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.

Intravenous fluids for reducing the duration of labour in low risk nulliparous women.

BACKGROUND: Several factors may influence the progression of normal labour. It has been postulated that the routine administration of intravenous fluids to keep women adequately hydrated during labour may reduce the period of contraction and relaxation of the uterine muscle, and may ultimately reduce the duration of the labour. It has also been suggested that intravenous fluids may reduce caesarean sections (CS) for prolonged labour. However, the routine administration of intravenous fluids to labouring women has not been adequately elucidated although it is a widely-adopted policy, and there is no consensus on the type or volume of fluids that are required, or indeed, whether intravenous fluids are at all necessary. Women may be able to adequately hydrate themselves if they were allowed oral fluids during labour.Furthermore, excessive volumes of intravenous fluids may pose risks to both the mother and her newborn and different fluids are associated with different risks. OBJECTIVES: To evaluate whether the routine administration of intravenous fluids to low-risk nulliparous labouring women reduces the duration of labour and to evaluate the safety of intravenous fluids on maternal and neonatal health. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (13 February 2013). SELECTION CRITERIA: Randomised controlled trials of intravenous fluid administration to spontaneously labouring low-risk nulliparous women. DATA COLLECTION AND ANALYSIS: The review authors independently assessed trials for inclusion, trial quality and extracted data. MAIN RESULTS: We included nine randomised trials with 1781 women. Three trials had more than two treatment arms and were included in more than one comparison.Two trials compared women randomised to receive up to 250 mL/hour of Ringer's lactate solution as well as oral intake versus oral intake only. For women delivering vaginally, there was a reduction in the duration of labour in the Ringer's lactate group (mean difference (MD) -28.86 minutes, 95% confidence interval (CI) -47.41 to -10.30). There was no statistical reduction in the number of CS in the Ringer's lactate group (risk ratio (RR), 0.73 95% CI 0.49 to 1.08).Three trials compared women who received 125 mL/hour versus 250 mL/hour of intravenous fluids with free oral fluids in both groups. Women receiving a greater hourly volume of intravenous fluids (250 mL) had shorter labours than those receiving 125 mL (MD 23.87 minutes, 95% CI 3.72 to 44.02, 256 women). There was no statistically significant reduction in the number of CS in the 250 mL intravenous fluid group (average RR 1.00, 95% CI 0.54 to1.87, three studies, 334 women). In one study the number of assisted vaginal deliveries was lower in the group receiving 125 mL/hour (RR 0.47, 95% CI 0.27 to 0.81).Four trials compared rates of intravenous fluids in women where oral intake was restricted (125 mL/hour versus 250 mL/hour). There was a reduction in the duration of labour in women who received the higher infusion rate (MD 105.61 minutes, 95% CI 53.19 to 158.02); P < 0.0001, however, findings must be interpreted with caution as there was high heterogeneity amongst trials (I(2) = 53%). There was a significant reduction in CS in women receiving the higher rate of intravenous fluid infusion (RR 1.56, 95% CI 1.10 to 2.21; P = 0.01). There was no difference identified in the assisted delivery rate (RR 0.78, 95% CI 0.44 to 1.40). There was no clear difference between groups in the number of babies admitted to the NICU (RR 0.48, 95% CI 0.07 to 3.17).Two trials compared normal saline versus 5% dextrose. Only one reported the mean duration of labour, and there was no strong evidence of a difference between groups (MD -12.00, 95% CI -30.09 to 6.09). A trial reporting the median suggested that the duration was reduced in the dextrose group. There was no significant difference in CS or assisted deliveries (RR 0.77, 95% CI 0.41 to 1.43, two studies, 284 women) and (RR 0.59, 95% CI 0.21 to 1.63, one study, 93 women) respectively. Only one trial reported on maternal hyponatraemia (serum sodium levels < 135 mmol/L ). For neonatal complications, there was no difference in the admission to NICU) or in low Apgar scores, however 33.3% of babies developed hyponatraemia in the dextrose group compared to 13.3 % in the normal saline group (RR 0.40, 95% CI 0.17 to 0.93) (P = 0.03). One trial reported a higher incidence of neonatal hyperbilirubinaemia in the dextrose group of babies. There was no difference in neonatal hypoglycaemic episodes between groups. AUTHORS' CONCLUSIONS: Although the administration of intravenous fluids compared with oral intake alone demonstrated a reduction in the duration of labour, this finding emerged from only two trials. The findings of other trials suggest that if a policy of no oral intake is applied, then the duration of labour in nulliparous women may be shortened by the administration of intravenous fluids at a rate of 250 mL/hour rather than 125 mL/hour. However, it may be possible for women to simply increase their oral intake rather than being attached to a drip and we have to consider whether it is justifiable to persist with a policy of 'nil by mouth'. One trial raised concerns about the safety of dextrose and this needs further exploration.None of the trials reported on the evaluation of maternal views of being attached to a drip during their entire labour. Furthermore, there was no objective assessment of dehydration. The evidence from this review does not provide robust evidence to recommend routine administration of intravenous fluids. Interpreting the results from trials was hampered by the low number of trials contributing data and by variation between trials. In trials where oral fluids were not restricted there was considerable variation in the amount of oral fluid consumed by women in different arms of the same trial, and between different trials. In addition, results from trials were not consistent and risk of bias varied. Some important research questions were addressed by single trials only, and important outcomes relating to maternal and infant morbidity were frequently not reported.

