Autologous platelet-rich plasma for assisted reproduction.

BACKGROUND: Autologous platelet-rich plasma (PRP) consists of plasma and a concentrate of platelets extracted from fresh whole blood of the person being treated. Research has suggested that intrauterine or intraovarian infusion/injection of PRP before embryo transfer may improve endometrial receptivity and response to ovarian stimulation in women undergoing assisted reproduction. We compared these interventions to standard treatment, placebo, or other interventions (mechanical or pharmacological). OBJECTIVES: To assess the effectiveness and safety of intrauterine and intraovarian infusion/injection of platelet-rich plasma in infertile women undergoing assisted reproductive technology cycles. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group's Specialised Register, CENTRAL, MEDLINE, Embase, and the Epistemonikos database in January 2023. We also searched the reference lists of relevant articles and contacted the trial authors and experts in the field for any additional trials. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that evaluated the application of PRP in the uterine cavity, ovaries, or both versus no intervention, placebo, or any other intervention (either mechanical or pharmacological) in women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles. DATA COLLECTION AND ANALYSIS: We followed standard methodological procedures recommended by Cochrane, including use of the updated risk of bias tool (RoB 2). The primary outcomes were live birth (or ongoing pregnancy) and miscarriage. The secondary outcomes were clinical pregnancy, complications of the procedure, multiple pregnancy, ectopic pregnancy, fetal growth restriction, preterm delivery, and fetal abnormality. We estimated the average effect of the interventions by fitting a Der Simonian-Laird's random-effects meta-analysis model. We reported pooled odds ratios (ORs) with 95% confidence intervals (CIs). We restricted the primary analyses to trials at low risk of bias for the outcomes and performed sensitivity analyses that included all studies. MAIN RESULTS: We included 12 parallel-group RCTs that recruited a total of 1069 women. We identified three different comparison groups. Using GRADE, we assessed the certainty of evidence as very low for almost all outcomes. Intrauterine injection/infusion of platelet-rich plasma versus no intervention or placebo Nine studies evaluated intrauterine PRP versus no intervention or placebo. Eight included women with at least two or three previous implantation failures. Only one was assessed at low risk of bias for each outcome. This study provided very low-certainty evidence about the effect of intrauterine PRP injection versus no intervention on live birth (OR 1.10, 95% CI 0.38 to 3.14; 94 women) and miscarriage (OR 0.96, 95% CI 0.13 to 7.09; 94 women). If the likelihood of live birth following no intervention is assumed to be 17%, then the likelihood following intrauterine PRP would be 7% to 40%; and if the risk of miscarriage following no intervention is 4%, then the risk following intrauterine PRP would be 1% to 24%. When we analyzed all studies (regardless of risk of bias), we found very low-certainty evidence about the effect of intrauterine PRP compared with placebo or no intervention on live birth or ongoing pregnancy (OR 2.38, 95% CI 1.16 to 4.86; I² = 54%; 6 studies, 564 women) and miscarriage (OR 1.54, 95% CI 0.59 to 4.01; I² = 0%; 5 studies, 504 women). The study at low risk of bias provided very low-certainty evidence about the effect of intrauterine PRP compared with no intervention on clinical pregnancy (OR 1.55, 95% CI 0.64 to 3.76; 94 women) and ectopic pregnancy (OR 2.94, 95% CI 0.12 to 73.95; 94 women). The synthesis of all studies provided very low-certainty evidence about the effect of intrauterine PRP compared with placebo or no intervention on clinical pregnancy (OR 2.22, 95% CI 1.50 to 3.27; I² = 24%; 9 studies, 824 women), multiple pregnancy (OR 2.68, 95% CI 0.81 to 8.88; I² = 0%; 2 studies, 240 women), and ectopic pregnancy (OR 2.94, 95% CI 0.12 to 73.95; 1 study, 94 women; very low-certainty evidence). Intrauterine infusion of PRP may increase the risk of preterm delivery compared with no intervention (OR 8.02, 95% CI 1.72 to 37.33; 1 study, 120 women; low-certainty evidence). No studies reported pain, infection, allergic reaction, fetal growth restriction, or fetal abnormality. Intrauterine infusion of platelet-rich plasma versus intrauterine infusion of granulocyte colony-stimulating factor Two RCTs evaluated intrauterine PRP versus intrauterine granulocyte colony-stimulating factor (G-CSF); both included women with thin endometrium, and neither was judged at low risk of bias for any outcome. We are uncertain about the effect of intrauterine PRP compared with intrauterine G-CSF on live birth (OR 0.88, 95% CI 0.43 to 1.81; 1 study, 132 women; very low-certainty evidence), miscarriage (OR 1.94, 95% CI 0.63 to 5.96; 1 study, 132 women; very low-certainty evidence), and clinical pregnancy (OR 1.24, 95% CI 0.66 to 2.35; 2 studies, 172 women; very low-certainty evidence). Neither study reported adverse outcomes other than miscarriage. Intraovarian injection of platelet-rich plasma versus no intervention One RCT evaluated PRP injection into both ovaries versus no intervention; it was judged at high risk of bias for the two outcomes it reported. We are uncertain about the effect of intraovarian PRP injection compared with no intervention on ongoing pregnancy (OR 1.09, 95% CI 0.33 to 3.63; 73 women; very low-certainty evidence) and clinical pregnancy (OR 0.90, 95% CI 0.31 to 2.60; 73 women; very low-certainty evidence). The study examined no safety outcomes. AUTHORS' CONCLUSIONS: We are uncertain about the effect of intrauterine or intraovarian administration of PRP on outcomes of assisted reproduction technology in infertile women. The pooled results should be interpreted with caution. Only one of the 12 included studies was judged at low risk of bias. Other limitations of the included trials were failure to report live birth, poor reporting of methods, lack of prospective protocol registration, low precision due to the small number of enrolled participants, indirectness due to the specific subpopulations and settings studied, and insufficient or absent safety data.

Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction.

