Women's decision-making related to induced abortion - a cross sectional study during a period of Covid-19 pandemic, in Sweden.

OBJECTIVES: To investigate women's decision-making on induced abortion. MATERIALS AND METHODS: A multi-centre cross-sectional survey among 623 abortion-seeking women in Sweden (2021). The perceived difficulty to decide on abortion was measured using a 7-point Likert scale, and analysed with univariate and multivariate analysis (odds ratios [OR], 95% confidence intervals [CI]). RESULTS: About half (n = 322;52%) scored 1-4, suggesting the decision was perceived as easier compared to those (n = 292;48%) who scored 5-7. Reasons for the abortion were: poor economy (n = 166;27%), too early in the relationship (n = 154;25.1%), want to work first (n = 147;23.9%), want to study first (n = 132;21.5%), uncertain about the relationship (104;16.9%), and too young (n = 104;16.9%). Predictors for perceiving the decision as difficult: partner's hesitance (OR = 3.18, CI:1.76-5.73), being born outside the Nordic countries (OR = 2.23, CI:1.28-3.87), having discussed the decision with someone (OR = 2.42, CI:1.67-3.50), age ≥30 (OR = 2.22, CI:1.03-4.76), the Covid-19 pandemic (OR = 2.08, CI:1.20-3.59), and the desire to have children in the future (OR = 1.96, CI:1.18-3.28). After confirmed pregnancy, poor mental well-being was more common among those who scored 5-7 (n = 140;47.9%) compared to those who scored 1-4 (n = 122;37.9), p = .029. CONCLUSION: Women's decision-making on abortion is complex; in times of crises, the decision procedure may be even more difficult. This valuable knowledge could be used to improve and promote satisfactory counselling beyond medical routines.

10-year evaluation of the use of medical abortion through telemedicine: a retrospective cohort study.

OBJECTIVE: To provide a descriptive overview and evaluate changes in the use and outcome of abortions provided worldwide by telemedicine in the past 10 years. DESIGN: Retrospective cohort study. SETTING: Multi-country. POPULATION/SAMPLE: 30 344 women who completed the follow-up survey of the telemedical abortion service Women on Web from January 2009 till January 2020. METHODS: Analyses of follow-up surveys, binary logistic regressions to test the association between year and outcomes. MAIN OUTCOME MEASURES: Rate of complete abortions, surgical interventions, ongoing pregnancies, blood transfusions per year, socio-economic situation, knowledge on medical abortion, acceptability of receiving service, appropriateness of method and the likelihood of recommending the service to a friend. RESULTS: Medical abortions were provided to 81 683 women, of whom 30 344 (37.2%) completed the follow-up survey. In total, 26 076 women reported doing the medical abortion, of whom 1.5% reported an ongoing pregnancy, 10.2% a surgical intervention and 0.6% a blood transfusion. Acceptability of the service was 99%, and 59.2% of the users reported previous knowledge of medical abortion. We found a significant increase in complete abortions in 2019 (odds ratio 1.92; 95% CI 1.59-2.31) and decrease in surgical interventions (odds ratio 0.49; 95% CI 0.40-0.60) compared with 2009. CONCLUSION: Low follow-up rates present a limitation in analysing trends in telemedical abortion usage. However, our findings suggest that it is a highly acceptable method around the world and that there has been an increase in complete abortions by telemedical abortions and a decrease in surgical interventions in the last 10 years. TWEETABLE ABSTRACT: In the last 10 years, there has been an increase in complete abortions and decrease in surgical interventions of telemedical abortion.

Estetrol-Drospirenone combination oral contraceptive: a clinical study of contraceptive efficacy, bleeding pattern and safety in Europe and Russia.

OBJECTIVES: To assess the contraceptive efficacy, bleeding pattern and safety of a combined oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg. DESIGN: Multicenter, open-label, phase 3 trial. SETTING: Sixty-nine sites in Europe and Russia. POPULATION: Sexually active women aged 18-50 years with regular menstrual cycles and body mass index ≤35 kg/m2 . METHODS: E4/DRSP was administered in a 24 active/4 placebo regimen for up to 13 cycles. Visits were scheduled during Cycles 2, 4, 7 and 10 and after completing treatment during which adverse events (AEs) were collected. Participants recorded medication intake, vaginal bleeding/spotting, use of other contraceptive methods and sexual intercourse on a daily diary. MAIN OUTCOME MEASURES: Pearl Index (PI) for women 18-35 years (overall and method-failure), bleeding pattern and AEs. RESULTS: A total of 1553 women aged 18-50 years, including 1353 from 18 to 35 years old, received the study medication. PI was 0.47 pregnancies/100 woman-years (95% CI 0.15-1.11); method failure PI was 0.29 pregnancies/100 woman-years (95% CI 0.06-0.83). Scheduled bleeding/spotting occurred in 91.9-94.4% of women over Cycles 1 to 12 and lasted a median of 4-5 days per cycle. The percentage of women with unscheduled bleeding/spotting episodes decreased from 23.5% in Cycle 1 to <16% from Cycle 6 onwards. The most common AEs were headache (7.7%), metrorrhagia (5.5%), vaginal haemorrhage (4.8%) and acne (4.2%). One treatment-related serious AE was reported, a lower extremity venous thromboembolism. One-hundred and forty-one (9.1%) women discontinued study participation because of treatment-related adverse events. CONCLUSION: E4/DRSP provides effective contraception, a predictable bleeding pattern and a favourable safety profile. TWEETABLE ABSTRACT: A phase 3 trial with E4/DRSP shows high contraceptive efficacy, a predictable bleeding pattern and favourable safety profile.

There is no association between combined oral hormonal contraceptives and depression: a Swedish register-based cohort study.

