Timed artificial insemination in crossbred mares: Reproductive efficiency and costs.

Timed artificial insemination (TAI) has boosted the use of conventional artificial insemination (CAI) by employing hormonal protocols to synchronize oestrus and ovulation. This study aimed to evaluate the efficiency of a hormonal protocol for TAI in mares, based on a combination of progesterone releasing intravaginal device (PRID), prostaglandin (PGF2α ) and human chorionic gonadotropin (hCG); and compare financial costs between CAI and TAI. Twenty-one mares were divided into two groups: CAI group (CAIG; n = 6 mares; 17 oestrous cycles) and TAI group (TAIG; n = 15 mares; 15 oestrous cycles). The CAIG was subjected to CAI, involving follicular dynamics and uterine oedema monitoring with ultrasound examinations (US), and administration of hCG (1,600 IU) when the dominant follicle (DF) diameter's ≥35 mm + uterine oedema + cervix opening. The AI was performed with fresh semen (500 × 106 cells), and embryo was recovered on day 8 (D8) after ovulation. In TAI, mares received 1.9 g PRID on D0. On D10, PRID was removed and 6.71 mg dinoprost tromethamine was administered. Ovulation was induced on D14 (1,600 IU of hCG) regardless of the DF diameter's, and AI was performed with fresh semen (500 × 106 cells). On D30 after AI, pregnancy was confirmed by US. The pregnancy rate was 80.0% in TAIG and 82.3% in CAIG (p > .05). The TAI protocol resulted in 65% reduction in professional transport costs, and 40% reduction in material costs. The TAI was as efficient as CAI, provided reduction in costs and handlings, and is recommended in mares.

Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT.

BACKGROUND: Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage. OBJECTIVES: (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding. DESIGN: A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding. SETTING: A total of 48 hospitals in the UK. PARTICIPANTS: Women aged 16-39 years with early pregnancy bleeding. INTERVENTIONS: Women aged 16-39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation. MAIN OUTCOME MEASURES: The primary outcome was live birth at ≥ 34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective. RESULTS: A total of 4153 women from 48 hospitals in the UK received either progesterone (n = 2079) or placebo (n = 2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p = 0.08). A significant subgroup effect (interaction test p = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p = 0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p = 0.07); and three or more (72% in the progesterone group vs. 57% in the placebo group; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p = 0.004). A significant post hoc subgroup effect (interaction test p = 0.01) was identified in the subgroup of participants with early pregnancy bleeding and any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p = 0.003). There were no significant differences in the rate of adverse events between the groups. The results of the health economics analysis show that progesterone was more costly than placebo (£7655 vs. £7572), with a mean cost difference of £83 (adjusted mean difference £76, 95% confidence interval -£559 to £711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as £3305 per additional live birth at ≥ 34 weeks of gestation. CONCLUSIONS: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall, but an important subgroup effect was identified. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks. For future work, we plan to conduct an individual participant data meta-analysis using all existing data sets. TRIAL REGISTRATION: Current Controlled Trials ISRCTN14163439, EudraCT 2014-002348-42 and Integrated Research Application System (IRAS) 158326. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 33. See the NIHR Journals Library website for further project information.

Miscarriage is a common complication of pregnancy that affects one in five pregnancies. Several small studies have suggested that progesterone, a hormone essential for maintaining a pregnancy, may reduce the risk of miscarriage in women presenting with early pregnancy bleeding. This research was undertaken to test whether or not progesterone given to pregnant women with early pregnancy bleeding would increase the number of live births when compared with placebo (dummy treatment). The women participating in the study had an equal chance of receiving progesterone or placebo, as determined by a computer; one group received progesterone (400 mg twice daily as vaginal pessaries) and the other group received placebo with an identical appearance. Treatment began when women presented with vaginal bleeding, were < 12 weeks of gestation and were found to have at least a pregnancy sac on an ultrasound scan. Treatment was stopped at 16 weeks of gestation, or earlier if the pregnancy ended before 16 weeks. Neither the participants nor their health-care professionals knew which treatment was being received. In total, 23,775 women were screened and 4153 women were randomised to receive either progesterone or placebo pessaries. Altogether, 2972 participants had a live birth after at least 34 weeks of gestation. Overall, the live birth rate in the progesterone group was 75% (1513 out of 2025 participants), compared with 72% (1459 out of 2013 participants) in the placebo group. Although the live birth rate was 3% higher in the progesterone group than in the placebo group, there was statistical uncertainty about this finding. However, it was observed that women with a history of one or more previous miscarriages and vaginal bleeding in their current pregnancy may benefit from progesterone. For women with no previous miscarriages, our analysis showed that the live birth rate was 74% (824 out of 1111 participants) in the progesterone group compared with 75% (840 out of 1127 participants) in the placebo group. For women with one or more previous miscarriages, the live birth rate was 75% (689 out of 914 participants) in the progesterone group compared with 70% (619 out of 886 participants) in the placebo group. The potential benefit appeared to be most strong for women with three or more previous miscarriages, who had a live birth rate of 72% (98 out of 137 participants) in the progesterone group compared with 57% (85 out of 148 participants) in the placebo group. Treatment with progesterone did not appear to have any negative effects.