BACKGROUND: Practitioners in the field of assisted reproductive technology (ART) continually seek alternative or adjunct treatments to improve ART outcomes. This Cochrane review investigates the adjunct use of synthetic versions of two naturally produced hormones, dehydroepiandrosterone (DHEA) and testosterone (T), in assisted reproduction. Steroid hormones are proposed to increase conception rates by positively affecting follicular response to gonadotrophin stimulation. This may lead to a greater oocyte yield and, subsequently, an increased chance of pregnancy. OBJECTIVES: To assess the effectiveness and safety of DHEA and T as pre- or co-treatments in infertile women undergoing assisted reproduction. SEARCH METHODS: We searched the following electronic databases up to 8 January 2024: the Gynaecology and Fertility Group (CGF) Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and trial registries for ongoing trials. We also searched citation indexes, Web of Science, PubMed, and OpenGrey. We searched the reference lists of relevant studies and contacted experts in the field for any additional trials. There were no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing DHEA or T as an adjunct treatment to any other active intervention, placebo, or no treatment in women undergoing assisted reproduction. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, extracted relevant data, and assessed risk of bias. We pooled data from studies using fixed-effect models. We calculated odds ratios (ORs) for each dichotomous outcome. Analyses were stratified by type of treatment. We assessed the certainty of evidence for the main findings using GRADE methods. MAIN RESULTS: We included 29 RCTs. There were 1599 women in the intervention group and 1469 in the control group. Apart from three trials, the trial participants were women identified as 'poor responders' to standard in vitro fertilisation (IVF) protocols. The included trials compared either T or DHEA treatment with placebo or no treatment. Pre-treatment with DHEA versus placebo/no treatment: DHEA likely results in little to no difference in live birth/ongoing pregnancy rates (OR 1.30, 95% confidence interval (CI) 0.95 to 1.76; I² = 16%, 9 RCTs, N = 1433, moderate certainty evidence). This suggests that in women with a 12% chance of live birth/ongoing pregnancy with placebo or no treatment, the live birth/ongoing pregnancy rate in women using DHEA will be between 12% and 20%. DHEA likely does not decrease miscarriage rates (OR 0.85, 95% CI 0.53 to 1.37; I² = 0%, 10 RCTs, N =1601, moderate certainty evidence). DHEA likely results in little to no difference in clinical pregnancy rates (OR 1.18, 95% CI 0.93 to 1.49; I² = 0%, 13 RCTs, N = 1886, moderate certainty evidence). This suggests that in women with a 17% chance of clinical pregnancy with placebo or no treatment, the clinical pregnancy rate in women using DHEA will be between 16% and 24%. We are very uncertain about the effect of DHEA on multiple pregnancy (OR 3.05, 95% CI 0.47 to 19.66; 7 RCTs, N = 463, very low certainty evidence). Pre-treatment with T versus placebo/no treatment: T likely improves live birth rates (OR 2.53, 95% CI 1.61 to 3.99; I² = 0%, 8 RCTs, N = 716, moderate certainty evidence). This suggests that in women with a 10% chance of live birth with placebo or no treatment, the live birth rate in women using T will be between 15% and 30%. T likely does not decrease miscarriage rates (OR 1.63, 95% CI 0.76 to 3.51; I² = 0%, 9 RCTs, N = 755, moderate certainty evidence). T likely increases clinical pregnancy rates (OR 2.17, 95% CI 1.54 to 3.06; I² = 0%, 13 RCTs, N = 1152, moderate certainty evidence). This suggests that in women with a 12% chance of clinical pregnancy with placebo or no treatment, the clinical pregnancy rate in women using T will be between 17% and 29%. We are very uncertain about the effect of T on multiple pregnancy (OR 2.56, 95% CI 0.59 to 11.20; 5 RCTs, N = 449, very low certainty evidence). We are uncertain about the effect of T versus oestradiol or T versus oestradiol + oral contraceptive pills. The certainty of the evidence was moderate to very low, the main limitations being lack of blinding in the included trials, inadequate reporting of study methods, and low event and sample sizes in the trials. Data on adverse events were sparse; any reported events were minor. AUTHORS' CONCLUSIONS: Pre-treatment with T likely improves, and pre-treatment with DHEA likely results in little to no difference, in live birth and clinical pregnancy rates in women undergoing IVF who have been identified as poor responders. DHEA and T probably do not decrease miscarriage rates in women under IVF treatment. The effects of DHEA and T on multiple pregnancy are uncertain. Data regarding adverse events were very limited; any reported events were minor. Research is needed to identify the optimal duration of treatment with T. Future studies should include data collection on adverse events and multiple pregnancy.

The role of maternal physical activity on in vitro fertilization outcomes: a systematic review and meta-analysis.

PURPOSE: This systematic review is designed to summarize the evidence concerning the impact of maternal physical activity on the reproductive outcomes following assisted reproduction techniques (ART), namely in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). METHODS: We searched for eligible studies on PubMed, EMBASE databases and the Cochrane Library from their inception until September 2021. Our primary outcomes were live birth rate and miscarriage, while secondary ones included clinical pregnancy and implantation rates. The quality of the evidence was evaluated using a study-specific adaptation of the Robins I tool. RESULTS: Quantitative data from 10 cohort studies (CS) and 2 randomized control trials (RCT), involving 3431 women undergoing ART treatments, were included in the analyses. The pooled results exhibited uncertainty regarding the effect of physical activity on live birth rate per woman (OR 1.15, 95% CI 0.92-1.43, p = 0.23, I2 = 61%, 9 studies) and miscarriage rates (OR 0.79, 95% CI 0.44-1.43, p = 0.43, I2 = 44%, 6 studies). However, physical activity was associated with significantly improved clinical pregnancy rate after ART (OR 1.39, 95% CI 1.08-1.79, p = 0.0009, I2 = 68%, 10 studies), whereas implantation rate after ART almost reached statistical significance (OR = 1.95, 95% CI 0.99-3.82, p = 0.05, I2 = 77%). CONCLUSION: The current evidence is still insufficient to firmly conclude on the effect of maternal physical activity on live birth, miscarriage and implantation rates. Although clinical pregnancy rates favored physical activity in this group of patients, these results must be undertaken with caution due to the low quality and the high heterogeneity of the studies included.

TGF-ß Physiology as a Novel Therapeutic Target Regarding Autoimmune Thyroid Diseases: Where Do We Stand and What to Expect.

Transforming growth factor beta (TGF-ß), as a master regulator of immune response, is deeply implicated in the complex pathophysiology and development of autoimmune thyroid diseases. Based on the close interplay between thyroid autoimmunity and TGF-ß, scientific interest was shifted to the understanding of the possible role of this molecule regarding the diagnosis, prognosis, and therapy of these diseases. The main aim of this review is to present research data about possible treatment options based on the role of TGF-ß in thyroid autoimmunity. Suggested TGF-ß-mediated therapeutic strategies regarding autoimmune thyroid diseases include either the enhancement of its immunosuppressive role or inhibition of its facilitatory role in thyroid autoimmunity. For example, the application of hr-TGF-ß can be used to bolster the inhibitory role of TGF-ß regarding the development of thyroid diseases, whereas anti-TGF-ß antibodies and similar molecules could impede its immune-promoting effects by blocking different levels of TGF-ß biosynthesis and activation pathways. In conclusion, TGF-ß could evolve to a promising, novel therapeutic tool for thyroid autoimmunity.

Maternal polycystic ovarian syndrome in autism spectrum disorder: a systematic review and meta-analysis.