OBJECTIVE: To investigate whether users of hormonal contraceptives (HCs) are at increased risk of depression compared with non-users. DESIGN: Register-based cohort study. SETTING: Sweden. SAMPLE: Women aged 15-25 years between 2010 and 2017 with no prior antidepressant treatment, psychiatric diagnose or contraindication for HCs (n = 739 585). METHODS: Women with a prescription of HC were identified via the Swedish Prescribed Drug Register (SPDR). Relative risks (RRs) for first depression diagnosis in current HC-users compared with non-users were modelled by Poisson regression. Adjustments included age, medical indication for HC-use and parental history of mental disorders, among others. MAIN OUTCOME MEASURES: Depression, captured by a redeemed prescription of antidepressant treatment, or a first depression diagnosis in the SPDR and the National Patient Register. RESULTS: Compared with non-users, women on combined oral contraceptives (COCs) and oral progestogen-only products had lower or no increased risk of depression, relative risk (RR) 0.89 (95% CI 0.87-0.91) and 1.03 (95% CI 0.99-1.06) after adjustments, respectively. Age-stratified analyses demonstrated that COC use in adolescents conferred no increase in risk (RR 0.96, 95% CI 0.93-0.98), whereas use of progestogen-only pills (RR 1.13, 95% CI 1.07-1.19), contraceptive patch/vaginal ring (RR 1.43, 95% CI 1.30-1.58), implant (RR 1.38, 95% CI 1.30-1.45) or a levonorgestrel intrauterine device (RR 1.59, 95% CI 1.46-1.73) were associated with increased risks. CONCLUSIONS: This study did not find any association between use of COCs, which is the dominating HC in first time users, and depression. Non-oral products were associated with increased risks. Residual confounding must be addressed in the interpretation of the results. TWEETABLE ABSTRACT: There is no association between combined hormonal contraceptives and depression.

Increasing uptake of long-acting reversible contraception with structured contraceptive counselling: cluster randomised controlled trial (the LOWE trial).

OBJECTIVE: To evaluate the effect of structured contraceptive counselling on the uptake of long-acting reversible contraceptives (LARCs) and pregnancy rates. DESIGN: Cluster randomised trial. SETTING: Abortion, youth and maternal health clinics in Stockholm, Sweden. POPULATION: Sexually active women aged ≥18 years without a wish for pregnancy seeking abortion and/or contraceptive counselling. METHODS: For participants in clinics randomised to intervention, trained healthcare providers implemented a study-specific intervention package designed for structured contraceptive counselling. Participants in the control clinics received routine counselling. MAIN OUTCOME MEASURES: The primary outcome was choice of LARCs at first visit. Secondary outcomes were LARC initiation at 3 months and pregnancy rates at 3 and 12 months. We used logistic mixed-effects models with random intercept for clinic to account for clustering. RESULTS: From September 2017 to May 2019, 28 randomised clinics enrolled 1364 participants. Analyses including 1338 subjects showed that more participants in the intervention group compared with the control group chose LARCs: 267/658 (40.6%) versus 206/680 (30.3%) (OR 2.77, 95% CI 1.99-3.86). LARC initiation was higher in the intervention group compared with the control group: 213/528 (40.3%) versus 153/531 (28.8%) (OR 1.74, 95% CI 1.22-2.49). At the abortion clinics, the pregnancy rate was significantly lower at 12 months in the intervention group compared with the control group: 13/101 (12.9%) versus 28/103 (27.2%) (OR 0.39, 95% CI 0.18-0.88). CONCLUSIONS: Structured contraceptive counselling increased LARC uptake in all clinics and significantly reduced unintended pregnancy rates in abortion clinics at the 12 months follow-up. TWEETABLE ABSTRACT: Structured contraceptive counselling increased LARC uptake and reduced pregnancy rates at 12 months.

Management of pain associated with up-to-9-weeks medical termination of pregnancy (MToP) using mifepristone-misoprostol regimens: expert consensus based on a systematic literature review.

Evidence-based guidelines on the management of pain associated with first-trimester medical abortion are lacking. Most published clinical trials have failed to report on this important aspect of the procedure. The aim of this comprehensive work was to provide clinical advice based on a comprehensive literature review, supplemented by the clinical experience of a group of European experts in case no evidence is available. Pain level ranged from 5 to 8 in 80% of studies where pain was measured on a 0-10 visual analogue scale; severe pain was reported by 20-80% of women. Pain assessment was rarely reported in studies. Pain treatment should be preventive and avoidance of unnecessary uterine contractions should be considered. Analgesic treatment should follow the WHO three-step ladder, starting with the use of NSAIDs and allowing for easily available back-up treatment with weak opioids.

Telemedicine for medical abortion: a systematic review.

BACKGROUND: Telemedicine is increasingly being used to access abortion services. OBJECTIVE: To assess the success rate, safety, and acceptability for women and providers of medical abortion using telemedicine. SEARCH STRATEGY: We searched PubMed, EMBASE, ClinicalTrials.gov, and Web of Science up until 10 November 2017. STUDY CRITERIA: We selected studies where telemedicine was used for comprehensive medical abortion services, i.e. assessment/counselling, treatment, and follow up, reporting on success rate (continuing pregnancy, complete abortion, and surgical evacuation), safety (rate of blood transfusion and hospitalisation) or acceptability (satisfaction, dissatisfaction, and recommendation of the service). DATA COLLECTION AND ANALYSIS: Quantitative outcomes were summarised as a range of median rates. Qualitative data were summarised in a narrative synthesis. MAIN RESULTS: Rates relevant to success rate, safety, and acceptability outcomes for women ≤10+0 weeks' gestation (GW) ranged from 0 to 1.9% for continuing pregnancy, 93.8 to 96.4% for complete abortion, 0.9 to 19.3% for surgical evacuation, 0 to 0.7% for blood transfusion, 0.07 to 2.8% for hospitalisation, 64 to 100% for satisfaction, 0.2 to 2.3% for dissatisfaction, and 90 to 98% for recommendation of the service. Rates in studies also including women >10+0 GW ranged from 1.3 to 2.3% for continuing pregnancy, 8.5 to 20.9% for surgical evacuation, and 90 to 100% for satisfaction. Qualitative studies on acceptability showed no negative impacts for women or providers. CONCLUSION: Based on a synthesis of mainly self-reported data, medical abortion through telemedicine seems to be highly acceptable to women and providers, success rate and safety outcomes are similar to those reported in literature for in-person abortion care, and surgical evacuation rates are higher. TWEETABLE ABSTRACT: A systematic review of medical abortion through telemedicine shows outcome rates similar to in-person care.