Progesterone and preterm birth.

Progestogens (vaginal progesterone and intramuscular 17-hydroxyprogesterone acetate) are widely recommended for women at high risk of preterm birth. Typical regimens include 17-hydroxyprogesterone caproate (250 mg intramuscularly weekly), starting at 16-20 gestational weeks until 36 weeks or delivery for women with a singleton gestation and a history of spontaneous preterm birth, or vaginal progesterone (90-mg vaginal gel or 200-mg micronized vaginal soft capsules) for women with a short cervix (typically ≤25 mm). Although some randomized trials support this approach, neither of the largest trials (PROLONG for 17-hydroxyprogesterone acetate or OPPTIMUM for vaginal progesterone) demonstrated efficacy. There are almost no data on long-term effects, and none that shows benefit beyond the neonatal period. Although some analyses suggest the cost-effectiveness of the approach, a cervical length screening program followed by progesterone for those with a short cervix will reduce preterm birth rates by less than 0.5%. The present review assesses evidence on the efficacy, likely impact, and long-term effects of implementing the recommendations for progestogens in full. Clinicians and pregnant women can look forward to resolution of the conflicting views on efficacy once the Patient-Centered Outcomes Research Initiative (PCORI)-funded individual patient data meta-analysis is published.

Cervical pessary vs vaginal progesterone for prevention of preterm birth in women with twin pregnancy and short cervix: economic analysis following randomized controlled trial.

OBJECTIVE: To compare the cost-effectiveness of cervical pessary vs vaginal progesterone to prevent preterm birth and neonatal morbidity in women with twin pregnancy and a short cervix. METHODS: Between 4 March 2016 and 3 June 2017, we performed this economic analysis following a randomized controlled trial (RCT), performed at My Duc Hospital, Ho Chi Minh City, Vietnam, that compared cervical pessary to vaginal progesterone in women with twin pregnancy and cervical length < 38 mm between 16 and 22 weeks of gestation. We used morbidity-free neonatal survival as a measure of effectiveness. Data on pregnancy outcome, maternal morbidity and neonatal complications were collected prospectively from medical files; additional information was obtained via telephone interviews with the patients. The incremental cost-effectiveness ratio was calculated as the incremental cost required to achieve one extra surviving morbidity-free neonate in the pessary group compared with in the progesterone group. Probabilistic and one-way sensitivity analyses were also performed. RESULTS: During the study period, we screened 1113 women with twin pregnancy, of whom 300 fulfilled the inclusion criteria of the RCT and gave informed consent to participate. These women were assigned randomly to receive cervical pessary (n = 150) or vaginal progesterone (n = 150), with two women and one woman, respectively, being lost to follow-up. The rate of morbidity-free neonatal survival was significantly higher in the pessary group compared with the progesterone group (n = 241/296 (81.4%) vs 219/298 (73.5%); relative risk, 1.11 (95% CI, 1.02-1.21), P = 0.02). The mean total cost per woman was 3146 € in the pessary group vs 3570 € in the progesterone group (absolute difference, -424 € (95% CI, -842 to -3 €), P = 0.048). The cost per morbidity-free neonate was significantly lower in the pessary group compared with that in the progesterone group (2492 vs 2639 €; absolute difference, -147 € (95% CI, -284 to 10 €), P = 0.035). CONCLUSION: In women with twin pregnancy and a short cervix, cervical pessary improves significantly the rate of morbidity-free neonatal survival while reducing costs, as compared with vaginal progesterone. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy.

BACKGROUND: Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data. RESULTS: A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P = 0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08). The incidence of adverse events did not differ significantly between the groups. CONCLUSIONS: Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439.).

Assessment of ovulation synchronization protocols in goats and use of pregnancy specific protein B (PSPB) enzyme linked immunsorbent assay (ELISA) to determine kid number at birth.

