Medical treatment of second-trimester fetal miscarriage; A retrospective analysis

Objectives Research on the treatment of second-trimester miscarriages is scarce. We studied the outcomes, and the factors associated with adverse events and need for hospital resources in the medical treatment of second-trimester miscarriage. Materials and methods In these retrospective analyses we studied women treated for spontaneous fetal miscarriage with misoprostol-only (n = 24) or mifepristone and misoprostol (n = 177) in duration of gestation 12+ 1-21+ 6. Primary outcomes were the risk factors for surgical evacuation and excessive bleeding. Secondary outcomes were total misoprostol dose, time to expulsion and the length of hospital stay. Results History of surgical evacuation of the uterus increased the risk of surgical evacuation (p = 0.027). Excessive bleeding was not associated with any of the studied variables. More misoprostol was needed when the duration of gestation exceeded 17+0 weeks (p = 0.036). In multivariate analysis the time to fetal expulsion was shorter in women with history of 1-2 deliveries (hazard ratio [HR] 1.49, 95% confidence interval [CI]; 1.07-2.07), >= 3 deliveries (HR 1.63, 95% CI; 1.11-2.38) and with a two-day interval between mifepristone-misoprostol administration (HR 1.71, 95% CI; 1.05-2.81). Patients with symptoms (i.e. uterine bleeding or pain) at baseline had longer hospital stay (HR 0.66, 95% CI; 0.47-0.92). Conclusions The factors affecting the outcomes of medical treatment of second-trimester fetal miscarriage are similar to those of second-trimester induced abortion. Two-day interval between mifepristone-misoprostol administration might decrease the time to fetal expulsion and the need of hospital resources.Peer reviewe

Estradiol Valerate Vs. Ethinylestradiol In Combined Oral Contraceptives : Effects On The Pituitary-Ovarian Axis

Context There are limited studies comparing the effects of combined oral contraceptives (COCs) containing natural estrogens and synthetic ethinylestradiol (EE) on reproductive hormones. Objective To compare estradiol valerate (EV)+dienogest (DNG), EE+DNG, and DNG alone (an active control) on levels of follicle stimulating hormone (FSH), luteinizing hormone, Anti-Mullerian hormone (AMH), ovarian steroids, sex hormone binding globulin (SHBG), and the Free Androgen Index (FAI). Design Spin-off study from a randomized trial. Setting Outpatient setting at Helsinki and Oulu University Hospitals, Finland. Participants 59 healthy, 18-35-year-old ovulatory women were enrolled. Three women discontinued. The groups were comparable as regards age and body mass index. Interventions EV 2mg+DNG 2-3mg (n=20), EE 0.03mg+DNG 2mg (n=20) and DNG 2mg (n=19) were used continuously for nine weeks. Blood samples were drawn at baseline, and at 5 and 9 weeks. Main Outcome Measures EV+DNG suppressed FSH by -27% (-51:-3) (median [95%CI]) vs. EE+DNG, -64% (-78: -51), P=0.04, but AMH levels decreased similarly by -9% (-18: -0.1) vs. -13% (-28:0.2), P=0.38, respectively. EV+DNG increased SHBG levels by 56% (30:82) and EE+DNG by 385% (313:423), PPeer reviewe

Combined oral contraceptives containing estradiol valerate vs ethinylestradiol on coagulation : A randomized clinical trial