Slow-release vaginal insert of misoprostol versus orally administrated solution of misoprostol for the induction of labour in primiparous term pregnant women: a randomised controlled trial.

OBJECTIVE: To compare the World Health Organization (WHO) recommended orally administrated dosage of misoprostol (25 µg) with a vaginal slow-release (7 µg/hour) insert of misoprostol regarding time from induction to delivery and safety of the method. DESIGN: Open label, Randomised controlled trial (RCT). SETTING: Delivery ward at a secondary referral hospital in Stockholm, Sweden, from 1 October 2016 to 21 February 2018. POPULATION: One hundred and ninety-six primiparous women with singletons in cephalic presentation at ≥37 weeks of gestation and with a Bishop score of ≤4. METHODS: Women were randomised to an oral solution of misoprostol (Cytotec® n = 99) or vaginal slow-release misoprostol (Misodel® [MVI] n = 97). MAIN OUTCOME MEASURES: Primary outcome: time from induction to vaginal delivery. SECONDARY OUTCOMES: mode of delivery; proportion of vaginal deliveries within 24 hours (VD24); neonates with an Apgar score of <7 at 5 minutes; pH < 7.10; postpartum haemorrhage (PPH) of >1000 ml; hyperstimulation; and women's delivery experience (VAS). RESULTS: There was no difference in the time to delivery [corrected] (median 21.1 hours in the MVI group and 23.2 hours in the oral group; Kaplan-Mayer log rank P = 0.31). There was no difference regarding the proportion of VD24 (50.5 versus 55.7%, P = 0.16). Hyperstimulation with non-reassuring cardiotocography (CTG) was more common in the MVI group (14.4 versus 3.0%, P < 0.01). Terbutaline (Bricanyl® ) was used more often for hyperstimulation in the MVI group (22.7 versus 4.0%, P < 0.01). There was no difference in the numbers of children admitted to the neonatal intensive care unit (NICU). CONCLUSIONS: Vaginal delivery after induction of labour (IOL) with slow-release misoprostol did not result in a shorter time from induction to vaginal delivery, compared with oral misoprostol solution, but was associated with a higher risk for hyperstimulation and fetal distress. There were no differences in mode of delivery or neonatal outcome. TWEETABLE ABSTRACT: IOL with MVI was similar to oral solution of misoprostol but hyperstimulation and fetal distress were more common.

Safety and acceptability of medical abortion through telemedicine after 9 weeks of gestation: a population-based cohort study.

OBJECTIVE: To assess the safety and acceptability of abortion through telemedicine at >9+0  weeks of gestation. DESIGN: Cohort study. SETTING: Poland. POPULATION: Six hundred and fifteen women who requested and underwent a abortion through telemedicine from 1 June to 31 December 2016. METHODS: Risks of adverse outcomes were calculated as adjusted odds ratios (aORs) with 95% confidence intervals (95% CIs) by unconditional logistic regression according to gestational age at abortion: ≤9 or >9 weeks of gestation. MAIN OUTCOME MEASURES: Self-reported clinical visits for complaints related to the abortion within 0-1 days of the treatment, heavy bleeding, pain or bleeding more than expected, and low satisfaction. RESULTS: Among women undergoing a abortion at ≤9 or >9 weeks of gestation, 3.3 versus 11.7% went to hospital with concerns within 0-1 days of the termination (aOR 3.82, 95% CI 1.90-7.69). Among women undergoing a abortion from 11+1 to 14+2  weeks of gestation, the rate was 22.5% (aOR 9.20, 95% CI 3.58-23.60). Among women undergoing a abortion at ≤9 or >9 weeks of gestation, the rate of heavy bleeding was 6.8 versus 10.1% (aOR 1.65, 95% CI 0.90-3.04), the rate of low satisfaction was 2.4 versus 1.6% (aOR 0.69, 95% CI 0.14-3.36), the rate of bleeding more than expected was 45.6 versus 57.8% (aOR 1.26, 95% CI 0.78-2.02), and the rate of pain more than expected was 35.6 versus 38.8% (aOR 1.11, 95% CI 0.71-1.71). CONCLUSIONS: Medical abortion through telemedicine at >9 weeks of gestation is associated with a higher risk of same-day or day-after clinical visits for concerns related to the procedure, and this risk increases with gestational age. Self-reported rates of heavy bleeding, low satisfaction, or unmet expectations with medical abortion do not increase with gestational age. TWEETABLE ABSTRACT: A cohort study shows that abortion through telemedicine at >9 weeks of gestation is associated with more hospital visits but not with increased bleeding.

Mifepristone treatment prior to insertion of a levonorgestrel releasing intrauterine system for improved bleeding control - a randomized controlled trial.