The efficacy of several protocols for ovulation synchronization and timed artificial insemination (TAI) in goats was examined. In addition, the relationship between levels of pregnancy specific protein B (PSPB) during gestation assessed with a commercially available ELISA and the number of offspring at birth was determined. In Experiment 1, 70 does were randomized into four treatments: (1) breed by estrus [BBE], (2) 6-d treatment with a new [C6N], (3) once-used [C61], or (4) twice-used Controled Internal Drug Release (CIDR) device [C62)]. BBE does received two 15 mg doses of prostaglandin-F2α (PGF) at a 10-d interval and were bred 12 h after estrus onset. CIDR groups received a CIDR for 6 d with 15 mg PGF given at CIDR removal. TAI was performed 48 h after CIDR removal and does were given 50 µg GnRH. All does were inseminated with a single dose of frozen semen using a non-surgical, transcervical technique. Pregnancy rates for the BBE, C6N, C61 and C62 treatment groups were 39% ± 12%, 64% ± 12%, 77% ± 12% and 57% ± 12%, respectively, and did not differ. Reuse of CIDRs, even with reuse extending for a total of 21 d, was as effective as new CIDRs for synchronization of ovulation. In Experiment 2, 68 does were randomized into four treatments: (1) BBE, (2) C6N, (3) NC.Synch [NCS], (4) modified NCS [NCSM]. The BBE and C6N groups were as described for Experiment 1. The NCS and NCSM groups received 15 mg PGF on Day 1, 50 µg GnRH on Day 8 and 15 mg PGF on Day 15 (NCS) or Day 15.5 (NCSM). Does were bred by TAI at 72 h (NCS) or 60 h (NCSM) after the second PGF injection. All does in the NCS and NCSM groups received 50 µg GnRH at TAI. Pregnancy rates were 53% ± 12%, 30% ± 11%, 50% ± 11% and 41% ± 12% for does in the BBE, C6N, NCS and NCSM group, respectively, and did not differ. In Experiment 3, 62 does pregnant to TAI were bled at Days 48 and 85 post-insemination for PSPB. Data on kid numbers and birth weights were subsequently recorded. At Day 48 of gestation, PSPB levels for does birthing singletons were lower than for does birthing twins or triplets (25.0 ± 0.1a, 28.8 ± 0.1b and 30.7 ± 0b ng/mL, respectively, abP<0.05). At Day 85 of gestation, PSPB levels were progressively greater for does birthing singletons versus twins versus triplets (27.0 ± 0.1a, 28.5 ± 0.1b and 31.6 ± 0c ng/mL, abcP<0.05). In conclusion, PSPB concentrations detected using a commercially available ELISA at Day 48 or 85 of gestation could distinguish does carrying single versus multiple fetuses.

Efficacy of using previously used controlled internal drug release (CIDR) insert on the reproductive performance, hormone profiles and economic measures of sheep.

This study was conducted using 120 multiparous Awassi ewes during the breeding season to compare the effects of using previously used controlled internal drug release (CIDR) on the hormone profiles, reproductive performance and economic measures of ewes. Ewes were randomized to receive one of five previously used CIDR (previously used for 6, 12, 18, 24 or 30 days) or the new CIDR as a control for 6 days (CIDR6, CIDR12, CIDR18, CIDR24, CIDR30, and CIDR0 [control], respectively). Blood samples were collected on four occasions, at the time of CIDR insertion, after 3 days of insertion, and at the time of withdrawal and insemination. Serum estradiol (E2) and progesterone (P4) concentrations were measured. Timed insemination was performed 48 hr post-CIDR withdrawal. Pregnancy was diagnosed by ultrasonography 23 days after insemination and confirmed on day 35. The heat detection rate was significantly (p < 0.05) higher in the CIDR0 and CIDR6 groups than in the CIDR18 and CIDR30 groups. The total pregnancy rate and fecundity were significantly (p < 0.05) higher in the CIDR6 group than in other groups. P4 level was significantly (p < 0.05) higher in the CIDR0 group than in the CIDR30 group at the time of removal. At each time point, the E2 level was significantly (p < 0.05) higher in the CIDR6 group than at the other groups. The total variable cost, total cost, return and net profit were higher in the CIDR6 and CIDR0 groups than in the other groups. In conclusion, although previously used CIDRs are efficient at synchronizing oestrus in ewes, the duration of previously usage significantly affected the reproductive parameters and economic profit. CIDRs previously used for 6 days and new CIDRs provided the highest fertility and fecundity rates, besides return and net profit. Economically, it is not advisable to use CIDRs that previously used for 12 days or more.

Do Women Find the Progesterone Vaginal Ring Acceptable? Findings from Kenya, Nigeria, and Senegal.

The progesterone vaginal ring (PVR) is a contraceptive designed for use by breastfeeding women in the first year postpartum. This Report presents results of an acceptability study of the PVR in Kenya, Nigeria, and Senegal. Women seeking postpartum family planning services were offered various contraceptive options including the PVR. Of the 174 participating women, 110 (63 percent) used one ring and 94 (54 percent) completed the study by using two rings over a six-month period. Women were interviewed up to three times: at the time they entered the study, at 3 months (the end of the first ring cycle), and at 6 months (the end of the second ring cycle or when they exited if they had discontinued earlier). Many participants found the ring to be acceptable, with over three-quarters reporting that it was easy to insert, remove, and reinsert. While a small proportion of women experienced ring expulsion, the majority did not. These findings suggest that even in countries with little or no use of vaginal health products, contraceptive vaginal rings offer women a new option that they are able and willing to use.