Introduction Contraceptives containing ethinylestradiol (EE) induce changes in the coagulation system and are associated with a risk of venous thromboembolism. However, studies comparing the effects of combined oral contraceptives containing EE and low-potency estrogens (ie, estradiol [E-2] and estradiol valerate [EV]) on coagulation biomarkers are limited. This study represents secondary outcomes of a randomized trial comparing combined oral contraceptives containing EV + dienogest (DNG), EE + DNG, and DNG alone on selected coagulation biomarkers. We could compare the specific effects of the different estrogen components owing to the inclusion of preparations containing the same progestin. Material and methods We enrolled 59 healthy, 18- to 35-year-old, non-smoking women, of whom three discontinued. The participants were randomly allocated to 9 weeks of continuous treatment with EV 2 mg + DNG 2-3 mg (n = 20), EE 0.03 mg + DNG 2 mg (n = 20), or DNG 2 mg (n = 19). Blood samples were collected at baseline and after 9 weeks. We assessed coagulation in vitro by thrombin generation using the Calibrated Automated Thrombogram. Thrombin generation was evaluated by lag time, time to thrombin peak, thrombin peak, and endogenous thrombin potential in response to tissue factor (1 pm). In vivo coagulation assessment was based on levels of prothrombin fragment 1 + 2 (F1 + 2) (thrombin generation) and D-dimer (fibrin turnover). Clinical trial registration: NCT02352090. Results Lag time and time to thrombin peak remained unaltered after exposure to EV + DNG, whereas EE + DNG shortened both lag time (mean percentage change -24%, 95% confidence interval [CI] -32% to -15%; p < 0.01) and time to thrombin peak (-26%, 95% CI -37% to -16%; p < 0.01). EV + DNG induced lower thrombin peak and endogenous thrombin potential than EE + DNG (peak; +45%, 95% CI 22%-67% vs +147%,95% CI 96%-198%; p < 0.01, and endogenous thrombin potential; +26%, 95% CI 15%-38% vs +64%, 95% CI 51%-76%; p < 0.01). Median F1 + 2 levels remained unchanged with EV + DNG (p = 0.22) but increased within normal ranges with EE + DNG (from 152 pmol/L, 95% CI 127-206] pmol/L to 194 pmol/L, 95% CI 149-250 pmol/L, p = 0.04). The within-group change in D-dimer levels was not significant in any of the groups. DNG alone did not affect these biomarkers. Conclusions Both in vitro and in vivo thrombin generation was lower after exposure to EV + DNG compared with EE + DNG. The lower thrombin generation measures after treatment with EV + DNG indicate less enhancement of coagulation potential and suggest that EV may be favorable to EE as a component of combined oral contraceptives.Peer reviewe

Combined oral contraceptives containing estradiol valerate vs ethinylestradiol on coagulation : A randomized clinical trial

Introduction Contraceptives containing ethinylestradiol (EE) induce changes in the coagulation system and are associated with a risk of venous thromboembolism. However, studies comparing the effects of combined oral contraceptives containing EE and low-potency estrogens (ie, estradiol [E-2] and estradiol valerate [EV]) on coagulation biomarkers are limited. This study represents secondary outcomes of a randomized trial comparing combined oral contraceptives containing EV + dienogest (DNG), EE + DNG, and DNG alone on selected coagulation biomarkers. We could compare the specific effects of the different estrogen components owing to the inclusion of preparations containing the same progestin. Material and methods We enrolled 59 healthy, 18- to 35-year-old, non-smoking women, of whom three discontinued. The participants were randomly allocated to 9 weeks of continuous treatment with EV 2 mg + DNG 2-3 mg (n = 20), EE 0.03 mg + DNG 2 mg (n = 20), or DNG 2 mg (n = 19). Blood samples were collected at baseline and after 9 weeks. We assessed coagulation in vitro by thrombin generation using the Calibrated Automated Thrombogram. Thrombin generation was evaluated by lag time, time to thrombin peak, thrombin peak, and endogenous thrombin potential in response to tissue factor (1 pm). In vivo coagulation assessment was based on levels of prothrombin fragment 1 + 2 (F1 + 2) (thrombin generation) and D-dimer (fibrin turnover). Clinical trial registration: NCT02352090. Results Lag time and time to thrombin peak remained unaltered after exposure to EV + DNG, whereas EE + DNG shortened both lag time (mean percentage change -24%, 95% confidence interval [CI] -32% to -15%; p < 0.01) and time to thrombin peak (-26%, 95% CI -37% to -16%; p < 0.01). EV + DNG induced lower thrombin peak and endogenous thrombin potential than EE + DNG (peak; +45%, 95% CI 22%-67% vs +147%,95% CI 96%-198%; p < 0.01, and endogenous thrombin potential; +26%, 95% CI 15%-38% vs +64%, 95% CI 51%-76%; p < 0.01). Median F1 + 2 levels remained unchanged with EV + DNG (p = 0.22) but increased within normal ranges with EE + DNG (from 152 pmol/L, 95% CI 127-206] pmol/L to 194 pmol/L, 95% CI 149-250 pmol/L, p = 0.04). The within-group change in D-dimer levels was not significant in any of the groups. DNG alone did not affect these biomarkers. Conclusions Both in vitro and in vivo thrombin generation was lower after exposure to EV + DNG compared with EE + DNG. The lower thrombin generation measures after treatment with EV + DNG indicate less enhancement of coagulation potential and suggest that EV may be favorable to EE as a component of combined oral contraceptives.Peer reviewe