There is evidence showing a positive correlation between prenatal androgens and their effect on the development of central nervous system and the autistic spectrum disorder (ASD) phenotype in offspring of mothers with polycystic ovary syndrome (PCOS). We applied a systematic review to investigate whether women with PCOS have increased odds of having a child with ASD, while, secondarily, if these women themselves are at high risk of having the disease. Major databases from inception until 14th October 2018 were searched. The primary outcome measure was the odds of an ASD diagnosis in children of mothers with diagnosed PCOS, while the secondary outcome was the odds of ASD diagnosis in women with PCOS. Scheduled subgroup analyses were according to the time of birth and maternal age. We assessed the odds ratio (OR), using a random-effects model; heterogeneity was assessed by I2 and τ2 statistics. The quality of the evidence was evaluated using the Newcastle-Ottawa Scale. Ten studies were eligible for inclusion, including a total of 33,887 ASD children and 321,661 non-ASD children. Diagnosed PCOS was associated with a 1.66 times increase in the odds of ASD in the offspring [95% CI: 1.51, 1.83, p = 1.99 × 10-25, 7 studies, I2 = 0%, τ2 = 0]. Women with PCOS were 1.78 times more likely to be diagnosed with ASD (95% CI: 1.10, 2.87, p = 0.0179, 5 studies, I2 = 85.4%, τ2 = 0.2432). Additional analyses did not change the initial result. The overall quality of the evidence was high. The pooled effects size displayed low heterogeneity (I2 = 0%) for the primary outcome. While the heterogeneity in the secondary outcome appears to attenuate when only high quality studies are synthesized, still the result exhibits significant heterogeneity. Τhe available data allowed a subgroup analysis only for classification system for PCOS diagnosis and showed a significant increase of ASD diagnosis in the offspring of women with Read Code and ICD diagnosed PCOS. In conclusion, the available evidence suggests that women with PCOS have increased odds of having a child with ASD, an effect size estimate based on a large number of patients from studies of good quality. Regarding the evidence on the prevalence of ASD in PCOS women, results suggest that women with PCOS are more likely to be diagnosed with ASD.

Endometrial injection of embryo culture supernatant for subfertile women in assisted reproduction.

BACKGROUND: Despite substantial improvements in the success of assisted reproduction techniques (ART), live birth rates may remain consistently low, and practitioners may look for innovative treatments to improve the outcomes. The injection of embryo culture supernatant in the endometrial cavity can be undertaken at various time intervals before embryo transfer. It provides an altered endometrial environment through the secretion of factors considered to facilitate implantation. It is proposed that injection of the supernatant into the endometrial cavity prior to embryo transfer will stimulate the endometrium and provide better conditions for implantation to take place. An increased implantation rate would subsequently increase rates of clinical pregnancy and live birth, but current robust evidence on the efficacy of injected embryo culture supernatant is lacking. OBJECTIVES: To evaluate the effectiveness and safety of endometrial injection of embryo culture supernatant before embryo transfer in women undergoing ART. SEARCH METHODS: Our search strategies were designed with the help of the Cochrane Gynaecology and Fertility Group Information Specialist. We sought to identify all published and unpublished randomised controlled trials (RCTs) meeting inclusion criteria. Searches were performed on 2 December 2019. We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, CINAHL, trials registries and grey literature. We made further searches in the UK National Institute for Health and Care Excellence (NICE) fertility assessment and treatment guidelines. We handsearched reference lists of relevant systematic reviews and RCTs, together with searches of PubMed and Google for any recent trials that have not yet been indexed in the major databases. We had no language or location restrictions. SELECTION CRITERIA: We included RCTs testing the use of endometrial injection of embryo culture supernatant before embryo transfer during an ART cycle, compared with the non-use of this intervention, the use of placebo or the use of any other similar drug. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, extracted data from studies and attempted to contact the authors where data were missing. We pooled studies using a fixed-effect model. Our primary outcomes were live birth/ongoing pregnancy and miscarriage. We performed statistical analysis using Review Manager 5. We assessed evidence quality using GRADE methods. MAIN RESULTS: We found five RCTs suitable for inclusion in the review (526 women analysed). We made two comparisons: embryo culture supernatant use versus standard care or no intervention; and embryo culture supernatant use versus culture medium. All studies were published as full-text articles. Data derived from the reports or through direct communication with investigators were available for the final meta-analysis performed. The GRADE evidence quality of studies ranged from very low-quality to moderate-quality. Factors reducing evidence quality included high risk of bias due to lack of blinding, unclear risk of publication bias and selective outcome reporting, serious inconsistency among study outcomes, and serious imprecision due to wide confidence intervals (CIs) and low numbers of events. Comparison 1. Endometrial injection of embryo culture supernatant before embryo transfer versus standard care or no intervention: One study reported live birth only and two reported the composite outcome live birth and ongoing pregnancy. We are uncertain whether endometrial injection of embryo culture supernatant before embryo transfer during an ART cycle improves live birth/ongoing pregnancy rates compared to no intervention (odds ratio (OR) 1.11, 95% CI 0.73 to 1.70; 3 RCTs; n = 340, I2 = 84%; very low-quality evidence). Results suggest that if the chance of live birth/ongoing pregnancy following placebo or no treatment is assumed to be 42%, the chance following the endometrial injection of embryo culture supernatant before embryo transfer would vary between 22% and 81%. We are also uncertain whether the endometrial injection of embryo culture supernatant could decrease miscarriage rates, compared to no intervention (OR 0.89, 95% CI 0.44 to 1.78, 4 RCTs, n = 430, I2 = 58%, very low-quality evidence). Results suggest that if the chance of miscarriage following placebo or no treatment is assumed to be 9%, the chance following injection of embryo culture supernatant would vary between 3% and 30%. Concerning the secondary outcomes, we are uncertain whether the injection of embryo culture supernatant prior to embryo transfer could increase clinical pregnancy rates (OR 1.13, 95% CI 0.80 to 1.61; 5 RCTs; n = 526, I2 = 0%; very low-quality evidence), decrease ectopic pregnancy rates (OR 0.32, 95% CI 0.01 to 8.24; n = 250; 2 RCTs; I2 = 41%; very low-quality evidence), decrease multiple pregnancy rates (OR 0.70, 95% CI 0.26 to 1.83; 2 RCTs; n = 150; I2 = 63%; very low-quality evidence), or decrease preterm delivery rates (OR 0.63, 95% CI 0.17 to 2.42; 1 RCT; n = 90; I2 = 0%; very low-quality evidence), compared to no intervention. Finally, there may have been little or no difference in foetal abnormality rates between the two groups (OR 3.10, 95% CI 0.12 to 79.23; 1 RCT; n = 60; I2 = 0%; low-quality evidence). Comparison 2. Endometrial injection of embryo culture supernatant versus endometrial injection of culture medium before embryo transfer We are uncertain whether the use of embryo culture supernatant improves clinical pregnancy rates, compared to the use of culture medium (OR 1.09, 95% CI 0.48 to 2.46; n = 96; 1 RCT; very low-quality evidence). No study reported live birth/ongoing pregnancy, miscarriage, ectopic or multiple pregnancy, preterm delivery or foetal abnormalities. AUTHORS' CONCLUSIONS: We are uncertain whether the addition of endometrial injection of embryo culture supernatant before embryo transfer as a routine method for the treatment of women undergoing ART can improve pregnancy outcomes. This conclusion is based on current available data from five RCTs, with evidence quality ranging from very low to moderate across studies. Further large well-designed RCTs reporting on live births and adverse clinical outcomes are still required to clarify the exact role of endometrial injection of embryo culture supernatant before embryo transfer.