Evaluation of Progesterone Utilization and Birth Outcomes in a State Medicaid Plan.

OBJECTIVES: Progesterone (hydroxyprogesterone caproate injection and vaginal progesterone) has been shown to reduce preterm birth (PTB) rates by a third among pregnant women at high risk. The purpose of this analysis is to report birth outcomes and medication adherence among Massachusetts Medicaid (MassHealth) members receiving progesterone, evaluate the association between member characteristics and birth outcomes and medication adherence, and compare cost of care with a prior preterm pregnancy. METHODS: This retrospective cohort study used medical claims, pharmacy claims, and prior authorization (PA) request data for MassHealth members who had a PA submitted for progesterone between January 1, 2011, and March 31, 2015. Members were excluded due to breaks in coverage, progesterone was not indicated for prevention of PTB, and if current gestational week or date of delivery was unavailable. MAIN RESULTS: A total of 418 members were screened for inclusion of whom 190 met criteria and 169 filled progesterone. Mean age was 29.2 years (SD = 5.23), and clinical comorbidities were identified in 90.5% of members. Consistent with clinical trials on progesterone effectiveness, 62.1% of members had a term delivery (37 wks of gestation). Among members with prior gestational age at delivery available, the average difference in gestational age between pregnancies was 8.25 weeks (SD = 6.11). In addition, 66.3% of members were adherent to progesterone based on proportion of days covered (PDC) of 0.8 or higher. The overall mean PDC was 0.79 (SD = 0.26). CONCLUSION: Despite similar birth outcomes in clinical trials and national trends, medication adherence is low in this state Medicaid program. Therefore, members may benefit from adherence support.

Assessment of the usage of biodegradable polymeric matrix in vaginal devices to sustain progesterone release in cows.

The usage of timed artificial insemination (TAI) at a low cost leading to better reproductive rates has been the aim of several research groups in the field. Usually during TAI protocols, sustained progesterone (P4 ) release devices are employed. Most devices are constituted of a nylon skeleton covered with a silicon layer with P4 . A device based on biopolymers was developed in order to reduce costs and decrease its environmental impact. In this study, we compared the kinetics of sustained progesterone release among devices manufactured with a polymeric blend made of polyhydroxybutyrate-valerate (PHBV) and poly-ε-caprolactone (PCL) (DISP) which were compared with DIB® (Internal Bovine Device) used as the control. In the in vitro and in vivo progesterone release tests, two types of biopolymer-based devices with a superficial area of 147 cm2 were used: DISP8 (46% PHBV, 46% PCL and 8% P4 ; n = 4), DISP10 (45% PHBV, 45% PCL, 10% P4 ; n = 4) and DIB® (1 g P4 , 120 cm2 area; n = 3). The in vitro tests were carried out according to USP XXIII specifications and were performed in a dissolutor sink using an alcohol/water mixture (60/40 v/v) as a release media and samples were collected at 2 min, 2, 4, 8, 12, 24, 48, 60, 72, 84 and 96 h. P4 concentrations were measured through spectrophotometry in a 244 nm long wave. Three to 3 comparisons of angular coefficients of the straight lines obtained by regression analysis of accumulated P4 concentrations as a function of square root of time were carried out. Furthermore, the diffusion coefficient values of P4 were also determined for DISP8 and DISP10. The results showed that the concentrations of P4 were higher in the DISP10 (774.63 ± 45.26 µg/cm2 /t1/2 ) compared to DISP8 (566.17 ± 3.68 µg/cm2 /t1/2 ) (P < 0.05). However, both DISP10 and DISP8 P4 concentrations did not differ from DIB® (677.39 ± 16.13 µg/cm2 /t1/2 ). For the analysis of released quantities per day of the in vitro test, four periods were considered: 0-24, 24-48, 48-72 and 72-96 h. In the first 24 h, DISP8 released significantly less P4 than DISP10 or DIB®, which did not differ among them. Between 24 and 48 h, DISP10 released significantly more P4 than DIB®. DISP8 released an intermediate P4 amount and did not differ significantly from DIB® or DISP10. Between 48 and 72 h, P4 quantity released by DISP10 was significant higher (P < 0.01) than that of DIB® and DISP8, which did not differ among themselves. Between 72 and 96 h, DISP10 released significantly more P4 than DIB®, and DISP8 released an intermediate amount which did not differ from DIB® or DISP10 (P < 0.01). There was interaction between treatment and time (P = 0.0024). The diffusion coefficient values were: 1.36 × 10-8 (cm2 /s) for DISP10 and 1.12 × 10-8 (cm2 /s) for DISP8. For the in vivo test, ovariectomized crossbred cows received DIB® (n = 4) or DISP8 (n = 8) in an alternate design with a non-balanced sequence (cross-over) added of measures repeated in time referring to 16 days of blood samples collection. Samples were analyzed through radioimmunoassay in solid phase using the commercial kit of DPC (Diagnostics Products Corporation). Plasma concentrations of P4 peaked at 4 h after the placement of the device, this being the only time in which plasma P4 concentrations differed between DIB® (11.45 ± 1.96) compared with DISP8 (9.23 ± 1.15 ng/mL) (P = 0.027). On day 8, plasma P4 concentrations were similar for DIB® (2.44 ± 0.09) and DISP8 (1.89 ± 0.13 ng/mL) (P = 0.58) showing that both devices were able to keep P4 concentrations above 1 ng/mL in the plasma of the cow during the 16 day in vivo test. In conclusion, devices manufactured with the blend of PHBV/PCL biopolymers can sustain the release of P4 in a similar manner as silicon.