Recurrent miscarriage and thrombophilia: an update.

PURPOSE OF REVIEW: Acquired and inherited thrombophilia is an important research avenue in the recurrent miscarriage field. The optimum treatment for patients with recurrent miscarriage and a confirmed thrombophilia remains a contentious issue. We aim to appraise and explore the latest research in the field of thrombophilia and recurrent miscarriage in this review. RECENT FINDINGS: Antiphospholipid syndrome (APS) is the only proven thrombophilia that is associated with adverse pregnancy outcomes. Research involving inherited thrombophilia and recurrent miscarriage is limited to small observational studies with small and heterogeneous populations. Aspirin and heparin therapy are frequently prescribed for APS, yet there is no robust evidence for the most efficacious regime. The combination of inherited hypercoagulability and environmental factors in association with recurrent miscarriage has recently been explored as an aid to identify high-risk individuals. SUMMARY: The cause of recurrent miscarriage is multifactorial and appropriate treatment continues to be a challenge. Laboratory tests need to be standardized and well designed multicentre research trials are essential to expand on the current knowledge base with the aim to produce strong evidence-based medicine.

Transabdominal cerclage: preconceptual versus first trimester insertion.

OBJECTIVE: Transabdominal cerclage (TAC) is an effective intervention to prevent spontaneous mid-trimester loss and preterm delivery when a transvaginal cerclage has failed. A TAC may be inserted during the first trimester of pregnancy or preconceptually. The objective of this study was to determine whether or not preconceptual transabdominal cerclage (TAC) confers any benefit over first trimester TAC insertion in terms of associated surgical and pregnancy-related morbidity and subsequent pregnancy outcome. STUDY DESIGN: This was a retrospective and prospective cohort study of 161 consecutive women who underwent preconceptual (PC) TAC versus first trimester (T1) TAC over a 22-year period from January 1993 to January 2015 at a tertiary referral miscarriage clinic. Data was obtained from case note review retrospectively from 1993 to 2006 and prospectively between 2006 and 2015. Inclusion criteria comprised a history of at least one previous spontaneous mid-trimester loss coupled with at least one failed transvaginal cerclage and screening for antiphospholipid syndrome and bacterial vaginosis. Of 144 patients who conceived, 121 had complete pregnancy outcomes; 62 in the preconceptual group and 59 in the first trimester group. Both groups had similar previous pregnancy losses and previous transvaginal cerclage history. RESULTS: Successful pregnancies >24 weeks occurred in 97% of PC TACs compared to 93% in the T1 group. Furthermore, a successful pregnancy >34 weeks occurred in 90% (56/62) in the PC group compared to 74% (44/59) in the T1 group (OR 3.18; CI 1.14-8.8). Significantly fewer patients needed emergency caesarean section for preterm delivery in the PC group (7/62 (12%) versus 21/59 (36%); OR 4.34; CI 1.68-11.32). All 6 failures before 24 weeks gestation (T1=4, PC=2) were associated with antiphospholipid syndrome or bacterial vaginosis. In the T1 group 3/65 (5%) of patients suffered serious surgical complications and haemorrhage >500mls occurred in 32/65(50%) of cases whereas no surgical complications occurred in the PC group. CONCLUSIONS: Preconceptual TAC is more successful in preventing repeat spontaneous mid-trimester loss and preterm labour, and is associated with less surgical and pregnancy-related morbidity compared to first trimester TAC insertion.

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.

Activated protein C resistance and pregnancy loss.

Activated protein C resistance is a thrombophilia with an established role in producing thrombosis which more recently has been implicated in the pathogenesis of pregnancy loss. This review will analyse recent literature to evaluate this association and address the gestation and type of pregnancy loss.

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.

Genetic polymorphisms on the factor V gene in women with recurrent miscarriage and acquired APCR.

BACKGROUND: Recurrent miscarriage (RM) has been associated with the thrombophilia, activated protein C resistance (APCR). The factor V Leiden mutation located on the B domain of the factor V gene, causes 95% of APCR and since the B domain is pivotal to APCR, it seemed plausible that other mutations or polymorphisms affecting this active domain may instigate acquired APCR. The objective of this study was to determine whether other polymorphisms exist on the parts of the gene encoding the B domain of the factor V in women with acquired APCR and RM. METHODS: There were 51 women with RM and acquired APCR, 24 parous women (with no history of miscarriage and at least one normal full-term delivery) and 15 women with a history of idiopathic RM, who formed the study and two control groups, respectively. Six exons of the B domain of the factor V gene were intensely analysed using polymerase chain reactions, single-strand conformation polymorphism, genetic sequencing and restriction enzyme digestion analysis to identify single-nucleotide polymorphisms (SNPs). RESULTS: A significantly increased frequency of some SNPs on the factor V gene were observed in the women with acquired APCR and RM when compared with the control groups. CONCLUSIONS: The presence of some of these SNPs may predispose these women to acquired APCR and RM.