Estradiol valerate vs. ethinylestradiol in combined oral contraception : effects on metabolism, reproductive hormones and blood coagulation

Over time, reductions in the ethinylestradiol (EE) dose of combined oral contraceptives (COCs) from 100 μg to 20–30 μg have resulted in a lowered risk of COC-associated venous thromboembolism (VTE). Additionally, the development and incorporation of less androgenic progestins, administered in lower doses, have improved the tolerability and metabolic impact of COCs. EE in COCs has recently been replaced with estrogens based on natural estradiol (E2). E2-based COCs are expected to cause more moderate metabolic, endocrine and hemostatic effects than EE-based COCs. However, evidence remains limited, and previous studies investigating EE versus EV are difficult to interpret since they have compared COCs that also differ based on the progestin type. A meaningful comparison of the estrogens in COCs should focus on COCs differing only by the estrogen component since the progestin component exerts its own effects in addition to modulating the effects of the estrogen. Therefore, this thesis aimed to compare the metabolic, endocrine and hemostatic effects of COCs containing E2 (esterified with valeric acid; estradiol valerate [EV]) and EE. To this end, we conducted an open-label, randomized study. Participants were allocated to nine weeks of continuous treatment with 1) EV 2 mg and dienogest (DNG) 2–3 mg, 2) EE 0.03 mg and DNG 2 mg and 3) DNG 2 mg, which was included to specify the progestin effects. Participants were assessed at baseline, five and nine weeks of treatment for changes in insulin sensitivity (the Matsuda index; study I); the lipid profile and markers of low-grade inflammation (high sensitivity C-reactive protein [hs-CRP] and pentraxin-3 [PTX-3]; study II); levels of reproductive hormones (gonadotropins and ovarian hormones) and the induction of hepatic metabolism (sex hormone-binding globulin [SHBG]; study III); and blood coagulation biomarkers (in vitro thrombin generation and markers of in vivo coagulation activation; study IV). We recruited 77 women, of whom 59 were enrolled. The main inclusion criteria were being 18–35 years of age, a two-month wash-out from previous hormonal contraceptive use and normal body weight (body mass index 19–24.9 kg/m2). Three women discontinued participation due to mild side effects. The primary endpoint measure of this study was a change in the Matsuda Index, a whole-body insulin sensitivity index derived from the oral glucose tolerance test (OGTT). The Matsuda index, as well as glucose levels during the OGTT, remained unchanged after treatment with both EV+DNG and EE+DNG. By contrast, fasting insulin levels increased within the normal ranges in the EE+DNG group by +39% (p = 0.03) and in the DNG-alone group by +45% (p = 0.01), whereas they remained unchanged in the EV+DNG group (study I). In the EV+DNG group, the lipid profile changed negligibly. The mean triglyceride levels were minimally elevated at nine weeks, increasing by 0.18 mmol/L (p = 0.02). In the EE+DNG