Comparative assessment of arabin pessary, cervical cerclage and medical management for preterm birth prevention in high-risk pregnancies.

OBJECTIVE: This study aimed to compare the efficacy of combined use of Arabin pessary, cervical cerclage and progesterone with progesterone-only management of pregnant women at high risk of preterm birth. MATERIALS AND METHODS: The study included 203 pregnant women at high risk of preterm birth who were randomised to receive Arabin pessary (Group 1, n = 82) and progesterone, circular cervical cerclage and progesterone (Group 2, n = 121) or progesterone treatment only (Group3, controls, n = 50). Patients in the pessary and cerclage group also received progesterone. RESULTS: The use of Arabin pessary combined with progesterone resulted in a 2.5-fold decrease in the rate of vaginal dysbiosis in pregnancy (p = 0.015) and almost three-fold reduction in in the postpartum period (p = 0.037), combined with circular cervical cerclage and progesterone. Suture eruption was observed in 4.3% of women. In patients with abnormal placental location, placental migration was observed in 62.1% of patients in Group I, 52.1% in Group II and a significantly lower proportion of patients (14.0%) in Group III (p = 0.001). Bleeding during pregnancy was observed significantly more often in both comparison groups (p = 0.005). Incidence of intrapartum bleeding was 17.4% (p = 0.011) in Group II and 24.5% in Group III (p = 0.002). Intrapartum chorioamnionitis was observed in 4.3% of patients in Group II and 2.04% of patients in Group III. CONCLUSIONS: The use of Arabin pessary compbined with progesterone reduces the rate of infectious complications and bleeding during pregnancy and the postpartum period.

Universal cervical length screening for singleton pregnancies with no history of preterm delivery, or the inverse of the Pareto principle.

Ultrasound measurement of cervical length in the general population enables the identification of women at risk for spontaneous preterm delivery. Vaginal progesterone is effective in reducing the risk of preterm delivery in this population. This screening associated with treatment by vaginal progesterone is cost-effective. Universal screening of cervical length can therefore be considered justified. Nonetheless, this screening will not appreciably reduce the preterm birth prevalence: in France or UK, where the preterm delivery rate is around 7.4%, this strategy would make it possible to reduce it only to 7.0%. This small benefit must be set against the considerable effort required in terms of screening ultrasound scans. TWEETABLE ABSTRACT: Universal ultrasound screening of cervical length is the inverse of Pareto's principle: a small benefit against a considerable effort.

PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation.

BACKGROUND AND OBJECTIVES: Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted. DESIGN AND SETTING: A randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites). PARTICIPANTS AND INTERVENTIONS: Women with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan(®), Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks). MAIN OUTCOME MEASURES: Live birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6-8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use. METHODS: Participants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth. RESULTS: A total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15; p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence's threshold of £20,000-30,000 per quality-adjusted life-year as between 0.7145 and 0.7341. CONCLUSIONS: There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM. LIMITATIONS: This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle. FUTURE WORK: Future research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM. TRIAL REGISTRATION: Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 41. See the NIHR Journals Library website for further project information.

Efficacy and Safety Profile of Diclofenac/Cyclodextrin and Progesterone/Cyclodextrin Formulations: A Review of the Literature Data.