Special characteristics, reproductive, and clinical profile of women with unexplained infertility versus other causes of infertility: a comparative study.

PURPOSE: To investigate whether women with unexplained infertility (UI) demonstrate different demographic and IVF characteristics compared to those with other causes of infertility. METHODS: Data on 245 couples that underwent a total of 413 IVF/ICSI cycles were analyzed (UI 114 cycles, 73 women; anovulation (PCO/PCOS) 83 cycles, 51 women; tubal factor 85 cycles, 47 women; male factor 131 cycles, 74 women). Features of UI were compared versus other infertility groups, after adjustment for multiple comparisons. Generalized least squares (GLS) and random-effects logistic regression analysis were also performed. RESULTS: Live birth rates, consisting of the primary outcome, were similar in all compared infertility groups. Compared to male infertility, UI was associated with woman's older age at cycle, lower body mass index (BMI), and higher follicle-stimulating hormone (FSH). Compared to tubal infertility, UI was linked to lower endometrial thickness at oocyte retrieval and lower BMI; compared to anovulatory infertility related to PCO/PCOS, UI was linked to woman's older age, more frequent smoking, and poorer ovarian reserve tests (FSH and antral follicle count). After adjustment for other types of infertility, woman's age, age at menarche, and FSH levels, anovulatory infertility presented with higher odds of clinical pregnancy compared to UI (adjusted OR = 2.13, 95% C: 1.01-4.52). CONCLUSIONS: Infertile women with UI undergoing assisted reproduction demonstrate different demographic and clinical characteristics compared to those of other causes of infertility, albeit live birth rates are similar.

Navigating assisted reproduction treatment in the time of COVID-19: concerns and considerations.

The COVID-19 pandemic has fueled numerous debates in the field of assisted reproductive technology (ART) as the effect of SARS-CoV-2 on pregnancy and infancy is still considered uncharted territory. Various theses and recommendations on what optimal practice is have emerged, as evidenced by surveys, webinars, and recent publications. ART specialists are faced with dilemmas in light of the lack of concrete scientific evidence required to pave the way towards future safe practice. Meanwhile, infertile couples were similarly left in limbo unable to exercise their reproductive autonomy unlike fertile couples-where achieving a pregnancy via natural conception is a matter of decision. ART treatment being classified as non-essential has only recently re-started, facing new challenges while enabling pregnancy at a time of uncertainty. This article highlights matters of bioethical nature to be considered in the ART world at the time of COVID-19 while presenting an all-inclusive critique of the current status. When pursuing pregnancy through IVF treatment during the pandemic, distancing and caution have the lead role in an effort to defend the health of the intended parents and future children. To promote patient autonomy along with our ethical, moral, and legal duty towards our patients, emphasis should be given on ascertaining shared decision-making, and ensuring that an appropriate all-inclusive informed consent is signed prior to initiating any IVF treatment.

First trimester neutrophil to lymphocyte ratio (NLR) and pregnancy outcome.

In early pregnancy, miscarriage is the most common complication. The early identification of women at high risk for miscarriage could improve pregnancy outcomes. We investigated whether the first trimester neutrophil to lymphocyte ratio (NLR) could be used as a prognostic marker for miscarriage, in pregnancies after spontaneous conception. We retrospectively identified 129 pregnant women who had a first trimester full blood count available and known pregnancy outcome. First trimester NLR was calculated for each woman and mean NLR values were compared between women with live births (group 1) with those with miscarriage (group 2). Mean NLR values were not significantly different between the two groups (2.5 ± 1.0 vs. 2.9 ± 1.5, p = .167) and were not associated with pregnancy outcomes. However, NLR values >5.8 were exclusively observed in the miscarriage group (p = .028).IMPACT STATEMENTWhat is already known on this subject? As a marker of inflammation, NLR has been found to be elevated in various diseases and complications that affect pregnancy outcome. Pregnancy complications, such as preeclampsia and gestational diabetes have been associated with an increased NLR, but little is known on their direct causal relationship. So far, there has been no evaluation of maternal NLR in regards to miscarriage in otherwise healthy women.What do the results of the study add? We found that NLR does not differ significantly between pregnant women with live birth and those whose pregnancy ended in miscarriage . However, NLR values >5.8 were solely found in the miscarriage group- an observation that was statistically significant.What are the implications of these findings for clinical practice and/or further research? The above finding supports high NLR values as a potential marker for the identification of the subset of miscarriages in otherwise healthy pregnant women. This may allow personalised approaches to prevent pregnancy loss.

Nonsteroidal anti-inflammatory drugs for assisted reproductive technology.

