Justin Chu

The effect of endometriosis on in vitro fertilisation outcome: a systematic review and meta-analysis

Endometriosis is found in 0.5–5% of fertile women and 25–40% of infertile women. It is known that endometriosis is associated with infertility, but there is uncertainty whether women with endometriosis have adverse pregnancy outcomes in in vitro fertilisation (IVF) treatment.

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.).

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 Excellences 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.

Epidemiology and outcomes of pregnancy and obstetric complications in trauma in the United Kingdom

OBJECTIVE To understand the epidemiology of pregnancy and obstetric complications encountered in the management of pregnant trauma patients. METHODS AND DESIGN Retrospective analysis of national trauma registry for recording of pregnancy status or obstetric complication in cases of trauma. Sub-division of patient cohort by severity of trauma and stage of pregnancy. Comparison of data sets between pregnant trauma patients and age-matched non-pregnant female trauma patients to determine patterns of injury and impact upon clinical outcomes. SETTINGS National registry data for the United Kingdom. OUTCOME For the five year period between 2009 and 2014, a total of 15,140 female patients, aged between 15 years old and 50 years old were identified within the trauma registry. A record of pregnancy was identified in 173 patients (1.14%) from within this cohort. Mechanisms of injury within the cohort of pregnant trauma patients saw increased rate of vehicular collision and interpersonal violence, especially penetrating trauma. Higher abbreviated injury scores were recorded for the abdominal region in pregnancy than in the non-pregnant cohort. Maternal mortality rates were seen to be higher, when compared with the non-pregnant trauma patient. Foetal survival rate from this series was 56% following trauma. Foetal death in pregnant trauma patients most frequently occurred in the 2nd trimester. No cases of isolated foetal survival were recorded following maternal trauma. CONCLUSIONS Trauma to pregnant patients is rare in the United Kingdom, encountered in 1% of female trauma patients of child bearing age. Observations in altered mechanisms of injury and clinical outcomes were recorded. This provides useful information regarding the clinical management of pregnant trauma patients and offers potential areas to investigate to optimise their care, as well as to focus injury prevention measures. LEVEL OF EVIDENCE IV--Case series.

Vitamin D and assisted reproductive treatment outcome: a systematic review and meta-analysis

STUDY QUESTION Is serum vitamin D associated with live birth rates in women undergoing ART? SUMMARY ANSWER Women undergoing ART who are replete in vitamin D have a higher live birth rate than women who are vitamin D deficient or insufficient. WHAT IS KNOWN ALREADY Vitamin D deficiency has been associated with an increased risk of abnormal pregnancy implantation as well as obstetric complications such as pre-eclampsia and fetal growth restriction. However, the effect of vitamin D on conception and early pregnancy outcomes in couples undergoing ART is poorly understood. STUDY DESIGN, SIZE, DURATION A systematic review and meta-analysis of 11 published cohort studies (including 2700 women) investigating the association between vitamin D and ART outcomes. PARTICIPANTS/MATERIALS, SETTINGS, METHODS Literature searches were conducted to retrieve studies which reported on the association between vitamin D and ART outcomes. Databases searched included MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and CINAHL. Eleven studies matched the inclusion criteria. MAIN RESULTS AND THE ROLE OF CHANCE Live birth was reported in seven of the included studies (including 2026 patients). Live birth was found to be more likely in women replete in vitamin D when compared to women with deficient or insufficient vitamin D status (OR 1.33 [1.08-1.65]). Five studies (including 1700 patients) found that women replete in vitamin D were more likely to achieve a positive pregnancy test than women deficient or insufficient in vitamin D (OR 1.34 ([1.04-1.73]). All 11 of the included studies (including 2700 patients) reported clinical pregnancy as an outcome. Clinical pregnancy was found to be more likely in women replete in vitamin D (OR 1.46 [1.05-2.02]). Six studies (including 1635 patients) reported miscarriage by vitamin D concentrations. There was no association found between miscarriage and vitamin D concentrations (OR 1.12 [0.81-1.54]. The included studies scored well on the Newcastle-Ottawa quality assessment scale. LIMITATIONS REASONS FOR CAUTION Although strict inclusion criteria were used in the conduct of the systematic review, the included studies are heterogeneous in population characteristics and fertility treatment protocols. WIDER IMPLICATIONS OF THE FINDINGS The findings of this systematic review show that there is an association between vitamin D status and reproductive treatment outcomes achieved in women undergoing ART. Our results show that vitamin D deficiency and insufficiency could be important conditions to treat in women considering ARTs. A randomized controlled trial to investigate the benefits of vitamin D deficiency treatment should be considered to test this hypothesis. STUDY FUNDING/COMPETING INTERESTS No external funding was either sought or obtained for this study. The authors have no competing interests to declare. REGISTRATION NUMBER N/A.