group, triglycerides increased by 0.45 mmol/L (p < 0.001) and high-density lipoproteins by 0.20 mmol/L (p < 0.01). These changes remained within the normal ranges and demonstrated changes in the lipid profile typical for estrogen treatment. Moreover, the mean levels of hs-CRP increased by 1.1 mg/L (p < 0.01) and PTX-3 by 0.22 ng/L (p = 0.02) in the EE+DNG-group, indicative of increased low-grade inflammation. In contrast, treatment with EV+DNG and DNG alone did not trigger increases in either inflammatory marker (study II). Compared with EE+DNG, treatment with EV+DNG resulted in less marked suppression of follicle-stimulating hormone (FSH), whereas luteinizing hormone levels were equally suppressed. As expected, all participants had low progesterone levels compatible with anovulation at five and nine weeks. As an indicator of follicular arrest, anti-Müllerian hormone (AMH) levels decreased in both COC groups by -9% (EV+DNG; p = 0.04) and -13% (EE+DNG; p = 0.01), while AMH remained unchanged in the DNG-alone group. The free androgen index (FAI), a surrogate for free testosterone levels, decreased less in the EV+DNG group than in the EE+DNG group (-39% vs. -72%, p < 0.001). In the EV+DNG group, reduced hepatic impact was demonstrated through a moderate increase in SHBG levels at nine weeks compared with the EE+DNG group, in which SHBG levels increased significantly more (+56% vs. +368%, p < 0.001) (study III). The effect on blood coagulation parameters differed between the EV+DNG and EE+DNG groups. In both groups, in vitro coagulation potential (assessed by thrombin generation) increased; however, the magnitude diverged in favor of EV+DNG, which induced a smaller increase in endogenous thrombin potential (+26% vs. +64%, p < 0.01). Levels of prothrombin fragment 1+2 (F1+2) were elevated in the EE+DNG group, compatible with coagulation activation in vivo, while F1+2 levels remained unaltered in the EV+DNG group (p = 0.04). In contrast, D-dimer levels remained unchanged in all groups. Treatment with DNG alone did not affect either the in vitro or in vivo coagulation parameters. These results indicate increased coagulation potential in the EE+DNG group compared with the EV+DNG group (study IV). In conclusion, these results show that in young, healthy women, short-term treatment with EV+DNG affected markers of low-grade inflammation, lipids, the FAI, SHBG synthesis and blood coagulation parameters less than treatment with EE+DNG. In addition, EV+DNG also appeared neutral on parameters of glucose metabolism, whereas EE+DNG elevated fasting insulin levels. The clinical significance of the differing effects of EV and EE on insulin levels, lipids, and inflammatory markers remains to be explored. However, the more minor impact of EV+DNG on the coagulation parameters may be clinically significant, possibly predicting a lower risk of venous thrombosis. These results encourage further development and research of E2-based COCs.Nykyaikaiset hormonaaliset yhdistelmäehkäisyvalmisteet sisältävät pääsääntöisesti synteettistä etinyyliestradiolia yhdistettynä synteettiseen