BACKGROUND: Despite substantial improvements in the success of treatments through assisted reproduction technologies (ART), live birth rates remain constantly low, and practitioners are seeking aetiologic treatments to improve the outcomes.Local inflammatory response is believed to contribute to implantation failure, where prostaglandins may increase uterine contractions and decrease uterine receptivity, decreasing the possibility of an IVF cycle leading to successful embryo transfer. In this context, nonsteroidal anti-inflammatory drugs (NSAIDs) have been employed to inhibit the negative prostaglandin effect. They are often offered in clinical practice to improve ART outcomes, but current robust evidence on their efficacy is lacking. OBJECTIVES: To evaluate the effectiveness and safety of nonsteroidal anti-inflammatory drugs as co-treatments in infertile women undergoing assisted reproduction, in terms of improving live birth and miscarriage rates. SEARCH METHODS: We designed the search using standard Cochrane methods and performed it on databases from their inception to 20 February 2019.We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL via the Cochrane Central Register of Studies Online, MEDLINE, Embase, CINAHL, and the trial registers for ongoing and registered trials, grey literature and treatment guidelines. We handsearched reference lists of relevant systematic reviews and RCTs, and PubMed and Google for any recent trials. There were no restrictions by language or country of origin. SELECTION CRITERIA: All RCTs on the use of NSAIDs as co-treatment during an ART cycle compared with no use or the use of placebo or any other similar drug, along with the comparison of any NSAID to another. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. Our primary outcomes were live birth/ongoing pregnancy and miscarriage. We performed statistical analysis using Review Manager 5. We assessed evidence quality using GRADE methods. MAIN RESULTS: We found 11 RCTs (1884 women) suitable for inclusion in the review. Most studies were at unclear or high risk of bias. The main limitations in the overall quality of the evidence were high risk of bias, unexplained heterogeneity and serious imprecision and indirectness.There were no data on our primary outcome - live birth per woman randomised - in any review comparisons.NSAIDs vs. placebo/no treatmentWe are uncertain of an effect on ongoing pregnancy when NSAIDs were compared to placebo/no treatment (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.71 to 1.59; 4 studies, 1159 participants; I² = 53%; very low quality evidence). Results suggest that if the chance of ongoing pregnancy following placebo or no treatment is assumed to be 15%, the chance following the use of NSAIDs is estimated to be between 12% and 24%. Subgroup analysis according to the type of NSAID yielded similar results.We are also uncertain of an effect on miscarriage rates when NSAIDs were compared to placebo/no treatment (RR 0.62, 95% CI 0.33 to 1.16; 4 studies, 525 participants; I² = 43%; very low quality evidence). Results suggest that if the chance of miscarriage following placebo or no treatment is assumed to be 21%, the chance following the use of NSAIDs is estimated to be between 7% and 27%. The results were similar when two studies were excluded due to high risk of bias.Concerning the secondary outcomes, we are uncertain of an effect on clinical pregnancy rates (RR 1.23, 95% CI 1.00 to 1.52; 6 studies, 1570 participants; I² = 49%; low-quality evidence); on ectopic pregnancy (RR 0.56, 95% CI 0.05 to 5.89; 1 study, 72 participants); on multiple pregnancy (RR 2.00, 95% CI 0.18 to 21.67; 1 study, 180 participants); and on side effects (RR 1.39, 95% CI 0.02 to 119.35; 3 studies, 418 participants; I² = 79%). The evidence suggests that if the chance of clinical pregnancy following placebo or no treatment is assumed to be 30%, the chance following the use of NSAIDs is estimated to be between 31% and 45%. If the chance of ectopic pregnancy following placebo or no treatment is assumed to be 5%, the chance following the use of NSAIDs is estimated to be between 0.3% and 31%. If the chance of multiple pregnancy following placebo or no treatment is assumed to be 1%, the chance following the use of NSAIDs is estimated to be between 0.2 % and 24%.There were no cases of congenital anomalies during antenatal ultrasound screening of the women in one study.NSAID vs. another NSAIDOnly one study compared piroxicam with indomethacin: we are uncertain of an effect on ongoing pregnancy (RR 1.12, 95% CI 0.63 to 2.00; 1 study, 170 participants; very low quality evidence); and on miscarriage (RR 1.00, 95% CI 0.44 to 2.28; 1 study, 170 participants; very low quality evidence). The evidence suggests that if the chance of ongoing pregnancy following indomethacin is assumed to be 20%, the chance following the use of piroxicam is estimated to be between 13% and 40%; while for miscarriage, the evidence suggests that if the chance following indomethacin is assumed to be 12%, the chance following the use of piroxicam is estimated to be between 5% and 27%.Similar results were reported for clinical pregnancy (RR 1.07, 95% CI 0.71 to 1.63; 1 study, 170 participants; very low quality evidence).There were no data for the other outcomes specified in this review.NSAID vs. aspirinNo study reported this comparison. AUTHORS' CONCLUSIONS: Currently we are uncertain of an effect of the routine use of NSAIDs as co-treatments in infertile women undergoing assisted reproduction in order to improve ongoing pregnancy and miscarriage rates. This is based on available data from RCTs, where very low quality evidence showed that there is no single outcome measure demonstrating a benefit with their use. Further large, well-designed randomised placebo-controlled trials reporting on live births are required to clarify the exact role of NSAIDs.

Age at menarche and clinical outcomes following medically assisted reproduction (MAR): a cohort study.

Medically assisted reproduction (MAR) technologies have advanced rapidly, but in contrast to the specificity of modern approaches, they provide limited effectiveness in the management of the infertile couple. The purpose of this study was to assess the possible relationship between age at menarche and MAR outcomes of clinical pregnancy, live birth and the adverse incident of miscarriage, and to determine the offspring sex ratio according to age at menarche. In a cohort of 254 infertile couples who underwent 426 IVF/ICSI cycles, statistical analysis was performed by applying Student's t-test, chi-square test, and logistic regression models, adequately in the respective parameters and outcomes. The results indicated a strong association of age at menarche with the outcomes of clinical pregnancy (p = .0007) and live birth (p < .0001), especially by applying a threshold of 12 years in the first occurrence of menstruation (p = .0019 for clinical pregnancy, p < .0001 for live birth), also demonstrating a negative effect for earlier menarche that acts in parallel with the increasing age of the woman. Calculation of sex ratio demonstrated a tendency towards female offspring close to the age at menarche of 12 years. Age at menarche could serve as a surrogate parameter for reproductive potential towards personalized management of infertility.

First trimester neutrophil-to-lymphocyte ratio (NLR) and pregnancy outcomes in medically assisted reproduction (MAR): a case control study.

As success rates after medically assisted reproduction (MAR) technologies have remained constantly limited during the last years, there has been a systematic effort to predict clinical outcomes. There is currently weak evidence to name the neutrophil-to-lymphocyte ratio (NLR), as an accurate predictor in MAR. Through a case control study, and by setting strict eligibility criteria, we enrolled 66 women (35 with negative outcome and 31 cycles with live birth), in terms of NLR at the time of oocyte retrieval. Clinical and IVF cycle characteristics were comparable in a normalized population. There was a positive correlation between NLR and the age of the woman (r = 0.310, p=.011 and rs =0.363, p=.033). Higher odds ratios (ORs) of MAR positive outcome were detected only at higher NLR values, when NLR was divided into quartiles, but only in the 4th quartile [OR =4.33 (95%CI: 1.02-10.79)]. ROC curve resulted on an AUC equal to 0.660 (95%CI: 0.529-0.791) and p value .025. The estimated specificity, sensitivity and cutoff point were 0.57, 0.548, and 1.98, respectively, while PPV and NPV values were 70.6% and 59.3%, respectively. In conclusion, NLR was positively correlated with maternal age; in our study cohort, MAR failure was associated with lower NLR values.

An artificial neural network for the prediction of assisted reproduction outcome.

PURPOSE: To construct and validate an efficient artificial neural network (ANN) based on parameters with statistical correlation to live birth, to be used as a comprehensive tool for the prediction of the clinical outcome for patients undergoing ART. METHODS: Data from 257 infertile couples that underwent a total of 426 IVF/ICSI cycles from 2010 to 2017 was collected on an ensemble of 118 parameters for each cycle. Statistical correlation of the parameters with the outcome of live birth was performed, using either t test or χ2 test, and the parameters that demonstrated statistical significance were used to construct the ANN. Cross-validation was performed by random separation of data and repeating the training-testing procedure by 10 times. RESULTS: 12 statistically significant parameters out of the initial ensemble were used for the ANN construction, which exhibited a cumulative sensitivity and specificity of 76.7% and 73.4%, respectively. During cross-validation, the system exhibited the following: sensitivity 69.2% ± 2.36%, specificity 69.19% ± 2.8% (OR 5.21 ± 1.27), PPV 36.96 ± 3.44, NPV 89.61 ± 1.09, and OA 69.19% ± 2.69%. A rather small standard deviation in the performance indices between the training and test sets throughout the validation process indicated a stable performance of the constructed ANN. CONCLUSIONS: The constructed ANN is based on statistically significant variables with the outcome of live birth and represents a stable and efficient system with increased performance indices. Validation of the system allowed an insight of its clinical value as a supportive tool in medical decisions, and overall provides a reliable approach in the routine practice of IVF units in a user-friendly environment.

