol 2 mg either alone (E2 group, n=16), or sequentially combined with dydrogesterone 10 mg (E2 + D group, n=14) or trimegestone 0.5 mg (E2 + T, n=14), or placebo (n=16) for 12 weeks. Main outcome measure. ProCPU concentrations at baseline, and at 4 and 12 weeks of treatment. Results. Four weeks of E2 + T was associated with a significant decrease in the fasting proCPU concentration, which was sustained after 12 weeks [t=0: 636 ± 57 U L–1 (mean ± SD); t=4: 583 ± 63 U L–1; t=12: 589 ± 48 U L–1; ANCOVA versus placebo: P=0.011]. The percentage change from baseline versus placebo in this group was –8.4% [95% confidence interval (CI) –15.7 to –1.1] after 4 weeks and –5.9% (95% CI –11.7 to –0.1) after 12 weeks. There were no significant changes versus placebo in the E2 group nor in the E2 + D group. Conclusion. Short-term treatment with E2 + T, but not E2 alone or E2 + D, lowers proCPU concentration. These findings add to accumulating evidence suggesting that different progestagens added to oestrogen replacement may differentially affect the risk of arterial and venous disease.

In this randomised, placebo-controlled 12-week study, sixty healthy postmenopausal women received either placebo (N = 16) or daily 2 mg micronised oestradiol, either unopposed (N = 16, E2 group) or combined with a progestagen for 14 days of each cycle (N = 28, E2+P group).As compared to placebo, plasma levels of AT III were reduced only in the E2 group (approximately 28%), plasma levels of protein C decreased only in the E2+P group (approximately 4%) and plasma levels of protein S decreased in both the E2 and E2+P group (approximately 21%). In both the E2 and E2+P groups, the plasma levels of factor VII (antigen and activity) showed a borderline significant increase (approximately 10%), whereas no significant change was observed in active factor VII. Plasma levels of tissue-type plasminogen activator (approximately 22%), urokinase plasminogen activator (approximately 25%) and plasminogen activator inhibitor type-1 (approximately 43%) decreased in the E2 and E2+P groups, whereas those of plasminogen increased (approximately 12%). Treatment was associated with an increase in levels of prothrombin fragment 1+2 (approximately 31%), but levels of thrombin-antithrombin III complexes, and of plasmin-alpha2-antiplasmin complexes and total fibrin(ogen) degradation products did not change significantly.Short-term E2 and E2+P treatment is associated with a shift in the procoagulant-anticoagulant balance towards a procoagulant state. A substantial proportion of women do not have a net increase in fibrinolytic activity. These data may be relevant in explaining the increased risk of venous thromboembolism associated with ERT and HRT, and possibly also in explaining the negative results of the Heart and Estrogen/progestin Replacement Study.

Epidemiological data have suggested that the use of hormone replacement therapy (HRT) is associated with a decreased risk of cardiovascular disease. Vascular endothelium and adhesion molecules play an important role in the initiation and progression of atherosclerosis.Prospective, randomized, placebo-controlled 12-week study. Sixty healthy, normotensive postmenopausal women received either micronised oestradiol 2 mg alone (n = 16, E2 group), or sequentially combined with a progestagen; E2 + P groups trimegestone 0.5 mg (E2 + T, n = 14) or dydrogesterone 10 mg (E2 + D group, n = 14) or placebo (n = 16). Data were collected at baseline and at 4 and 12 weeks.Twelve weeks of treatment with E2 or E2 + P was associated with a significant decrease in the plasma concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and thrombomodulin (sTM). The average decrease in these markers was about 9%. In women treated with trimegestone the decreases were larger than in those treated with dydrogesterone; for sICAM-1 (-15% vs. -2%; P0.0001), sVCAM-1 (-15% vs. +3%; P = 0. 003) and sTM (-9% vs. -4%; P = 0.11). Plasma levels of endothelin-1 (ET-1) decreased (by 13%) only in women treated with E2 + P. In the E2 group, flow-mediated, endothelium-dependent vasodilatation increased by 6 percentage points after 12 weeks (P = 0.07 vs. baseline, P = 0.02 vs. E2 + P, and P = 0.17 vs. placebo).Short-term treatment with E2 or E2 + trimegestone reduces plasma levels of sICAM-1, sVCAM-1 and sTM. ET-1 decreased only in the E2 + P groups. Different types of progestagens may differentially affect sICAM-1, sVCAM-1 and sTM levels, which may be relevant for the choice of type HRT.