BACKGROUND: According to health technology assessment, patients deserve the best medicine. The development of drugs associated with solubility enhancers, such as cyclodextrins, represents a measure taken in order to improve the management of patients. Different drugs, such as estradiol, testosterone, dexamethasone, opioids, non-steroidal anti-inflammatories (NSAIDs; i.e. diclofenac), and progesterone are associated with cyclodextrins. Products containing the association of diclofenac/cyclodextrins are available for subcutaneous, intramuscular, and intravenous administration in doses that range from 25 to 75 mg. Medicinal products containing the association of progesterone/cyclodextrins are indicated for intramuscular and subcutaneous injection at a dose equal to 25 mg. OBJECTIVES AND METHODS: The effects of cyclodextrins have been discussed in the solubility profile and permeability through biological membranes of drug molecules. A literature search was performed in order to give an overview of the pharmacokinetic characteristics, and efficacy and safety profiles of diclofenac/hydroxypropyl-ß-cyclodextrin (HPßCD) and progesterone/HPßCD associations. RESULTS: The results of more than 20 clinical studies were reviewed. It was suggested that the new diclofenac/HPßCD formulation gives a rapid and effective response to acute pain and, furthermore, has pharmacokinetic and efficacy/safety profiles comparable to other medicinal products not containing cyclodextrins. One of the principal aspects of these new diclofenac formulations is that in lowering the dose (lower than 50 mg) the drugs could be more tolerable, especially in patients with comorbid conditions. Moreover, results of studies investigating the characteristics of progesterone and cyclodextrins showed that the new formulation (progesterone/HPßCD 25 mg solution) has the same bioavailability as other products containing progesterone. It is more rapidly absorbed and allows the achievement of peak plasma concentrations in a shorter time. Finally, the new formulation of progesterone was shown to be safe and not inferior to other products already on the market, with the exception of progesterone administered vaginally. CONCLUSIONS: As shown by the results of clinical studies presented in this review, the newly approved medicines containing cyclodextrins have been found to be as effective and as well-tolerated as other medicinal products that do not contain cyclodextrins. Moreover, the newly approved lower dose of diclofenac associated with cyclodextrins is consistent with the European Medicines Agency recommendations reported in the revision of the Assessment Report for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Cardiovascular Risk. Finally, the use of cyclodextrins led to significant increases in solubility and bioavailability of drugs, such as diclofenac and progesterone, and improvement in the efficacy and safety of these drugs.

Revisiting the cost-effectiveness of universal cervical length screening: importance of progesterone efficacy.

BACKGROUND: Preterm birth (PTB) is a significant cause of neonatal morbidity and mortality. Studies have shown that vaginal progesterone therapy for women diagnosed with shortened cervical length can reduce the risk of PTB. However, published cost-effectiveness analyses of vaginal progesterone for short cervix have not considered an appropriate range of clinically important parameters. OBJECTIVE: To evaluate the cost-effectiveness of universal cervical length screening in women without a history of spontaneous PTB, assuming that all women with shortened cervical length receive progesterone to reduce the likelihood of PTB. STUDY DESIGN: A decision analysis model was developed to compare universal screening and no-screening strategies. The primary outcome was the cost-effectiveness ratio of both the strategies, defined as the estimated patient cost per quality-adjusted life-year (QALY) realized by the children. One-way sensitivity analyses were performed by varying progesterone efficacy to prevent PTB. A probabilistic sensitivity analysis was performed to address uncertainties in model parameter estimates. RESULTS: In our base-case analysis, assuming that progesterone reduces the likelihood of PTB by 11%, the incremental cost-effectiveness ratio for screening was $158,000/QALY. Sensitivity analyses show that these results are highly sensitive to the presumed efficacy of progesterone to prevent PTB. In a 1-way sensitivity analysis, screening results in cost-saving if progesterone can reduce PTB by 36%. Additionally, for screening to be cost-effective at WTP=$60,000 in three clinical scenarios, progesterone therapy has to reduce PTB by 60%, 34% and 93%. Screening is never cost-saving in the worst-case scenario or when serial ultrasounds are employed, but could be cost-saving with a two-day hospitalization only if progesterone were 64% effective. CONCLUSION: Cervical length screening and treatment with progesterone is a not a dominant, cost-effective strategy unless progesterone is more effective than has been suggested by available data for US women. Until future trials demonstrate greater progesterone efficacy, and effectiveness studies confirm a benefit from screening and treatment, the cost-effectiveness of universal cervical length screening in the United States remains questionable.

Combined use of progesterone inserts, ultrasongraphy, and GnRH to identify and resynchronize nonpregnant cows and heifers 21 days after timed artificial insemination.