In vitro maturation in subfertile women with polycystic ovarian syndrome undergoing assisted reproduction.

BACKGROUND: Polycystic ovarian syndrome (PCOS) occurs in 4% to 7% of all women of reproductive age and 50% of women presenting with subfertility. Subfertility affects 15% to 20% of couples trying to conceive. A significant proportion of these women ultimately need assisted reproductive technology (ART). In vitro fertilisation (IVF) is one of the assisted reproduction techniques employed to raise the chances of achieving a pregnancy. For the standard IVF technique, stimulating follicle development and growth before oocyte retrieval is essential, for which a large number of different methods combining gonadotrophins with a gonadotrophin-releasing hormone (GnRH) agonist or antagonist are used. In women with PCOS, the supra-physiological doses of gonadotrophins used for controlled ovarian hyperstimulation (COH) often result in an exaggerated ovarian response, characterised by the development of a large cohort of follicles of uneven quality, retrieval of immature oocytes, and increased risk of ovarian hyperstimulation syndrome (OHSS). A potentially effective intervention for women with PCOS-related subfertility involves earlier retrieval of immature oocytes at the germinal-vesicle stage followed by in vitro maturation (IVM). So far, the only data available have derived from observational studies and non-randomised clinical trials. OBJECTIVES: To assess the effectiveness and safety of IVM followed by IVF or ICSI versus conventional IVF or ICSI among women with PCOS undergoing assisted reproduction. SEARCH METHODS: This is the second update of this review. We performed the search on 17 April 2018.The search was designed with the help of the Cochrane Gynaecology and Fertility Group Information Specialist, for all published and unpublished randomised controlled trials (RCTs).We searched the the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL via the Cochrane Central Register of Studies Online, MEDLINE, Embase, CINAHL, and the trial registers for ongoing and registered trials and the Open Grey database for grey literature from Europe. We made further searches in the National Institute for Health and Care Excellence (NICE) fertility assessment and treatment guidelines. We handsearched reference lists of relevant systematic reviews and RCTs, together with PubMed and Google for any recent trials that have not yet been indexed in the major databases. SELECTION CRITERIA: All RCTs on the intention to perform IVM before IVF or ICSI compared with conventional IVF or ICSI for subfertile women with PCOS, irrespective of language and country of origin. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, extracted data from studies, and attempted to contact the authors of studies for which data were missing. Our primary outcomes were live birth per woman randomised and miscarriage. We performed statistical analysis using Review Manager 5. We assessed evidence quality using GRADE methods. MAIN RESULTS: We found two RCTs suitable for inclusion in the review and six ongoing trials that have not yet reported results. Both included studies were published as abstracts in international conferences.Both studies were at unclear or high risk of bias for most of the seven domains assessed. Common problems were unclear reporting of study methods and lack of blinding. The main limitations in the overall quality of the evidence were high risk of bias and serious imprecision.There were no data on the primary outcomes of this review, namely live birth per woman randomised and miscarriage.Both studies reported clinical pregnancy rate: there was evidence of an effect between IVM and IVF, favouring the former (odds ratio 3.10, 95% confidence interval 1.06 to 9.00; 71 participants; 2 studies; I2 = 0%; very low-quality evidence). The incidence of OHSS was zero in both studies in both groups.There were no data for the other outcomes specified in this review. AUTHORS' CONCLUSIONS: Though promising data on the in vitro maturation (IVM) technique have been published, unfortunately there is still no evidence from properly conducted randomised controlled trials upon which to base any practice recommendations regarding IVM before in vitro fertilisation (IVF) or intracytoplasmic sperm injection for women with polycystic ovarian syndrome. Regarding our secondary outcomes, very low-quality evidence showed that clinical pregnancy was higher with IVM when compared to IVF, whereas the incidence of ovarian hyperstimulation syndrome was zero in both studies in both groups. We are awaiting the results of six ongoing trials and eagerly anticipate further evidence from good-quality trials in the field.

Metabolomics for improving pregnancy outcomes in women undergoing assisted reproductive technologies.

BACKGROUND: In order to overcome the low effectiveness of assisted reproductive technologies (ART) and the high incidence of multiple births, metabolomics is proposed as a non-invasive method to assess oocyte quality, embryo viability, and endometrial receptivity, and facilitate a targeted subfertility treatment. OBJECTIVES: To evaluate the effectiveness and safety of metabolomic assessment of oocyte quality, embryo viability, and endometrial receptivity for improving live birth or ongoing pregnancy rates in women undergoing ART, compared to conventional methods of assessment. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, CINAHL and two trial registers (Feburary 2018). We also examined the reference lists of primary studies and review articles, citation lists of relevant publications, and abstracts of major scientific meetings. SELECTION CRITERIA: Randomised controlled trials (RCTs) on metabolomic assessment of oocyte quality, embryo viability, and endometrial receptivity in women undergoing ART. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently assessed trial eligibility and risk of bias, and extracted the data. The primary outcomes were rates of live birth or ongoing pregnancy (composite outcome) and miscarriage. Secondary outcomes were clinical pregnancy, multiple and ectopic pregnancy, cycle cancellation, and foetal abnormalities. We combined data to calculate odds ratios (ORs) for dichotomous data and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I² statistic. We assessed the overall quality of the evidence for the main comparisons using GRADE methods. MAIN RESULTS: We included four trials with a total of 924 women, with a mean age of 33 years. All assessed the role of metabolomic investigation of embryo viability. We found no RCTs that addressed the metabolomic assessment of oocyte quality or endometrial receptivity.We found low-quality evidence of little or no difference between metabolomic and non-metabolomic assessment of embryos for rates of live birth or ongoing pregnancy (OR 1.02, 95% CI 0.77 to 1.35, I² = 0%; four RCTs; N = 924), live birth alone (OR 0.99, 95% CI 0.69 to 1.44, I² = 0%; three RCTs; N = 597), or miscarriage (OR 1.18, 95% CI 0.77 to 1.82; I² = 0%; three RCTs; N = 869). A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for live birth or ongoing pregnancy (OR 0.90, 95% CI 0.66 to 1.25, I² = 0%; two RCTs; N = 744). Our findings suggested that if the rate of live birth or ongoing pregnancy was 36% in the non-metabolomic group, it would be between 32% and 45% with the use of metabolomics.We found low-quality evidence of little or no difference between groups in rates of clinical pregnancy (OR 1.11, 95% CI 0.85 to 1.45; I²= 44%; four trials; N = 924) or multiple pregnancy (OR 1.50, 95% CI 0.70 to 3.19; I² = 0%; two RCTs, N = 180). Rates of cycle cancellation were higher in the metabolomics group (OR 1.78, 95% CI 1.18 to 2.69; I² = 51%; two RCTs; N = 744, low quality evidence). There was very low-quality evidence of little or no difference between groups in rates of ectopic pregnancy rates (OR 3.00, 95% CI 0.12 to 74.07; one RCT; N = 417), and foetal abnormality (no events; one RCT; N = 125). Data were lacking on other adverse effects. A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for clinical pregnancy (OR 1.03, 95% CI 0.76 to 1.38; I² = 40%; two RCTs; N = 744).The overall quality of the evidence ranged from very low to low. Limitations included serious risk of bias (associated with poor reporting of methods, attrition bias, selective reporting, and other biases), imprecision, and inconsistency across trials. AUTHORS' CONCLUSIONS: According to current trials in women undergoing ART, there is no evidence to show that metabolomic assessment of embryos before implantation has any meaningful effect on rates of live birth, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy or foetal abnormalities. The existing evidence varied from very low to low-quality. Data on other adverse events were sparse, so we could not reach conclusions on these. At the moment, there is no evidence to support or refute the use of this technique for subfertile women undergoing ART. Robust evidence is needed from further RCTs, which study the effects on live birth and miscarriage rates for the metabolomic assessment of embryo viability. Well designed and executed trials are also needed to study the effects on oocyte quality and endometrial receptivity, since none are currently available.