STUDY QUESTION: Does pre-treatment with a low dose of mifepristone improve irregular vaginal bleeding patterns during the initial 3 months after LNG-IUS placement? SUMMARY ANSWER: Mifepristone treatment prior to LNG-IUS insertion results in significantly lower bleeding and spotting rates but no significant reduction post insertion. WHAT IS KNOWN ALREADY: One of the leading causes of premature discontinuation of the LNG-IUS is unscheduled bleeding in the first months following its insertion. Up to now, there has been no effective treatment to prevent this side effect which reduces continuation rates for one of the most effective contraceptives. STUDY DESIGN, SIZE, DURATION: This randomized, double blinded, controlled trial was conducted between 2009 and 2015. In total, 68 women opting for a LNG-IUS were screened for eligibility, of whom 58 were randomized at a ratio of 1:1 in blocks of 10 to pre-treatment with mifepristone or a comparator. The main outcome was the rate of bleeding and spotting days reported during the first 3 months post LNG-IUS 52 mg placement. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthy women with regular and normal menstrual cycles aged 18-43 years were enrolled at a single center in a university hospital; 29 were allocated to 2 months pre-treatment with a low dose mifepristone and 29 to the comparator prior to insertion of the LNG-IUS. Women were advised to use barrier methods during the pre-treatment period. Bleeding diaries were collected for the pre-treatment period and for the first 6 months after the LNG-IUS placement. MAIN RESULTS AND THE ROLE OF CHANCE: There were no differences in demographics or baseline characteristics between the study groups. Data for analysis of the main outcome were contributed by a per protocol population of 19 women per group. There was a significant lower bleeding and spotting rate in the mifepristone group (-17.8% points, P < 0.001) after 2 months of pretreatment but after the LNG-IUS insertion no significant difference could be seen. While no pregnancies occurred prior to LNG-IUS insertion in the mifepristone group, there were three unintended pregnancies in the comparator group which emphasizes the need for a reliable contraceptive potential in any pre-treatment regiment used in clinical practice. LIMITATIONS, REASONS FOR CAUTION: The use of mifepristone prior to the LNG-IUS insertion in this trial was used as prophylaxis against unscheduled bleeding after the placement of the device. Although this side effect constitutes a major concern in a clinical setting, only a subset of women are at risk. This is the first study using pre-treatment to attempt improved bleeding control. The differences were small and the effect was short lasting but the reduced rate of bleeding and spotting observed during the first month following LNG-IUS insertion, even though not statistically significant, indicates that this approach may be further explored. The fact that there were three pregnancies in the comparator group stresses the need for any pre-treatment to also protect against unplanned pregnancy. WIDER IMPLICATIONS OF THE FINDINGS: Modified treatment protocols of mifepristone could be used prior to the LNG-IUS insertion to investigate possible further improvement of the outcome. The effect size of the current dose used might have been more prominent in women with LNG-IUS if the treatment also continued some weeks after the placement of the device. Although the low dose of mifepristone used in this trial is not available in Europe, other progesterone receptor modulators currently available could be investigated in larger clinical trials. To avoid unintended pregnancy in the pretreatment period, the dosage used should, ideally, also be effective for contraception and the pretreatment period should be kept as short as possible. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Swedish Research Council (2012-2844, 2017-00932), Stockholm County Council and Karolinska Institutet (ALF). Conflicts of interests for K.G.D. and H.K.K. are listed at the end of the paper. The other authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: EudraCT number 2009-009014-40. Regional ethical review board at Karolinska Institutet permit 2009/144-31/4. TRIAL REGISTRATION DATE: 20 July 2009. DATE OF FIRST PATIENT'S ENROLMENT: 24 November 2009.

Effect of mifepristone on the transcriptomic signature of endometrial receptivity.

STUDY QUESTION: How does a single dose of mifepristone on Day 2 after the LH peak (LH + 2) affect the endometrial receptivity transcriptome as assessed by the receptive signature established by the endometrial receptivity analysis (ERA)? SUMMARY ANSWER: A single dose of mifepristone on day LH + 2 renders the endometrium non-receptive by altering the transcriptome associated with endometrial receptivity. WHAT IS KNOWN ALREADY: Mifepristone is a progesterone receptor modulator that has been shown to alter endometrial receptivity. The ERA is a computational predictor that utilizes gene expression data of 248 genes from next generation sequencing to identify endometrial receptivity status. STUDY DESIGN, SIZE, DURATION: Endometrial biopsies were collected on day LH + 7 from controls (n = 11) and from women treated with mifepristone (n = 7). For further comparative analysis, samples were also obtained from women in the proliferative phase (n = 7). PARTICIPANTS/MATERIALS, SETTING, METHODS: Mifepristone treatment consisted of 200 mg administered on day LH + 2. Endometrial biopsies were treated for RNA isolation and cDNA conversion and sequencing. Endometrial receptivity status was assessed by the ERA computational predictor. Differential gene expression between groups was also assessed. Ingenuity Pathway Analysis was used for network analysis. Validation of gene expression results was done by qPCR. MAIN RESULTS AND THE ROLE OF CHANCE: Control samples were all staged around 'receptive' as would be clinically expected for LH + 7. Treatment samples were all staged as non-receptive (all but one was classified as 'proliferative' and the last as 'pre-receptive'). Differential gene expression analysis yielded 60 differentially expressed genes between the control and treatment groups. Bioinformatic pathway analysis for differential expression showed inactivation of the progesterone and glucocorticoid receptors, consistent with mifepristone action. LIMITATIONS, REASONS FOR CAUTION: The primary limitations are the relative small number of subjects and the use of a limited gene panel. WIDER IMPLICATIONS OF THE FINDINGS: This study sheds further light on the endometrial receptivity altering effects of mifepristone and on progesterone action. It further shows the capacity of the ERA to identify pharmacologically induced non-receptive endometrium, which expands its possible use clinically and in research. STUDY FUNDING/COMPETING INTEREST(S): C.v.G. and N.R.B. have no conflicts of interest. P.G.L. reports honorarium from University of HK/Shenzhen, other from NIF, India, outside the submitted work. K.G.D. reports consultancy for Bayer AG, Exelgyn, HRA-Pharma, Gedeon Richter, MSD, Mithra, Exeltis and Natural cycles, payment for lectures from Bayer AG, NSD, Ferring, HRA-Pharma, Exelgyn and Exeltis and clinical trials for Bayer AG, MSD, Exeltis, Mithra, HRA-Pharma and Sun Pharma. C.S. has a patent gene expression profile (ERA) issued to Igenomix and is scientific director of Igenomix S.L. M.R., R.N. and J.M.V. are employees of Igenomix S.L. TRIAL REGISTRATION NUMBER: N/A.

