A Randomized Trial of Progesterone in Women with Recurrent Miscarriages.

BACKGROUND: Progesterone is essential for the maintenance of pregnancy. However, whether progesterone supplementation in the first trimester of pregnancy would increase the rate of live births among women with a history of unexplained recurrent miscarriages is uncertain. METHODS: We conducted a multicenter, double-blind, placebo-controlled, randomized trial to investigate whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage. We randomly assigned women with recurrent miscarriages to receive twice-daily vaginal suppositories containing either 400 mg of micronized progesterone or matched placebo from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation. RESULTS: A total of 1568 women were assessed for eligibility, and 836 of these women who conceived naturally within 1 year and remained willing to participate in the trial were randomly assigned to receive either progesterone (404 women) or placebo (432 women). The follow-up rate for the primary outcome was 98.8% (826 of 836 women). In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (relative rate, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 percentage points; 95% CI, -4.0 to 9.0). There were no significant between-group differences in the rate of adverse events. CONCLUSIONS: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with a history of unexplained recurrent miscarriages. (Funded by the United Kingdom National Institute of Health Research; PROMISE Current Controlled Trials number, ISRCTN92644181.).

Is subclinical hypothyroidism associated with lower live birth rates in women who have experienced unexplained recurrent miscarriage?

Thyroid disorders have been associated with recurrent miscarriage. Little evidence is available on the influence of subclinical hypothyroidism on live birth rates. In this cohort study, women who had experienced miscarriage and subclinical hypothyroidism (defined as thyroid-stimulating hormone >97.5th percentile mU/l with a normal thyroxine level) were investigated; the control group included women who had experienced recurrent miscarriage and normal thyroid function. Multivariable logistic regression was used to investigate the association of subclinical hypothyroidism. Data were available for 848 women; 20 (2.4%) had subclinical hypothyroidism; 818 women (96%) had euthyroidism; and 10 (1.2%) had overt hypothyroidism. The live birth rate was 45% in women with subclinical hypothyroidism and 52% in euthyroid women (OR 0.69, 95% CI 0.28 to 1.71). The ongoing pregnancy rate was 65% versus 69% (OR 0.82, 95% CI 0.32 to 2.10) and the miscarriage rate was 35% versus 28% (OR 1.43, 95% CI 0.56 to 3.68), respectively. No differences were found when thyroid stimulating hormone 2.5 mU/l was used as cut-off level to define subclinical hypothyroidism. In women with unexplained miscarriage, no differences were found in live birth, ongoing pregnancy and miscarriage rates between women with subclinical hypothyroidism and euthyroid women.

Screening and treatment for heritable thrombophilia in pregnancy failure: inconsistencies among UK early pregnancy units.

The significance of heritable thrombophilia in pregnancy failure is controversial. We surveyed all UK Early Pregnancy Units and 70% responded. The majority test routinely for heritable thrombophilias; 80%, 76% and 88% undertook at least one screening test in late miscarriage, recurrent miscarriage and placental abruption, respectively. The range of thrombophilias sought is inconsistent: testing for proteins C and S deficiency and F5 R506Q (factor V Leiden) is most prevalent. Detection of heritable thrombophilia frequently leads to administration of antithrombotics in subsequent pregnancies. Thus, thrombophilia testing and use of antithrombotics are widespread in the UK despite controversies regarding the role of heritable thrombophilia in the pathogenesis of pregnancy complications, and the lack of robust evidence for the efficacy of antithrombotic therapy.

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.

Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment.

OBJECTIVE: To compare the efficacy of low-dose aspirin alone versus low-dose aspirin plus low molecular weight heparin in pregnant women with antiphospholipid syndrome and recurrent miscarriage as prophylaxis against pregnancy loss. METHODS: From a regional miscarriage clinic, 119 consecutive women with persistently positive tests for lupus anticoagulant and/or anticardiolipin immunoglobulin G and M antibody were invited to participate in a randomized, controlled trial between 1997 and 2000. After ethical approval and adherence to a written protocol, 12 women were unwilling to participate, five failed exclusion/inclusion criteria, and four were nonpregnant. Laboratory analysis was performed by Sheffield University Coagulation Department, electronically generated randomization by Manchester University Centre for Cancer Epidemiology, and data collection and analysis by a research officer at Leeds University. Viability ultrasound every 2 weeks was provided until 12 weeks' gestation before transfer to the pregnancy support antenatal clinic. RESULTS: Ninety-eight women were randomized before 12 weeks' gestation. Forty-seven received low-dose aspirin 75 mg daily (group A), and 51 received low-dose aspirin plus low molecular weight heparin 5000 U subcutaneously daily (group B) throughout pregnancy. There were 13 pregnancy losses and 34 live births in group A and 11 losses and 40 live births in group B. The live-birth rate was 72% in group A and 78% in group B (odds ratio 1.39, 95% confidence interval 0.55, 3.47). There were no cases of maternal thrombosis in either group. CONCLUSION: A high success rate is achieved when low-dose aspirin is used for antiphospholipid syndrome in pregnancy. The addition of low molecular weight heparin does not significantly improve pregnancy outcome.