Administration of prednisolone and low molecular weight heparin in patients with repeated implantation failures: a cohort study.

Conflicting results exist for low molecular weight heparin (LMWH) and prednisolone when tested as separate adjuncts for the improvement of the clinical outcomes in patients with repeated implantation failures (RIF) undergoing IVF/ICSI treatment. Through a cohort study, we evaluated the combined effect of both drugs on pregnancy parameters in 115 women with RIF. Clinical pregnancy rate was the primary end point while the sample size was calculated through the results of a pilot study. Clinical and IVF cycle characteristics were also compared between the groups. Baseline and cycle characteristics were comparable between groups. Biochemical and clinical pregnancy rates were similar in both groups [23/57 (40.4%) vs. 14/58 (24.1%), and 17/57 (29.8%) vs. 11/58 (19%), p = .063, and .175, respectively]. Similarly, miscarriage rates were comparable between the groups (35.7% vs. 34.8%), as well as live birth rates [15/57 (26.3%) vs. 9/58 (15.5%), p = .154]. In conclusion, the administration of LMWH with prednizolone in subfertile women with RIF seems not to improve clinical pregnancy rates, but a full-scaled RCT would definitely be more accurate.

Administration of low-molecular-weight heparin in patients with two or more unsuccessful IVF/ICSI cycles: a multicenter cohort study.

To compare the effects of the administration of low-molecular-weight heparin (LMWH) in subfertile patients with two or more unsuccessful IVF/ICSI cycles. In this six-center two-arm retrospective cohort study, the study population (230 women) underwent a GnRH-antagonist protocol and was classified into two groups, according to the couse of LMWH or not. Groups were compared regarding the clinical and IVF/ICSI cycle characteristics and reproductive outcomes, whereas clinical pregnancy and miscarriage constituted the primary endpoints. Logistic regression analysis was performed to determine the potential predictors of clinical pregnancy, miscarriage and live birth rates using the Enter method. Baseline characteristics were comparable in the two groups. There was no statistically significant difference between the two study groups with regard neither to clinical pregnancy and miscarriage rates (33/133 vs. 20/97, p = .456 and 15/133 vs. 9/97, p = .624, respectively), nor to the secondary outcomes preset for this study (all p values >.05). Logistic regression revealed that age of the woman and ICSI and dose of gonadotrophins used were predictors of clinical pregnancy and live birth, respectively. In conclusion, there is no evidence to support the standard addition of LMWH in patients with two or more unsuccessful IVF/ICSI cycles.

Metabolomics for improving pregnancy outcomes in women undergoing assisted reproductive technologies.

BACKGROUND: In order to overcome the low effectiveness of assisted reproductive technologies (ART) and the high incidence of multiple births, metabolomics is proposed as a non-invasive method to assess oocyte quality, embryo viability, and endometrial receptivity, and facilitate a targeted subfertility treatment. OBJECTIVES: To evaluate the effectiveness and safety of metabolomic assessment of oocyte quality, embryo viability, and endometrial receptivity for improving live birth or ongoing pregnancy rates in women undergoing ART, compared to conventional methods of assessment. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, CINAHL and two trial registers (November 2016). We also examined the reference lists of primary studies and review articles, citation lists of relevant publications, and abstracts of major scientific meetings. SELECTION CRITERIA: Randomised controlled trials (RCTs) on metabolomic assessment of oocyte quality, embryo viability, and endometrial receptivity in women undergoing ART. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias, and extracted the data. The primary outcomes were rates of live birth or ongoing pregnancy (composite outcome) and miscarriage. Secondary outcomes were clinical pregnancy, multiple and ectopic pregnancy, cycle cancellation, and foetal abnormalities. We combined data to calculate odds ratios (ORs) for dichotomous data and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I² statistic. We assessed the overall quality of the evidence for the main comparisons using GRADE methods. MAIN RESULTS: We included four trials with a total of 802 women, with a mean age of 33 years. All assessed the role of metabolomic investigation of embryo viability. We found no RCTs that addressed the metabolomic assessment of oocyte quality or endometrial receptivity.We found low-quality evidence of little or no difference between metabolomic and non-metabolomic assessment of embryos for rates of live birth or ongoing pregnancy (OR 1.11, 95% CI 0.83 to 1.48; I² = 0%; four RCTs; N = 802), or miscarriage (OR 0.96, 95% CI 0.52 to 1.78; I² = 0%; two RCTs; N = 434). A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for live birth or ongoing pregnancy (OR 0.99, 95% CI 0.71 to 1.38; I² = 0%; two RCTs; N = 621). Our findings suggested that if the rate of live birth or ongoing pregnancy was 36% in the non-metabolomic group, it would be between 32% and 45% with the use of metabolomics.We found low-quality evidence of little or no difference between groups in rates of clinical pregnancy (OR 1.22, 95% CI 0.92 to 1.62; I²= 26%; four trials; N = 802), or multiple pregnancy (OR 1.52, 95% CI 0.71 to 3.23; I² = 0%; two RCTs, N = 181). There was very low-quality evidence of little or no difference between groups in ectopic pregnancy rates (OR 3.37, 95% CI 0.14 to 83.40; one RCT; N = 309), and foetal abnormalities (no events; one RCT; N = 125), and very low-quality evidence of higher rates of cycle cancellation in the metabolomics group (OR 1.78, 95% CI 1.18 to 2.69; I² = 51%; two RCTs; N = 744). Data were lacking on other adverse effects. A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for clinical pregnancy (OR 1.14, 95% CI 0.83 to 1.57; I² = 0%; two RCTs; N = 621).The overall quality of the evidence ranged from very low to low. Limitations included serious risk of bias (associated with poor reporting of methods, attrition bias, selective reporting, and other biases), imprecision, and inconsistency across trials. AUTHORS' CONCLUSIONS: According to current trials in women undergoing ART, there is insufficient evidence to show that metabolomic assessment of embryos before implantation has any meaningful effect on rates of live birth, ongoing pregnancy, or miscarriage rates. The existing evidence varied from very low to low-quality. Data on adverse events were sparse, so we could not reach conclusions on these. At the moment, there is no evidence to support or refute the use of this technique for subfertile women undergoing ART. Robust evidence is needed from further RCTs, which study the effects on live birth and miscarriage rates for the metabolomic assessment of embryo viability. Well designed and executed trials are also needed to study the effects on oocyte quality and endometrial receptivity, since none are currently available.