Current controversies with oral emergency contraception.

Emergency contraception (EC) is a method to be used in the case of unprotected sexual intercourse, failure of a regular contraceptive method, or after rape to try to prevent an unintended pregnancy. Oral EC remains surrounded by controversy, much due to myths and misconceptions among the public, policy makers and healthcare providers. This has resulted in restrictions on its availability in many parts of the world and restrictions on women's access to it. The aim of this article is to provide an evidence-based view on some of these common controversial issues surrounding oral EC in clinical practice. TWEETABLE ABSTRACT: Controversy about emergency contraception restricts access for women.

Effectiveness, safety, and acceptability of first-trimester medical termination of pregnancy performed by non-doctor providers: a systematic review.

BACKGROUND: Previous systematic reviews have concluded that medical termination of pregnancy (TOP) performed by non-doctor providers may be as effective and safe as when provided by doctors. Medical treatment of incomplete miscarriage by non-doctor providers and the treated women's acceptance of non-doctor providers of TOP has not previously been reviewed. OBJECTIVES: To review the effectiveness, safety, and acceptability of first-trimester medical TOP, including medical treatment for incomplete miscarriage, by trained non-doctor providers. SEARCH STRATEGY AND SELECTION CRITERIA: A search strategy using appropriate medical subject headings was developed. Electronic databases (PubMed, Popline, Cochrane, CINAHL, Embase, and ClinicalTrials.gov) were searched from inception through April 2016. Randomised controlled trials and comparative observational studies were included. DATA COLLECTION AND ANALYSIS: Meta-analyses were performed for included randomised controlled trials regarding the outcomes of effectiveness and acceptability to women. Certainty of evidence was established using the GRADE approach assessing study limitations, consistency of effect, imprecision, indirectness and publication bias. MAIN RESULTS: Six papers were included. Medical TOP and medical treatment of incomplete miscarriage is probably equally effective when performed by non-doctor providers as when performed by doctors (RR 1.00; 95% CI 0.99-1.01). Women's acceptance, reported as overall satisfaction with the allocated provider, is probably equally high between groups (RR 1.00; 95% CI 1.00-1.01). CONCLUSION: Medical TOP and medical treatment of incomplete miscarriage provided by trained non-doctor providers is probably equally as effective and acceptable to women as when provided by doctors. TWEETABLE ABSTRACT: Medical termination of pregnancy performed by doctors and non-doctors can be equally effective and acceptable.

Efficacy and safety of very early medical termination of pregnancy: a cohort study.

OBJECTIVE: To assess the efficacy and safety of medical termination of pregnancy (MTOP) when no intrauterine pregnancy (IUP) is confirmed on ultrasound. DESIGN: Retrospective case-note review. SETTING: Two gynaecological clinics in Vienna, Austria, and Gothenburg, Sweden. POPULATION: All women with gestations of ≤49 days undergoing an MTOP during 2004-14 (Vienna) and 2012-15 (Gothenburg). METHODS: Two study cohorts were created: women with and women without a confirmed IUP. An IUP was defined as the intrauterine location of a yolk sac or fetal structure visible by ultrasound. Women with an IUP were selected randomly and included in the IUP cohort. MAIN OUTCOME MEASURES: Efficacy of MTOP, defined as no continuing pregnancy and with no need of surgery for incomplete TOP. RESULTS: After excluding 11 women diagnosed with an extra-uterine or molar pregnancy, 2643 cases were included in the final analysis; 1120 (98.2%) had a successful TOP in the no-IUP group, compared with 1458 (97.1%) in the IUP group, with a risk difference of 1.09% (95% confidence interval, 95% CI, -0.14, 2.32%; P = 0.077). Significantly more women with confirmed IUP were diagnosed with incomplete TOP, and were treated with either surgery or additional medical treatment of misoprostol [64 (4.3%) versus 21 (1.8%); risk difference -2.42%; 95% CI -3.9, -1.1%; P < 0.001]. CONCLUSIONS: There was no difference between the groups in efficacy of MTOP, whereas early treatment resulted in significantly fewer interventions for incomplete TOP. The risk of ectopic pregnancy needs to be considered if treatment is initiated before an IUP is confirmed, but with structured clinical protocols the possibility of the early detection of an ectopic pregnancy in an asymptomatic phase may increase. TWEETABLE ABSTRACT: MTOP before confirmed intrauterine pregnancy is as effective as at later gestation with less incomplete TOP.

Pharmacokinetics of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women.

OBJECTIVES: Estetrol (E4) is a natural fetal estrogen. In this open-label, multiple-rising-dose study, the pharmacokinetic effects of E4 in postmenopausal women were investigated as a secondary objective. METHODS: In total, 49 postmenopausal women were randomized to receive either 2 mg E4 or 2 mg estradiol valerate (E2V) for 28 days, or were (non-randomized) assigned to 10, 20, or 40 mg E4. The main outcome measures were: E4 plasma concentrations at trough, and on days 1 and 28; and E4 pharmacokinetic parameters AUC, Cmax and tmax on days 1 and 28. RESULTS: After oral administration, E4 showed a very fast absorption, followed by a multiphasic elimination with an initial rapid decline, gradually continuing with a slower elimination, suggesting a long terminal half-life. Steady state was reached within 2 weeks of dosing and pharmacokinetic results were generally proportional to the dose. Estetrol concentrations on day 28 were slightly higher compared to day 1, indicating some accumulation. CONCLUSION: The pharmacokinetic profile of estetrol is characterized by a very fast absorption phase, followed by an initial rapid decline, and a slow terminal elimination phase. Based on its kinetic properties, estetrol seems suitable for use as a once-daily oral drug.