keltarauhashormoniin, progestiiniin. Etinyyliestradiolin haittavaikutukset, erityisesti sen laskimotukoksen riskiä lisäävä vaikutus, tunnetaan hyvin. Siksi etinyyliestradioliannosta on vuosien mittaan pienenetty. Tiedetään myös, että yhdistelmäehkäisyvalmisteet heikentävät sokeriaineenvaihduntaa ja lisäävät matala-asteista tulehdusta. Markkinoille on viimeisten vuosien aikana tullut luonnollista estradiolia sisältäviä yhdistelmäehkäisyvalmisteita, joilla on mahdollisesti vähemmän aineenvaihdunnallisia haittavaikutuksia ja pienempi laskimotukosriski. Väitöskirjatutkimuksessa verrattiin yhdistelmäehkäisyvalmisteita, jotka sisältävät luonnollista estradiolivaleraattia tai synteettistä etinyyliestradiolia, ja selvitettiin niiden vaikutuksia sokeri- ja rasva-aineenvaihduntaan ja matala-asteiseen tulehdukseen, lisääntymishormoneihin, ja veren hyytymisjärjestelmään. Ainoastaan keltarauhashormonia sisältävä valmiste toimi vertailuvalmisteena. Tutkimus toteutettiin satunnaistettuna kliinisenä lääkeainetutkimuksena. Tutkimukseen osallistui 59 vapaaehtoista, 18–35-vuotiasta naista. Osallistujat satunnaistettiin käyttämään joko 1) estradiolivaleraatin ja dienogestin yhdistelmää (EV 2 mg + DNG 2-3 mg), 2) etinyyliestradiolin ja dienogestin yhdistelmää (EE 0.03 mg + DNG 2 mg), tai 3) pelkkää dienogestiä (DNG 2 mg) yhtäjaksoisesti yhdeksän viikon ajan. Verikokeita otettiin ennen tutkimusjakson alkua sekä viidennen ja yhdeksännen tutkimusviikon aikana. Tutkimuksen päämuuttuja oli insuliiniherkkyys. Kummassakaan yhdistelmävalmisteryhmässä (EV+DNG ja EE+DNG) ei havaittu muutosta insuliiniherkkyydessä. Veren rasvaprofiili pysyi lähes muuttumattomana EV+DNG ryhmässä, kun taas EE+DNG ryhmässä triglyseridien ja HDL-kolesterolin pitoisuudet nousivat jonkin verran. EV+DNG ryhmässä matala-asteista tulehdusta kuvaavat merkkiaineet pysyivät muuttumattomina, mutta nousivat merkittävästi EE+DNG ryhmässä. EV+DNG ryhmässä havaittiin lievempi vaikutus follikkelia stimuloivan hormonin pitoisuuksiin. Kaikilla naisilla oli kuitenkin matalat progesteronitasot, sopien ovulaation estoon. Veren vapaa testosteroni laski vähemmän EV+DNG ryhmässä (-38 %) kuin EE+DNG ryhmässä (-72 %). Myös sukuhormoneja sitova globuliinin pitoisuus lisääntyi vähemmän EV+DNG (+56 %) ryhmässä verrattuna EE+DNG ryhmään (+368 %), osoittaen EV+DNG:n lievempää vaikutusta maksan estrogeeniherkkien proteiinien tuotantoon. EE+DNG-yhdistelmä vaikutti enemmän veren hyytymisjärjestelmään kuin EV+DNG. Plasmanäytteistä tutkittiin veren hyytymisen keskeisen entsyymin, trombiinin, tuotantoa. Kokeellisessa asetelmassa, EE+DNG-ryhmässä trombiinin tuotanto nousi lähtötilanteesta +64 % kun vastaava nousu EV+DNG-ryhmässä oli 26 %. Tulosten perusteella estradiolivaleraattia sisältävä yhdistelmäehkäisyvalmiste vaikutti vähemmän rasva-aineenvaihduntaan, matala-asteiseen tulehdukseen ja veren hyytymisjärjestelmään kuin etinyyliestradiolia sisältävä valmiste. Koska molemmilla valmisteilla on hyvä ehkäisyteho, estradiolivaleraatin lievemmät vaikutukset, varsinkin hyytymisjärjestelmään, viittaavat edullisempaan hyöty-haittasuhteseen