Risk of endometrial cancer in women treated with ovary-stimulating drugs for subfertility.

BACKGROUND: Medical treatment for subfertility principally involves the use of ovary-stimulating agents, including selective oestrogen receptor modulators (SERMs), such as clomiphene citrate, gonadotropins, gonadotropin-releasing hormone (GnRH) agonists and antagonists, as well as human chorionic gonadotropin. Ovary-stimulating drugs may act directly or indirectly upon the endometrium (lining of the womb). Nulliparity and some causes of subfertility are recognized as risk factors for endometrial cancer. OBJECTIVES: To evaluate the association between the use of ovary-stimulating drugs for the treatment of subfertility and the risk of endometrial cancer. SEARCH METHODS: A search was performed in CENTRAL, MEDLINE (Ovid) and Embase (Ovid) databases up to July 2016, using a predefined search algorithm. A search in OpenGrey, ProQuest, ClinicalTrials.gov, ZETOC and reports of major conferences was also performed. We did not impose language and publication status restrictions. SELECTION CRITERIA: Cohort and case-control studies reporting on the association between endometrial cancer and exposure to ovary-stimulating drugs for subfertility in adult women were deemed eligible. DATA COLLECTION AND ANALYSIS: Study characteristics and findings were extracted by review authors independently working in pairs. Inconsistency between studies was quantified by estimating I2. Random-effects (RE) models were used to calculate pooled effect estimates. Separate analyses were performed, comparing treated subfertile women versus general population and/or unexposed subfertile women, to address the superimposition of subfertility as an independent risk factor for endometrial cancer. MAIN RESULTS: Nineteen studies were eligible for inclusion (1,937,880 participants). Overall, the quality of evidence was very low, due to serious risk of bias and indirectness (non-randomised studies (NRS), which was reflected on the GRADE assessment.Six eligible studies, including subfertile women, without a general population control group, found that exposure to any ovary-stimulating drug was not associated with an increased risk of endometrial cancer (RR 0.96, 95% CI 0.67 to 1.37; 156,774 participants; very low quality evidence). Fifteen eligible studies, using a general population as the control group, found an increased risk after exposure to any ovary-stimulating drug (RR 1.75, 95% CI 1.18 to 2.61; 1,762,829 participants; very low quality evidence).Five eligible studies, confined to subfertile women (92,849 participants), reported on exposure to clomiphene citrate; the pooled studies indicated a positive association ( RR 1.32; 95% CI 1.01 to 1.71; 88,618 participants; very low quality evidence), although only at high dosage (RR 1.69, 95% CI 1.07 to 2.68; two studies; 12,073 participants) and at a high number of cycles (RR 1.69, 95% CI 1.16 to 2.47; three studies; 13,757 participants). Four studies found an increased risk of endometrial cancer in subfertile women who required clomiphene citrate compared to a general population control group (RR 1.87, 95% CI 1.00 to 3.48; four studies, 19,614 participants; very low quality evidence). These data do not tell us whether the association is due to the underlying conditions requiring clomiphene or the treatment itself.Using unexposed subfertile women as controls, exposure to gonadotropins was associated with an increased risk of endometrial cancer (RR 1.55, 95% CI 1.03 to 2.34; four studies; 17,769 participants; very low quality evidence). The respective analysis of two studies (1595 participants) versus the general population found no difference in risk (RR 2.12, 95% CI 0.79 to 5.64: very low quality evidence).Exposure to a combination of clomiphene citrate and gonadotropins, compared to unexposed subfertile women, produced no difference in risk of endometrial cancer (RR 1.18, 95% CI 0.57 to 2.44; two studies; 6345 participants; very low quality evidence). However, when compared to the general population, an increased risk was found , suggesting that the key factor might be subfertility, rather than treatment (RR 2.99, 95% CI 1.53 to 5.86; three studies; 7789 participants; very low quality evidence). AUTHORS' CONCLUSIONS: The synthesis of the currently available evidence does not allow us to draw robust conclusions, due to the very low quality of evidence. It seems that exposure to clomiphene citrate as an ovary-stimulating drug in subfertile women is associated with increased risk of endometrial cancer, especially at doses greater than 2000 mg and high (more than 7) number of cycles. This may largely be due to underlying risk factors in women who need treatment with clomiphene citrate, such as polycystic ovary syndrome, rather than exposure to the drug itself. The evidence regarding exposure to gonadotropins was inconclusive.

Corifollitropin alfa compared with follitropin beta in GnRH-antagonist ovarian stimulation protocols in an unselected population undergoing IVF/ICSI.

Recombinant DNA technologies have produced Corifollitropin alfa (CFa) used during IVF/ICSI in order to keep the circulating FSH levels above the threshold necessary to support multi-follicular growth for a week. In this prospective case-control study, we compared 70 participants treated with 150 µg CFa combined with 150 IU of follitropin beta (study group) with 70 subfertile participants with matching baseline characteristics, conforming with the same inclusion criteria and treated with an antagonist protocol using follitropin beta (control group). Live birth was the primary outcome, while secondary outcome measures were IVF/ICSI cycles characteristics, including adverse events and complications. Live birth was determined in reduced rates in the study compared to the control group, reaching statistical significance [6/70 versus 20/70, p = 0.002], as also in the respective number of clinical pregnancies [9/70 versus 23/70, p = 0.005], although the incidence of miscarriage was similar for both groups [6/70 versus 5/70, p > 0.99]. Most of the secondary parameters examined were similar between groups. Logistic regression revealed that protocol and AFC had a direct impact on live birth. Ovarian stimulation with CFa does not seem to constitute an equally effective method as compared with follitropin beta to be offered in a general subfertile population seeking IVF/ICSI treatments.