Paracervical block as pain treatment during second-trimester medical termination of pregnancy: an RCT with bupivacaine versus sodium chloride.

STUDY QUESTION: Can paracervical block (PCB) administered before the onset of pain decrease women's pain experience during second-trimester medical termination of pregnancy (MToP)? SUMMARY ANSWER: There were no clinically significant differences between groups receiving PCB with bupivacaine or saline with regard to the highest and lowest pain intensity, morphine consumption or induction-to abortion interval. WHAT IS KNOWN ALREADY: The most common side effect of misoprostol is pain; nevertheless, there are sparse studies in pain and pain treatment during MToP, especially in second-trimester abortion. Pain reported in second-trimester medical abortion is often intense, and peaks when the fetal expulsion occurs. STUDY DESIGN, SIZE, DURATION: A double-blinded RCT was carried out from May 2012 until April 2015. A power calculation was based on a previous pilot study showing that the proportion of women with severe pain [visual analogue scale (VAS) ≥7] was 63%. A clinically significant reduction was considered to yield 35% with severe pain, and with a power of 80% and significance level of 5% (two-sided) 112 women were needed. Accounting for a 20% drop-out rate, a total of 140 women were needed. The primary outcome, pain intensity measured as any VAS ≥7, was analysed using a generalized estimating equations model. The level of significance was set to P < 0.05 two-sided. A computer generated randomization list with block size of 10 was used. The treatment allocation was placed in a sealed, opaque, envelope and picked consecutively. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 589 women attending a gynaecological clinic had a second-trimester abortion during the study period and 276 were invited to participate. A total of 113 women undergoing abortion from 13 weeks of gestation and above were recruited, of which 55 were randomly allocated to receive a PCB with bupivacaine and 58 a PCB with sodium chloride 1 h after the first dose of misoprostol. The full analysis set (FAS) population was defined as all randomized women that had at least one value for any of the outcomes (n = 102). The per-protocol (PP) population was defined as a subset of the FAS excluding patients with major protocol deviations or without a value for the primary outcome (n = 99). Pain was measured by VAS at misoprostol initiation (baseline) and repeated every 30 min until fetal expulsion. The primary outcome was the highest VAS pain intensity at any time point. MAIN RESULTS AND THE ROLE OF CHANCE: The highest pain intensity, did not show any differences at a cut-off of VAS ≥7 [risk ratio (RR): 1.1; 95% confidence interval (CI): 0.9-1.5; P = 0.0.292]. In the PP analyses, there were 75% women in the bupivacaine group and 64% in the sodium chloride group with VAS ≥7 (RR: 1.2; 95% CI: 0.9-1.5; P = 0.235). Most women did not experience pain at the misoprostol start, 19 women scored a VAS of >0, ranging from 1 to 4 with a mean of 1.8 and median of 2 (P = 1.000). Immediately prior to PCB, 61 women scored a VAS of >0, from 1 to 10 with a mean of 2.0 and median of 1 (P = 0.771). There was a 48% loss of VAS scores at the time of expulsion and the remaining scores did not differ between groups (RR: 1.5; 95% CI: 0.9-2.5). A subgroup analysis of primipara did not show any difference in highest pain intensity VAS ≥7 (RR: 1.2; 95% CI: 0.9-1.6; P = 0.283). No statistically significant differences were observed between groups with regard to the highest and lowest (P = 553 and 0.182) pain intensity and morphine consumption (P = 0.772). Side effects were reported by 28 women (14 women in each group), with no differences between groups. Most common was nausea and vomiting in connection to morphine injection. LIMITATIONS, REASONS FOR CAUTION: Nearly 60% of the invited women did not want to participate in the study (fear of needles and fear of receiving the placebo) therefore women who tolerate pain may have been overrepresented in the study population. Data collection was stopped, in error, when 113 participants had been recruited. The loss to follow-up was, however, only 11 women (10%), which was lower than expected but intrinsically the study did not fully reach the intended number of women, which may have influenced the results. In addition, the obstetrical and gynaecological background of participating women differs. The participants were informed that they had a 50% chance of receiving a PCB with active substance, which could theoretically have affected their expectations and pain experience (placebo effect). The frequent attention at VAS scoring and the overall care provided may also have affected the participants in a positive way, and helped women to feel supported and more relaxed during the abortion. WIDER IMPLICATIONS OF THE FINDINGS: The highest pain intensity was severe (VAS: 7-10) among 65-75% of the participants, as reported for first-trimester medical abortion; however, the maximal pain scores remain high despite the PCB. There is, therefore, a clear need for more optimal pain treatment but only limited data exist on pain treatment during MToP over all gestational lengths. As PCB was well tolerated, did not cause any serious side effects and had no negative impact on the abortion process and efficacy, another approach may be worth exploring, namely PCB given on demand at the onset of painful contractions. STUDY FUNDING/COMPETING INTERESTS: The study was supported by grants from the Swedish Research Council (grant no: 2012-2844), ALF (Karolinska Institutet - Stockholm County Council, Agreement on Medical Research and Training) funding, the Karolinska Institutet, Stockholm South General Hospital, and Swedish Nurses in the Area of Pain - SSOS together with GlaxoSmithKline. None of the authors have any conflicts of interest. TRIAL REGISTRATION NUMBER: The trial was registered with ClinicalTrials.gov (identifier: NCT01617564) and The EudraCT (number: 2010-020780-21) and was approved by The Regional Ethical Review Board at Karolinska Institutet (dnr: 2007/1277-31/2 and 2010/410-31/1). TRIAL REGISTRATION DATE: Clinical trial registration was done in May 2012 before initiation of patient recruitment. DATE OF FIRST PATIENT'S ENROLMENT: 29 May 2012.