Ehkäisyhormonien turvallisuus on parantunut

• Raskauden ehkäisyvalmisteet sisältävät estrogeenia ja progestiinia tai pelkästään progestiinia. • Kehitystyön tavoitteena on ollut progestiinien parempi siedettävyys ja estrogeenien aiheuttamien tukosriskien vähentäminen. • Uusimmat progestiinit ovat vaikutuksiltaan neutraaleja tai antiandrogeenisia ja niillä saavutetaan hyvä syklikontrolli. • Luonnolliset estrogeenit estradioli (E2) ja estetroli (E4) ovat perinteiseen etinyyliestradiolin (EE) verrattuna metabolisesti lähes neutraaleja ja vaikutukset hyytymisjärjestelmään ovat pienemmät.Peer reviewe

Ethinyl estradiol vs estradiol valerate in combined oral contraceptives - Effect on glucose tolerance : A randomized, controlled clinical trial

Objective: To compare the effects of two formulations of combined oral contraceptives (COCs), estradiol valerate (EV) and ethinyl estradiol (EE) combined with dienogest (DNG), and DNG-only, on glucose tolerance. Study Design: We performed a randomized, controlled 9-week clinical trial. Inclusion criteria were: age 18-35 years, regular menstrual cycle (28 +/- 7 days), no polycystic ovaries, non-smoking, no contraindications for COC use and a 2-month wash-out from hormonal contraceptive use. The women were randomized to EV + DNG (n = 20), EE + DNG (n = 20), and DNG-only (n = 19), and evaluated at baseline, at 4-5 weeks and 8-9 weeks of treatment. Study medications were used continuously for 63 days. Primary outcome measure was change in the whole-body insulin sensitivity index (Matsuda index) derived from the oral glucose tolerance test (OGTT) over the treatment period. Secondary outcome measures were area under curves (AUC) of glucose and insulin, homeostatic model assessment - insulin resistance (HOMA-IR) and Insulin Sensitivity Index (ISI). Results: Fifty-nine women enrolled, and 56 women completed the study. The Matsuda index changed from baseline as follows (mean percentage change, mean change [95%CI]): DNG-only -12%, -1.45 [95%CI -3.22-0.325] P = 0.10; EV + DNG + 2.7%, -0.10 [-1.34 to 1.14] P = 0.86; EE + DNG -5.5%, -1.02 [-2.51 to 0.46] P = 0.16, comparing the groups P = 0.27. There were no clinically significant differences in glucose tolerance between the COC groups, but the DNG-only group showed an improvement in the 2-h glucose levels (5.5 [95%CI 5.0-6.0] to 4.7 mmol/l [4.2-5.2], P = 0.001). Conclusion: We found no clinically significant differences between EV and EE combined with DNG and DNG-only on glucose tolerance in healthy, young, normal-weight women, indicating that these preparations appear close to neutral regarding glucose metabolism when used continuously for nine weeks. (C) 2020 Elsevier Inc. All rights reserved.Peer reviewe

Ehkäisyn yksilöllinen valinta pienentää riskejä

• Raskauden ehkäisyyn liittyvät vakavat riskit ovat harvinaisia nuorilla ja terveillä. • Riskit sekä hyödyt ja haitat tulee huomioida pohdittaessa sopivaa ehkäisymenetelmää. • Riskejä tulisi pohtia erityisesti ehkäisyä aloitettaessa ja valmistetta vaihdettaessa. • Yhdessä potilaan kanssa toteutettu yksilöllinen valinta voi pienentää raskauden ehkäisyyn liittyviä riskejä. Samalla voidaan optimoida hyödyt.Peer reviewe

Ehkäisyn yksilöllinen valinta pienentää riskejä

Tiivistelmä Raskauden ehkäisyyn liittyvät vakavat riskit ovat harvinaisia nuorilla ja terveillä. Riskit sekä hyödyt ja haitat tulee huomioida pohdittaessa sopivaa ehkäisymenetelmää. Riskejä tulisi pohtia erityisesti ehkäisyä aloitettaessa ja valmistetta vaihdettaessa. Yhdessä potilaan kanssa toteutettu yksilöllinen valinta voi pienentää raskauden ehkäisyyn liittyviä riskejä. Samalla voidaan optimoida hyödyt