Recombinant human granulocyte colony stimulating factor for unexplained recurrent miscarriage: A randomised placebo controlled multi-centre study

Immune mediated mechanisms are thought to contribute to recurrent pregnancy losses. A number of treatment options with limited evidence are being used in clinical practice to treat women with recurrent miscarriages. The objectives of this thesis was a. To summarise the available evidence for granulocyte colony stimulating factor (G-CSF) in reproductive medicine. b. To perform a randomised controlled study (RCT) to evaluate the efficacy and safety of recombinant human granulocyte colony stimulating factor (rhG-CSF) in women with unexplained recurrent miscarriages. The main conclusions from this thesis are: a. The systematic narrative review found that available evidence is of poor quality, but suggestive of benefit with granulocyte colony stimulating factor in women with recurrent miscarriages. b. The RCT concluded that administration of rhG-CSF does not improve pregnancy outcomes among women with a history of unexplained recurrent miscarriages. RhG-CSF appears to be safe for both mothers and their offspring/s

Amenorrhea and pituitary human chorionic gonadotrophin production in a 38-year-old presenting as pregnancy of unknown location: case report and review of literature

Background: Amenorrhea and extraplacental production of serum human chorionic gonadotropin (hCG), particularly in young women, can mimic a pregnancy of unknown location. Elevated serum hCG in the absence of pregnancy can pose a diagnostic dilemma and has led to potentially harmful and unwarranted interventions including chemotherapeutic agents like methotrexate or have led to delay in necessary medical interventions in women. We report a case to demonstrate that amenorrhea and extraplacental human chorionic gonadotropin (hCG) production in young women can mimic a pregnancy of unknown location. Furthermore, we performed a critical review of literature on pituitary hCG production. Case: A 38-year-old woman with a diagnosis of Silver-Russell syndrome, a unicornuate uterus, history of right oophorectomy for a benign serous cystadenoma and a desire for pregnancy presenting with a provisional diagnosis of pregnancy of unknown location.After performing a thorough review of history, physical examination, ultrasound exams, and a review of hormone analysis [including hCG, Tumor markers, Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), Anti-Mullerian Hormone (AMH), Estradiol (E2) levels], we confirmed the diagnosis of premature ovarian insufficiency and pituitary hCG production. Conclusions: In women, serum levels of hCG may increase with age, and are not always an indicator of pregnancy. Therefore, it is imperative to interpret false-positive test results and rule out the extraplacental production of hCG. This will help prevent unnecessary surgical procedures and treatment, including chemotherapy

Association between duration of controlled ovarian stimulation and live birth rate in women undergoing In Vitro Fertilization: a SART CORS analysis

Background: In-Vitro Fertilization (IVF) treatment involves synchronization of multiple time-sensitive events, most of which are rate-limiting too. Controlled ovarian stimulation (COS) is one such event. The reproductive outcomes based on the duration of COS (d-COS) in a fresh, IVF embryo transfer (ET) are not well established and therefore, remains largely uncertain. Objective: To evaluate the association between d-COS and live birth rate (LBR) in women undergoing a fresh IVF-ET using autologous oocytes. Methods: A retrospective cohort study was conducted using a US nationwide IVF register – SARTCORS (Society for Assisted Reproductive Technology Clinic Outcomes Reporting System). From a total of 93,889 cycles, we included 56,666 fresh, autologous, IVF - ET treatment cycles from January 2014 through December 2015, with follow-up until October 2016. Adjusted odds and risk ratio with 95% confidence intervals were estimated while controlling for multiple demographic factors and other potential confounders. Variables and outcomes: The primary exposure variable was d-COS defined as the difference in days between gonadotrophin administration and oocyte retrieval. The primary outcome measure was live birth following a fresh IVF-ET. Secondary outcome measures included biochemical pregnancy rate, miscarriage rate, implantation rate and clinical pregnancy rate. Results: A total of 56,666 treatment cycles (mean [SD] age of 33.9 [4.47], BMI of 26.1 [6.02], AMH value of 2.19 [3.37]), and a baseline FSH value of 7.62 [3.49]) underwent a fresh IVF-ET. The LBR after a combined analysis for all ages and all protocols was 44.2 % (n = 25043). In the combined analysis, there was a statistically significant decrease in the live birth rate with LBR with d-COS beyond 10 days. The adjusted OR (95% CI) of LBR for a woman who had 11, 12, 13 and ≥14 days of COS, compared to optimal duration of 10 days was 0.97 (0.87-0.99), 0.94 (0.8-1), 0.83 (0.77-0.89) and 0.73 (0.68-0.79) respectively. The AOR (95% CI) of miscarriage rates for a woman who had 11, 12, 13 and ≥14 days of COS, compared to referent was 1.12 (1-1.26), 0.99 (0.87-1.12), 1.03 (0.90 -1.17) and 1.04 (0.90 - 1.2) respectively. With increasing d-COS, the implantation rate (IR) and clinical pregnancy rate (CPR) also showed a decreasing trend, as with other reproductive outcomes. The RR (95% CI) for implantation rate in a woman who had 11, 12, 13 and ≥14 days of COS, compared to referent was 0.97 (0.93-1), 0.97 (0.93-1.01), 0.91 (0.87-0.95) and 0.86 (0.82-0.9). The adjusted OR (95% CI) of CPR for a woman who had 11, 12, 13 and ≥14 days of COS, compared to referent was 0.95 (0.89-1.01), 0.93 (0.87-0.99), 0.8 (0.75-0.86) and 0.7 (0.65-0.75) respectively. Conclusions and Relevance: In this nationwide cohort study of women undergoing fresh IVF-ET using autologous oocytes, controlled ovarian stimulation lasting approximately 10-days was associated with an optimal live birth rate

Methods for managing miscarriage:a network meta-analysis

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:The objectives of this review are:• to estimate the relative effectiveness and safety profiles for methods of management of miscarriage;• to provide a ranking of the available methods according to their effectiveness and safety profile

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. opens in new tab.