The effects on ovarian activity of ulipristal acetate when 'quickstarting' a combined oral contraceptive pill: a prospective, randomized, double-blind parallel-arm, placebo-controlled study.

STUDY QUESTION: What is the effect on ovarian activity of a preceding intake of ulipristal acetate (UPA) when starting a combined oral contraceptive (COC) in the mid- to late-follicular phase of the cycle? SUMMARY ANSWER: This study shows that UPA does not affect the ability of the COC to induce ovarian quiescence. WHAT IS KNOWN ALREADY: UPA is a progesterone receptor modulator that is available for emergency contraception (EC). In theory, UPA could alter the effectiveness of hormonal contraception started immediately following it and vice versa. Current guidelines regarding quick starting a COC following UPA are based on expert opinion only. STUDY DESIGN, SIZE, DURATION: A double-blind, randomized, placebo-controlled trial was conducted at three separate sites, Edinburgh (Scotland), Stockholm (Sweden) and Groningen (the Netherlands), over a 5-month period in 2012. Healthy female volunteers were randomized to take either UPA or an identically packaged placebo, at mid-cycle (once a lead ovarian follicle was determined to be >13 mm on transvaginal ultrasound imaging). Participants were randomized by a computer-generated randomization schedule, allocated by sequential, sealed envelopes. All women then started 21 days of the same COC the following day. The study was designed to show non-inferiority of UPA compared with placebo in terms of the proportion of women attaining ovarian quiescence, as measured by the Hoogland scoring system, while taking COC. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 76 women were recruited over the three sites, Edinburgh (n = 18), Stockholm (n = 13), Groningen (n = 45) and received either UPA (n = 39) or placebo (n = 37). MAIN RESULTS AND THE ROLE OF CHANCE: There were no significant differences in demographic characteristics of women in the UPA and placebo groups. Among the 76 participants treated, 47 (61.8%) reached quiescence and 25 (32.9%) ovulated. There were no significant differences between the groups in the odds ratio (OR) of reaching ovarian quiescence or not; OR 0.97 (95% CI: 0.39-2.46). All women who reached quiescence had done so after taking COCs for 14 days. LIMITATIONS, REASONS FOR CAUTION: The main limitations of the study were that measurements of follicle size and blood tests were performed every 2-3 days and so it was not possible to determine the actual day that follicle rupture occurred for the women who ovulated. Furthermore, the ultrasonography was conducted by a number of investigators at the sites which may introduce error in the form of inter-observer variability in measurements of follicle growth. Finally, the findings of the study cannot be extrapolated to other combined hormonal methods of contraception such as the patch or ring, nor to progestogen- only methods of contraception. WIDER IMPLICATIONS OF THE FINDINGS: This study provides evidence to suggest that UPA does not affect the ability of the COC to induce ovarian quiescence. However, this study design cannot determine whether the COC affects the ability of UPA to delay ovulation. STUDY FUNDING/COMPETING INTERESTS: Funding was provided by HRA Pharma Paris, France. C.K., S.T.C. and K.G.D. have received funds for conducting research studies and lectures for HRA Pharma. C.K. is director of a contract research organization (Dinox). The remaining authors declare no conflicts of interests. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT01569113.

Effects of ulipristal acetate on human embryo attachment and endometrial cell gene expression in an in vitro co-culture system.

STUDY QUESTION: Does ulipristal acetate (UPA) used for emergency contraception (EC) interfere with the human embryo implantation process? SUMMARY ANSWER: UPA, at the dosage used for EC, does not affect human embryo implantation process, in vitro. WHAT IS KNOWN ALREADY: A single pre-ovulatory dose of UPA (30 mg) acts by delaying or inhibiting ovulation and is recommended as first choice among emergency contraceptive pills due to its efficacy. The compound has also been demonstrated to have a dose-dependent effect on the endometrium, which theoretically could impair endometrial receptivity but its direct action on human embryo implantation has not yet been studied. STUDY DESIGN, SIZE, DURATION: Effect of UPA on embryo implantation process was studied in an in vitro endometrial construct. Human embryos were randomly added to the cultures and cultured for 5 more days with UPA (n = 10) or with vehicle alone (n = 10) to record the attachment of embryos. PARTICIPANTS/MATERIALS, SETTING, METHODS: Endometrial biopsies were obtained from healthy, fertile women on cycle day LH+4 and stromal and epithelial cells were isolated. A three-dimensional in vitro endometrial co-culture system was constructed by mixing stromal cells with collagen covered with a layer of epithelial cells and cultured in progesterone containing medium until confluence. The treatment group received 200 ng/ml of UPA. Healthy, viable human embryos were placed on both control and treatment cultures. Five days later the cultures were tested for the attachment of embryos and the 3D endometrial constructs were analysed for endometrial receptivity markers by real-time PCR. MAIN RESULTS AND THE ROLE OF CHANCE: There was no significant difference in the embryo attachment rate between the UPA treated group and the control group as 5 out of 10 human embryos exposed to UPA and 7 out of 10 embryos in the control group attached to the endometrial cell surface (P = 0.650). Out of 17 known receptivity genes studied here, only 2 genes, HBEGF (P = 0.009) and IL6 (P = 0.025) had a significant up-regulation and 4 genes, namely HAND2 (P = 0.003), OPN (P = 0.003), CALCR (P = 0.016) and FGF2 (P = 0.023) were down-regulated with the exposure of UPA, compared with control group. LIMITATIONS, REASONS FOR CAUTION: This proof of concept study was conducted with a few human embryos, as their availability was limited. Although the 3D model used for this study is well established and the artificial endometrial luminal epithelium shown to express progesterone regulated markers of endometrial receptivity it is still an in vitro model, lacking all cell types that constitute the receptive endometrium in vivo. WIDER IMPLICATIONS OF THE FINDINGS: This study provides new insights on the mechanism of action of UPA on human embryo implantation, demonstrating that UPA in a dosage used for EC does not affect embryo viability and the implantation process of embryo. Progesterone receptor modulators (PRMs) hold the potential to be attractive estrogen- and gestagen-free contraceptives and thus may be made available to a larger proportion of women globally due to these findings. STUDY FUNDING/COMPETING INTERESTS: Swedish Research Council (K2010-54X-14212-09-3) and support provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska University Hospital.