Salpingostomy in the treatment of hydrosalpinx: a systematic review and meta-analysis.

STUDY QUESTION What is the chance of natural conception when salpingostomy is used to treat hydrosalpinx?. SUMMARY ANSWER The natural clinical pregnancy rate following salpingostomy is 27%, in the hands of experienced surgeons who publish their results. WHAT IS KNOWN ALREADY Tubal surgery is not commonly offered for women with hydrosalpinges since the advent of assisted conception treatment. This is the first systematic review to investigate natural conception rates following salpingostomy in the treatment of hydrosalpinx. STUDY DESIGN, SIZE, DURATION A systematic review and meta-analysis of 22 observational studies encompasses 2810 patients undergoing salpingostomy and attempting natural conception. PARTICIPANTS/MATERIALS, SETTING, METHODS Literature searches were conducted to retrieve observational studies which reported salpingostomy for hydrosalpinx. Databases searched included MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and CINAHL, with no language restriction. Only studies that focused on salpingostomy (rather than other tubal conserving surgeries) for the treatment of hydrosalpinx were included. A total of 22 studies matched the inclusion criteria. MAIN RESULTS AND THE ROLE OF CHANCE The pooled natural clinical pregnancy rate from the 22 observational studies (including 2810 patients) was 27% (95% confidence interval (CI): 25-29%) after salpingostomy was performed for hydrosalpinx. The cumulative clinical pregnancy rates were 8.7% (95% CI: 6.6-11.5%) at 6 months, 13.3% (95% CI: 10.6-16.7%) at 9 months, 20.0% (95% CI: 17.5-22.8%) at 12 months, 21.2% (95% CI: 18.6-24.1%) at 18 months and 25.5% (95% CI: 22.2-29.4%) at 24 months after salpingostomy. The pooled live birth rate (10 studies, 1469 patients) was 25% (95% CI: 22-28%) after salpingostomy was performed for hydrosalpinx. The pooled ectopic pregnancy rate (19 studies, 2662 patients) was 10% (95% CI: 9-11%). The pooled miscarriage rate (seven studies, 924 patients) was 7% (95% CI: 6-9%). The included studies scored well on the Newcastle Ottawa quality assessment scale. LIMITATIONS, REASONS FOR CAUTION Strict inclusion criteria were used in the conduct of the systematic review. However, the studies included are clinically heterogeneous in many aspects including patient characteristics, surgical technique and duration of follow-up after salpingostomy. WIDER IMPLICATIONS OF THE FINDINGS The findings of this systematic review suggest that salpingostomy is an alternative treatment strategy to tubal clipping or salpingectomy in patients presenting to fertility services with hydrosalpinx. Further prospective, large and high quality studies are needed to identify the subpopulation that would most benefit from tube conserving surgery. STUDY FUNDING/COMPETING INTERESTS No external funding was either sought or obtained for this study. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER N/A.

Fallopian tube catheterization in the treatment of proximal tubal obstruction: a systematic review and meta-analysis

Study question What is the chance of clinical pregnancy when fallopian tube catheterization is used for proximal tubal obstruction? Summary answer The pooled clinical pregnancy rate of tubal catheterization after proximal tubal obstruction is 27% (95% CI 25-30%). What is known already Restoring fallopian tube patency by performing tubal catheterization has fallen out of favour since the increased availability of IVF. Our study is the first systematic review and meta-analysis to investigate reproductive outcomes following tubal catheterization for proximal tubal obstruction. Study design, size, duration We undertook a systematic review and meta-analysis of 27 observational studies consisting of 1720 patients undergoing tubal catheterization for proximal tubal obstruction, who attempted to conceive naturally after the procedure. Participants/materials, setting, methods Systematic literature searches were performed in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. A total of 2195 titles and abstracts were reviewed. Only studies that reported outcomes when tubal catheterization was performed with no other tubal surgery were included. Twenty-seven cohort studies matched the inclusion criteria for the meta-analysis. Main results and the role of chance The meta-analysis showed a pooled clinical pregnancy rate of 27% (95% CI 25-30%) after the use of tubal catheterization for unilateral or bilateral proximal tubal obstruction (27 studies, 1556 patients). In women with bilateral obstruction (14 studies, 617 patients), the clinical pregnancy rate was 27% (95% CI 23-32%). Our meta-analysis demonstrated that the pooled cumulative clinical pregnancy rates were 22.3% (95% CI 17.8-27.8%) at 6 months, 25.8% (95% CI 21.1-31.5%) at 9 months, 26.4% (95% CI 23.0-30.2%) at 12 months, 26.0% (95% CI 22.8-29.7%) at 18 months, 27.0% (95% CI 24.0-30.5%) at 24 months, 27.9% (95% CI 24.9-31.3%) at 36 months and 28.5% (95% CI 25.5-31.8%) at 48 months. The pooled live birth rate (14 studies, 551 patients) was 22% (95% CI 18-26%). The pooled ectopic pregnancy rate (27 studies, 1556 patients) was 4% (95% CI 3-5%). The included studies scored satisfactorily on the Newcastle-Ottawa quality assessment scale. Limitations, reasons for caution The pooled clinical pregnancy rate after tubal catheterization was found to be almost comparable to that after IVF. However, included studies were small, non-comparative series with significant clinical heterogeneity in population characteristics, follow-up and surgical equipment, technique and experience. Wider implications of the findings These findings suggest fallopian tube catheterization as an alternative strategy to IVF in patients presenting with proximal tubal obstruction. Further research should focus on comparing different surgical techniques of fallopian tube catheterization with IVF and provide cumulative reproductive outcomes over long-term follow-up. Study funding/competing interest(s) No funding was required and the authors have no competing interests to declare. Registration number N/A.