The objective was to decrease the reinsemination interval (RI) when dairy cows and heifers are inseminated using all timed artificial insemination (TAI) programs. Holstein cows (n = 211) and heifers (n = 153) were randomly assigned to a control or 21-day Resynch (21dRES) at 13 days after TAI. Animals in 21dRES (n = 109 cows and 77 heifers) had a progesterone device inserted on Day 13 and removed on Day 20 after TAI and ovaries scanned by ultrasonography. Animals found not to have an active CL (<15 mm) or a CL that decreased 10 mm or greater from Days 13 to 20, and to have a follicle of 12 mm or greater received GnRH and TAI on Day 21. Pregnancy diagnosis was performed on Day 32. Nonpregnant control cows (n = 102) were resynchronized immediately using Ovsynch-56, and control heifers (n = 76) were resynchronized using 5-day Cosynch starting on Day 34; therefore, cows and heifers were reinseminated on Day 42. Nonpregnant 21dRES animals that had not been reinseminated on Day 21 were resynchronized concurrently with the control animals. Pregnancy per AI (PAI) for the initial TAI was similar (P = 0.80) for 21dRES and control cows (30.3% vs. 29.4%) and heifers (49.4% vs. 51.3%). Of the nonpregnant 21dRES animals, 33 of 76 cows (43.4%) and 22 of 39 heifers (56.4%) had been reinseminated on Day 21. Therefore, the RI was decreased by 9.9 days (33.3 ± 1.0 vs. 43.2 ± 1.0 days; P < 0.001) in 21dRES cows and by 12.2 days in 21dRES heifers (30.1 ± 1.3 vs. 42.3 ± 1.3 days; P < 0.001) compared with controls. The overall resynchronized PAI was similar for 21dRES cows compared with controls (31.6% vs. 25.0%; P = 0.23). The PAI was 24.2% for 21dRES cows reinseminated on Day 21 and 37.2% for 21dRES cows reinseminated on Day 42. The overall resynchronized PAI was increased for 21dRES heifers compared with controls (57.5% vs. 32.4%; P = 0.03) because 21dRES heifers reinseminated on Day 21 had similar PAI compared with controls (43.5% vs. 32.4%; P = 0.39), but PAI was increased for 21dRES heifers reinseminated on Day 42 compared with controls (76.5% vs. 32.4%; P = 0.003). Consequently, the proportion of animals pregnant from the initial and resynchronized TAI tended to be increased in 21dRES heifers (79.0% vs. 67.1%; P = 0.09). Cost per pregnancy was decreased for the 21dRES in heifers. In conclusion, 21dRES provided a useful method to decrease the RI in cows and heifers, and to increase PAI and decrease cost per pregnancy in heifers.

Synchronized ovulation for first insemination improves reproductive performance and reduces cost per pregnancy in dairy heifers.

The objectives were to evaluate the effects of synchronizing estrus and ovulation to implement a timed artificial insemination (AI) at first insemination on reproductive performance and cost per pregnancy in dairy heifers. Six hundred eleven Holsteins heifers at approximately 400 d of age from 3 farms were enrolled in the study. Six days before moving to the breeding pens, heifers were allocated randomly to AI after detected estrus from study d 0 to 84 (CON, n=306), or to timed AI for first AI followed by detected estrus for the remainder of the 84-d study (TAI, n=305). Heifers receiving TAI were enrolled in the 5-d timed AI protocol on study d -6 (d -6, GnRH and a progesterone insert; d -1, PGF2α and insert removal; d 0, PGF2α; d 2, GnRH + AI), and they were allowed to be bred the day before scheduled timed AI if detected in estrus. Starting on study d 0, estrus was detected daily. Heifers in estrus were inseminated on the same morning as detected estrus. Control heifers not inseminated by study d 7 received PGF2α and this treatment was repeated every 2 wk until AI. The study lasted 84 d to allow a period of breeding equivalent to four 21-d estrous cycles. A herd budget accounting for inputs for both treatments was created to determine the cost per pregnancy. Sensitivity analysis compared economic differences between the 2 treatments under different input scenarios when detection of estrus after the first AI varied from 50 to 80%. Interval to first AI was 8 d shorter for TAI than for CON. Pregnancy at first AI did not differ between treatments (CON=58.3 vs. TAI=62.8%). In contrast, TAI increased pregnancy per AI (P/AI) compared with CON in heifers inseminated with sex-sorted semen (CON=31.6 vs. TAI=54.8%). The 21-d cycle insemination rate was greater for TAI (91.4%) than for CON (82.4%), even when evaluated after the first 21 d in the study (CON=68.2 vs. TAI=77.1%). The increased insemination rate improved the 21-d cycle pregnancy rate from 47.9% in CON to 57.2% in TAI heifers. In fact, the hazard of pregnancy was 60% greater for TAI than CON. The increased pregnancy rate in TAI reduced the median days to pregnancy by 12 d (CON=2.0 vs. TAI=14.0) and increased the proportion of pregnant heifers by 6.3 percentage points by study d 84 (CON=85.2 vs. TAI=91.5%). The cost per pregnancy was $17.00 less for TAI than CON. The sensitivity analysis indicated that TAI was economically more advantageous to produce a pregnancy compared with CON. Only when insemination rate after the first 21 d of breeding was very high and P/AI was relatively low did the cost per pregnancy become similar for the 2 treatments. Collectively, inseminating all heifers within 2 d of breeding with the 5-d timed AI protocol maintains P/AI, improves pregnancy rate, and reduces cost per pregnancy compared with insemination after detected estrus.

Assessment of sub-endometrial blood flow parameters following dydrogesterone and micronized vaginal progesterone administration in women with idiopathic recurrent miscarriage: a pilot study.