Mid-trimester pregnancy loss.

Mid-trimester pregnancy loss (MTL) occurs between 12 and 24 weeks' gestation. The true incidence of this pregnancy complication is unknown, because research into MTL in isolation is scarce, although the estimated incidence has been noted to be 2% to 3% of pregnancies. A comprehensive preconceptual screening protocol is recommended, because the cause for an MTL may be present in isolation or combined (dual pathology), and is often heterogeneous. Patients with a history of MTL are at an increased risk of future miscarriage and preterm delivery. This risk is increased further depending on the number of associative factors diagnosed.

Number and sequence of preceding miscarriages and maternal age for the prediction of antiphospholipid syndrome in women with recurrent miscarriage.

OBJECTIVE: To investigate the relationship between the number and sequence of preceding miscarriages and antiphospholipid syndrome (APS). DESIGN: Retrospective cohort study. SETTING: Recurrent miscarriage (RM) clinic. PATIENT(S): Women who attended the RM clinic from 1988 to 2006. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Number, type, and sequence of previous pregnancies were compared between women with APS and women with unexplained RM. RESULT(S): A total of 1,719 patients were included; 312 (18%) had APS, and 1,407 (82%) had unexplained RM. The mean maternal age (32.6 years) did not differ between women with and without APS. The median number of miscarriages was three in both groups. A total of 865 women (50%) had a history of at least one live birth, with no difference between the two groups. In both groups, 97% of the women had a history of consecutive miscarriages. CONCLUSION(S): The number of preceding miscarriage, type and sequence of previous pregnancies, and maternal age were not associated with APS in women with RM. There is no increased diagnostic yield for APS after three miscarriages rather than after two miscarriages and no increased diagnostic yield for APS after consecutive miscarriages rather than after nonconsecutive miscarriages. Therefore, APS testing should be considered for all women with two or more miscarriages.

Thrombophilia and early pregnancy loss.

Early pregnancy loss is the most common pregnancy complication. About 15% of pregnancies result in pregnancy loss and 1% of women experience recurrent miscarriage (more than three consecutive miscarriages). The influence of thrombophilia in pregnancy is a popular research topic in recurrent miscarriage. Both acquired and inherited thrombophilia are associated with a risk of pregnancy failure. Antiphospholipid syndrome is the only thrombophilia known to have a direct adverse effect on pregnancy. Historically, clinical research studying thrombophilia treatment in recurrent miscarriage has been of limited value owing to small participant numbers, poor study design and heterogeneity. The debate on the efficacy of aspirin and heparin has advanced with recently published randomised-controlled trials. Multi-centre collaboration is required to ascertain the effect of thrombophilia on early pregnancy loss and to establish an evidence-based treatment protocol.

Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage.

Recurrent miscarriage (RM; > or =3 consecutive early pregnancy losses) affects around 1% of fertile couples. Parental chromosomal anomalies, maternal thrombophilic disorders and structural uterine anomalies have been directly associated with recurrent miscarriage; however, in the vast majority of cases the pathophysiology remains unknown. We have updated the ESHRE Special Interest Group for Early Pregnancy (SIGEP) protocol for the investigation and medical management of RM. Based on the data of recently published large randomized controlled trials (RCTs) and meta-analyses, we recommend that basic investigations of a couple presenting with recurrent miscarriage should include obstetric and family history, age, BMI and exposure to toxins, full blood count, antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies), parental karyotype, pelvic ultrasound and/or hysterosalpingogram. Other investigations should be limited to particular cases and/or used within research programmes. Tender loving care and health advice are the only interventions that do not require more RCTs. All other proposed therapies, which require more investigations, are of no proven benefit or are associated with more harm than good.

Updated and revised nomenclature for description of early pregnancy events.

The nomenclature used to describe clinical events in early pregnancy has been criticized for lack of clarity and promoting confusion. There is no agreed glossary of terms or consensus regarding important gestational milestones. In particular there are old and poorly descriptive terms such as 'missed abortion' and 'blighted ovum', which have persisted since their introduction many years ago (Robinson, 1975) and have not undergone revision despite the widespread application of ultrasound for accurate clinical assessment and diagnosis. The authors are aware of these shortcomings in terminology and are keen to provide an updated glossary. We hope that this paper will facilitate the introduction of a revised terminology in an attempt to provide clarity and to enhance uptake and use in the literature as well as clinical assessment and documentation.

Transabdominal cerclage: the significance of dual pathology and increased preterm delivery.

Transabdominal cerclage is a recognised treatment for cervical weakness with a history of recurrent mid-trimester loss and a failed elective vaginal suture. The emergence of dual pathology, such as antiphospholipid syndrome and bacterial vaginosis, is associated with an increased risk of preterm delivery (RR 2.34, 95% CI 1.15-5.8). The first 40 cases are described where strict adherence to an investigation protocol and consistent treatment plan has been implemented.