The efficacy, safety and acceptability of medical termination of pregnancy provided by standard care by doctors or by nurse-midwives: a randomised controlled equivalence trial.

OBJECTIVE: To assess nurse-midwife provision of early medical termination of pregnancy (TOP) in a high-resource setting where ultrasound examination for dating of pregnancy is part of the protocol. DESIGN: Randomised controlled equivalence trial. SETTING: Out-patient family planning unit at a university hospital. POPULATION: Women seeking early medical TOP. METHODS: A total of 1180 women were randomised, without any prior examination, to counselling, examination, and treatment by either nurse-midwife or gynaecologist. Ultrasound was performed in all cases by the allocated provider. MAIN OUTCOME MEASURES: The primary outcome was efficacy, defined as the successful completion of TOP without need for vacuum aspiration. Secondary outcomes were safety, defined as need for hospitalisation or blood transfusion, and acceptability, defined as preferred provider were the women to have a medical TOP in the future. RESULTS: A total of 481 women in the nurse-midwife group and 457 women in the doctor group were available for the final analysis. The effectiveness of provision of medical TOP by nurse-midwife providers was superior to that provided by doctors (risk difference 1.6%, 95% confidence interval 0.2-3.0%, which was within the set margin of equivalence). There were no significant differences in safety parameters. Women examined and counselled by a nurse-midwife were significantly more likely (P < 0.001, 95% confidence interval 0.308-0.394) to prefer seeing a nurse-midwife for the consultation were they to have another medical TOP in the future. CONCLUSIONS: These findings show that nurse-midwife provision of early medical TOP in a high-resource setting, where ultrasound is part of the protocol, is effective, and can be safely implemented with high acceptability among women.

Bleeding pattern and user satisfaction in second consecutive levonorgestrel-releasing intrauterine system users: results of a prospective 5-year study.

STUDY QUESTION: What is the bleeding pattern during second consecutive levonorgestrel-releasing intrauterine system (LNG-IUS) use? SUMMARY ANSWER: Consecutive use of LNG-IUS is associated with a predictable bleeding pattern, characterized by the absence of the initial period of irregular bleeding seen after interval insertion of an LNG-IUS and a non-bleeding pattern in the vast majority of women. WHAT IS KNOWN ALREADY: With increased popularity of the LNG-IUS for long-term birth control and treatment of heavy menstrual bleeding (HMB), consecutive use of the system is becoming more frequent. One previous study showed 60% amenorrhea rate in consecutive IUS users; however, the sample size was small. STUDY DESIGN, SIZE, DURATION: A prospective multicenter study in four European countries recruited women who wished to continue with LNG-IUS use immediately after the first 5-year period. A total of 204 women were followed up until the end of the first year of the second IUS. Thereafter 170 women continued into the extension phase of the study up to the full 5 years of use of the second IUS and 144 women continued to the end of the study. PARTICIPANTS, SETTING, METHODS: A total of 170 women (mean age 39 years) who had been using their first LNG-IUS for between 4 years 3 months and 4 years 9 months, either for contraception or for treatment of HMB, and who planned to replace the device with a new LNG-IUS, were recruited and followed up to 5 years of the second IUS use. A total of 17 centers in four European countries were involved in the study. Bleeding patterns were analyzed using daily bleeding diaries using 90-day reference periods (RP) for the first year of the second IUS use and for the last RP of each year during Years 2-5 of use. MAIN RESULTS AND THE ROLE OF CHANCE: Approximately 70% of women were free of bleeding during Years 2-5 and up to 49% were amenorrheic. There was a slight increase in the number of bleeding/spotting days of ∼3 days during the first RP immediately after the placement of the second IUS, whereafter the number of bleeding/spotting days returned to the level preceding the second IUS insertion or below that. Absence of bleeding was associated with high overall satisfaction and continuation rates. No serious adverse events assessed as related to the LNG-IUS use occurred during the 5-year period. The cumulative expulsion rate during the 5-year study period was 1.2%. The sample size was large enough to study bleeding patterns, and subjects are likely to represent typical consecutive IUS users, and therefore, the role of chance is small. LIMITATIONS, REASONS FOR CAUTION: The women represent a selected group as they had already successfully used their first IUS for almost 5 years and were willing to continue its use-however, this is currently a common clinical situation. The results may therefore not be extrapolated to first-time users of the LNG-IUS. WIDER IMPLICATIONS OF THE FINDINGS: These data are of importance when counseling women who are making decisions concerning long-term contraception. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Bayer Pharma AG. P.I. and T.S. are full-time employees of Bayer Pharma AG. O.H. and K. G-D. have received consultancy fees from Bayer Pharma AG. The publication was developed jointly by all authors without third-party involvement and no honoraria were paid for any authors for their contribution to this manuscript. TRIAL REGISTRATION NUMBER: NCT00393198.