AIM: To evaluate differences in uteroplacental blood flow and pregnancy outcome in women with idiopathic recurrent spontaneous miscarriage (IRSM) following administration of micronized vaginal progesterone and oral dydrogesterone. METHODS: One hundred and thirty-three women (aged 23-40 years) who had had early miscarriages and spontaneous conception participated. Oral dydrogesterone (group A, n = 51) and micronized vaginal progesterone (group B, n = 50) were administrated for luteal support and compared. Pregnant women without history of recurrent miscarriage served as controls (group C, n = 32). The outcome measures consisted of endometrial blood flow parameters by Doppler indices and ongoing pregnancy rate. RESULTS: Before progesterone supplementation, resistivity index (RI) and pulsatility index (PI) were found to be significantly higher in groups A and B as compared to controls. Although statistically not significant, end diastolic velocity (EDV) and systolic/diastolic (S/D) ratio was found to be superior in controls than IRSM women. Peak systolic velocity (PSV) was comparable between IRSM and non-IRSM groups. Following progesterone supplementation, groups A and B showed a highly significant reduction in RI, PI and an increase in EDV. A relative increase in the value of PSV was observed in group A as compared to group B. There was remarkable difference in S/D in both groups. Although not statistically significant, group C showed reduction in RI, PI, PSV, EDV and S/D ratio. Pregnancy salvage rates were higher in group A (92.0%) as compared to group B (82.3%). CONCLUSION: Progesterone supplementation appears to lower vascular resistance in women with IRSM. Oral dydrogesterone appears to be equally effective in improving endometrial blood flow as compared with micronized progesterone.

Cost and cost effectiveness of vaginal progesterone gel in reducing preterm birth: an economic analysis of the PREGNANT trial.

BACKGROUND: Preterm birth (PTB) is a costly public health problem in the USA. The PREGNANT trial tested the efficacy of vaginal progesterone (VP) 8 % gel in reducing the likelihood of PTB among women with a short cervix. OBJECTIVE: We calculated the costs and cost effectiveness of VP gel versus placebo using decision analytic models informed by PREGNANT patient-level data. METHODS: PREGNANT enrolled 459 pregnant women with a cervical length of 10-20 mm and randomized them to either VP 8 % gel or placebo. We used a cost model to estimate the total cost of treatment per mother and a cost-effectiveness model to estimate the cost per PTB averted with VP gel versus placebo. Patient-level trial data informed model inputs and included PTB rates in low- and high-risk women in each study group at <28 weeks gestation, 28-31, 32-36, and ≥37 weeks. Cost assumptions were based on 2010 US healthcare services reimbursements. The cost model was validated against patient-level data. Sensitivity analyses were used to test the robustness of the cost-effectiveness model. RESULTS: The estimated cost per mother was $US23,079 for VP gel and $US36,436 for placebo. The cost-effectiveness model showed savings of $US24,071 per PTB averted with VP gel. VP gel realized cost savings and cost effectiveness in 79 % of simulations. CONCLUSION: Based on findings from PREGNANT, VP gel was associated with cost savings and cost effectiveness compared with placebo. Future trials designed to include cost metrics are needed to better understand the value of VP.

The potential association between postmenopausal hormone use and primary open-angle glaucoma.

IMPORTANCE: Retinal ganglion cells are known to express estrogen receptors and prior studies have suggested an association between postmenopausal hormone (PMH) use and decreased intraocular pressure, suggesting that PMH use may decrease the risk for primary open-angle glaucoma (POAG). OBJECTIVE: To determine whether the use of 3 different classes of PMH affects the risk for POAG. DESIGN, SETTING, AND PARTICIPANTS: Retrospective longitudinal cohort analysis of claims data from women 50 years or older enrolled in a US managed-care plan for at least 4 years in which enrollees had at least 2 visits to an eye care provider during the period 2001 through 2009. EXPOSURE: Postmenopausal hormone medications containing estrogen only, estrogen + progesterone, and estrogen + androgen, as captured from outpatient pharmacy claims over a 4-year period. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) for developing incident POAG. RESULTS: Of 152,163 eligible enrollees, 2925 (1.9%) developed POAG. After adjustment for confounding factors, each additional month of use of PMH containing estrogen only was associated with a 0.4% reduced risk for POAG (HR, 0.996 [95% CI, 0.993-0.999]; P = .02). The risk for POAG did not differ with each additional month of use of estrogen + progesterone (HR, 0.994 [95% CI, 0.987-1.001]; P = .08) or estrogen + androgen (HR, 0.999 [95% CI, 0.988-1.011]; P = .89). CONCLUSIONS AND RELEVANCE: Use of PMH preparations containing estrogen may help reduce the risk for POAG. If prospective studies confirm the findings of this analysis, novel treatments for this sight-threatening condition may follow.