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

Vitamin D and assisted reproductive treatment outcome: A prospective cohort study

Background: Vitamin D deficiency has been associated with an increased risk of abnormal pregnancy implantation leading to obstetric complications such as pre-eclampsia and fetal growth restriction. However, the effect of vitamin D on reproductive treatment outcomes in couples undergoing assisted reproductive treatment is poorly understood. This study investigates the association between vitamin D and reproductive treatment outcomes in women undergoing assisted reproductive treatments? Methods: A prospective cohort study conducted at a large tertiary teaching hospital, United Kingdom. Five hundred women undergoing assisted reproductive treatment were recruited between September 2013 and September 2015. All participants had their serum vitamin D measured and their reproductive treatment outcomes collated. Women were categorised in to three groups: vitamin D replete (> 75 nmol/L), insufficient (50-75 nmol/L) and deficient (< 50 nmol/L) according to Endocrine Society guidance. The primary outcome was live birth. Secondary outcomes included biochemical pregnancy, clinical pregnancy and pregnancy loss rates. Results: Vitamin D deficiency was found in 53.2% (266/500) of participants and vitamin D insufficiency was found in 30.8% (154/500) of participants. Only 16% (80/500) of women were vitamin D replete. The live birth rates for vitamin D deficient, insufficient and replete women were 23.2% (57/246), 27.0% (38/141) and 37.7% (29/77) respectively (p = 0.04). The respective live birth rates for vitamin D deficient, insufficient and replete women were 24.3, 27.1, 34.4% after adjustment for key prognostic factors (p = 0.25). Conclusions: Vitamin D deficiency and insufficiency are common in women undergoing assisted reproductive treatments. The crude live birth rate achieved in women undergoing assisted reproductive treatments are associated with serum vitamin D, although statistical significance is lost when adjusting for important prognostic variables. Vitamin D deficiency could be an important condition to treat in women considering fertility treatment. A research trial to investigate the benefits of vitamin D deficiency treatment would test this hypothesis. Trial registration: Clinicaltrials.gov - NCT02187146. © 2019 The Author(s).Funding text #1 The study was funded by the Birmingham Women’s and Children’s NHS Foundation Trust Research and Development Department and was approved by the National Research Ethics Service (NRES) Committee West Midlands – Black Country (REC 13/WM/0258). A total of 504 patients who underwent ART at the Birmingham Women’s Fertility Centre from September 2013 to September 2015 were recruited. Funding text #2 The cohort study was funded by a grant from the Research and Development Department at the Birmingham Women’s and Children’s NHS Foundation Trust. Funding text #3 This study was approved by the National Research Ethics Service (NRES) Committee West Midlands – Black Country (REC 13/WM/0258). All participants provided full written and informed consent. Funding text #4 1Tommy’s National Centre for Miscarriage Research, Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK. 2Birmingham Women’s and Children’s National Foundation Trust, Mindelsohn Way, Birmingham B15 2TG, UK. 3Spanish Council for Scientific Research, Institute of Environmental Assessment and Water Research, Barcelona, Spain. 4Birmingham Women’s Foundation NHS Trust, Edgbaston B15 2TG, UK.Peer reviewe

Subcutaneous progesterone versus vaginal progesterone gel for luteal phase support in in vitro fertilization: A noninferiority randomized controlled study

Objective To compare the safety, efficacy, and tolerability of subcutaneous progesterone (Prolutex, 25 mg; IBSA Institut Biochimique SA) with vaginal progesterone gel (Crinone, 8%; Merck Serono) for luteal phase support (LPS) in assisted reproduction technologies (ART) patients. Design Prospective, open-label, randomized, controlled, parallel-group, multicenter, two-arm, noninferiority study. Setting Thirteen European fertility clinics. Patient(s) A total of 683 ART patients randomized to two groups: Prolutex, 25 mg subcutaneously daily (n = 339); and Crinone, 90 mg 8% gel daily (n = 344). Intervention(s) In vitro fertilization and embryo transfer were performed according to site-specific protocols. On the day of oocyte retrieval, Prolutex or Crinone gel was begun for LPS and continued for up to 10 weeks. Main Outcome Measure(s) Ongoing pregnancy rate. Result(s) The primary end point, ongoing pregnancy rates at 10 weeks of treatment were 27.4% and 30.5% in the Prolutex and Crinone groups, respectively (intention to treat [ITT]). The nonsignificant difference between the groups was -3.09% (95% confidence interval [CI] -9.91-3.73), indicating noninferiority of Prolutex to Crinone. Delivery and live birth rates resulted to be equivalent between the two treatments (26.8% vs. 29.9% in the Prolutex and Crinone groups, respectively [ITT]; difference -3.10 [95% CI -9.87-3.68]). No statistically significant differences were reported for any of the other secondary efficacy endpoints, including comfort of usage and overall satisfaction. Conclusion(s) Implantation rate, pregnancy rate, live birth rate, and early miscarriage rate for Prolutex were similar to those for Crinone. The adverse event profiles were similar and Prolutex was safe and well tolerated. Clinical Trial Registration Number NCT00827983. © 2014 by American Society for Reproductive Medicine