The effect of peri-implantation administration of uterine relaxing agents in assisted reproduction treatment cycles: a systematic review and meta-analysis

Sub-endometrial junctional zone peristalsis is increased by ovarian stimulation and traumatic embryo transfer, and is linked with decreased implantation and pregnancy rates in assisted reproduction treatments. Various agents have been used to inhibit uterine hyper-peristalsis at the time of embryo transfer with conflicting results. This systematic review aimed to identify if uterine relaxants administered in the peri-implantation period during assisted reproduction treatments could improve pregnancy outcomes through literature search with no language restrictions. The review reports on 3546 patients in 17 randomized controlled trials published between 1993 and 2014. Women undergoing assisted reproduction techniques who either received a uterine relaxant agent in the peri-implantation period versus placebo or no treatment were included. Primary outcome was live birth rate. The meta-analyses did not show statistically significant benefit of any uterine relaxing agents on live birth rate. Other meta-analyses did not show a significant effect on the clinical pregnancy, spontaneous abortion, ectopic pregnancy and multiple pregnancy rate. Most of the included studies were of low quality and lacked significant power to detect minimally important effect. Evidence is insufficient to recommend using these agents in routine practice. Further methodologically robust randomized controlled trials with more refined selection criteria might reveal a beneficial effect.

Obstetrics in trauma

Trauma in pregnancy is the leading non-obstetrical cause of maternal death and remains the most common cause of foetal demise. Many diagnostic and management challenges are present when dealing with the injured pregnant patient. Anatomical and physiological variations of pregnancy need to be understood in order to adapt medical management and overcome the numerous challenges which exist for such patients. The relative unfamiliarity of anatomical and physiological changes experienced in pregnancy means great care must be taken when managing such patients, especially in high energy trauma injuries. Review of the available evidence provides an epidemiological understanding for provision of trauma services. Obstetrics in trauma is a relative rare condition in the United Kingdom, however evidence based in the UK regarding the epidemiology is limited. This article also outlines the principle factors for the assessment and treatment of the injured obstetric patients, as well as discussing areas of ongoing uncertainty.

Optimal endometrial thickness to maximize live births and minimize pregnancy losses: Analysis of 25,767 fresh embryo transfers

RESEARCH QUESTION What is the association of endometrial thickness with pregnancy losses and live births in IVF treatment and the optimal threshold that optimizes the IVF outcome? DESIGN Data were analysed from 25,767 IVF cycles from centres of the CARE Fertility Group in the UK between 2007 and 2016. Transvaginal ultrasound was conducted to measure the maximum endometrial thickness during gonadotrophin stimulation. Live birth rates were per embryo transfer. Pregnancy loss rates included the combination of biochemical and clinical pregnancy losses. RESULTS The live birth rate was 15.6% with 5 mm or less endometrial thickness and gradually increased to 33.1% with an endometrial thickness of 10 mm. On the other hand, the pregnancy loss rate was 41.7% with 5 mm or less endometrial thickness and gradually decreased to 26.5% with an endometrial thickness of 10 mm. Statistical modelling for optimal endometrial thickness threshold found 10 mm or more maximized live births and minimized pregnancy losses. This association was independent after adjusting for confounders such as age, oocyte number, number of transferred embryos, ovarian stimulation protocol and embryo quality for live births (crude RR 1.27; 95% CI 1.21 to 1.33; Adjusted RR 1.18; 95% CI 1.12 to 1.23) and pregnancy losses (crude RR 0.83; 95% CI 0.77 to 0.89; adjusted RR 0.86; 95% CI 0.8 to 0.92). CONCLUSIONS Endometrial thickness is strongly associated with pregnancy losses and live births in IVF, and the optimal endometrial thickness threshold of 10 mm or more maximized live births and minimized pregnancy losses.