Higher Probability Of Live Birth Research Articles

A heatmap for expected cumulative live birth rate in preimplantation genetic testing for monogenic disorders and chromosomal structural rearrangements

PurposeOur objective is to predict the cumulative live birth rate (CLBR) and identify the specific subset within the population undergoing preimplantation genetic testing for monogenic disorders (PGT-M) and chromosomal structural rearrangements (PGT-SR) which is likely to exhibit a diminished expected CLBR based on various patient demographics.MethodsWe performed a single-centre retrospective cohort study including 1522 women undergoing 3130 PGT cycles at a referral centre for PGT. A logistic regression analysis was performed to predict the CLBR per ovarian stimulation in women undergoing PGT-M by polymerase chain reaction (PCR) or single-nucleotide polymorphism (SNP) array, and in women undergoing PGT-SR by SNP array, array comparative genomic hybridization (CGH) or next-generation sequencing (NGS).ResultsThe mean age of women was 32.6 years, with a mean AMH of 2.75 µg/L. Female age and AMH significantly affected the expected CLBR irrespective of the inheritance mode or PGT technology. An expected CLBR < 10% was reached above the age of 42 years and AMH ≤ 1.25 µg/L. We found no significant difference in outcome per ovarian stimulation between the different PGT technologies, i.e. PCR, SNP array, array CGH and NGS. Whereas per embryo transfer, we noticed a significantly higher probability of live birth when SNP array, array CGH and NGS were used as compared to PCR.ConclusionIn a PGT-setting, couples with an unfavourable female age and AMH should be informed of the prognosis to allow other reproductive choices. The heatmap produced in this study can be used as a visual tool for PGT couples.

The role of endometrial scratching prior to in vitro fertilization: an updated systematic review and meta-analysis

Research questionTo evaluate the role of endometrial scratching performed prior to an embryo transfer cycle on the probability of pregnancy compared to placebo/sham or no intervention.DesignA computerized literature (using a specific search strategy) search was performed across the databases MEDLINE, EMBASE, COCHRANE CENTRAL, SCOPUS and WEB OF SCIENCE up to June 2023 in order to identify randomized controlled trials (RCTs) evaluating the effect of endometrial scratching prior to an embryo transfer cycle on the probability of pregnancy, expressed either as live birth, ongoing pregnancy or clinical pregnancy (in order of significance) compared to placebo/sham or no intervention. Data were pooled using random-effects or fixed-effects model, depending on the presence or not of heterogeneity. Heterogeneity was assessed using the I2 statistic. Subgroup analyses were performed based on the population studied in each RCT, as well as on the timing and method of endometrial biopsy. Certainty of evidence was assessed using the GRADEPro tool.ResultsThe probability of live birth was significantly higher in embryo transfer cycles after endometrial scratching as compared to placebo/sham or no intervention (relative risk-RR: 1.12, 95% CI: 1.05–1.20; heterogeneity: I2=46.30%, p<0.001, 28 studies; low certainty). The probability of ongoing pregnancy was not significantly difference between the two groups (RR: 1.07, 95% CI: 0.98–1.18; heterogeneity: I2=27.44%, p=0.15, 11 studies; low certainty). The probability of clinical pregnancy was significantly higher in embryo transfer cycles after endometrial scratching as compared to placebo/sham or no intervention (RR: 1.12, 95% CI: 1.06–1.18; heterogeneity: I2=47.48%, p<0.001, 37 studies; low certainty).A subgroup analysis was performed based on the time that endometrial scratching was carried out. When endometrial scratching was performed during the menstrual cycle prior to the embryo transfer cycle a significantly higher probability of live birth was present (RR: 1.18, 95% CI:1.09-1.27; heterogeneity: I2=39.72%, p<0.001, 21 studies; moderate certainty). On the contrary, no effect on the probability of live birth was present when endometrial injury was performed during the embryo transfer cycle (RR: 0.87, 95% CI: 0.67-1.15; heterogeneity: I2=65.18%, p=0.33, 5 studies; low certainty).In addition, a higher probability of live birth was only present in women with previous IVF failures (RR: 1.35, 95% CI: 1.20-1.53; heterogeneity: I2=0%, p<0.001, 13 studies; moderate certainty) with evidence suggesting that the more IVF failures the more likely endometrial scratching to be beneficial (p=0.004). The number of times endometrial scratching was performed, as well as the type of instrument used did not appear to affect the probability of live birth.ConclusionsEndometrial scratching during the menstrual cycle prior to an embryo transfer cycle can lead to a higher probability of live birth in patients with previous IVF failures.PROSPERO registrationPROSPERO CRD42023433538 (18 Jun 2023)

Phytoestrogens Present in Follicular Fluid and Urine Are Positively Associated with IVF Outcomes following Single Euploid Embryo Transfer

The impact and safety of phytoestrogens, plant-derived isoflavones with estrogenic activity predominantly present in soy, on female reproductive health and IVF outcomes continues to be hotly debated. In this prospective cohort study, 60 women attending IVI-RMA New Jersey undergoing IVF with single frozen embryo transfer (SET/FET) of good-quality euploid blastocyst after PGT-A analysis were recruited. Concentrations of two phytoestrogens (daidzein and genistein) in follicular fluid (FF) and urine (U) were measured by UPLC–MSMS, both collected on vaginal oocyte retrieval day. These measurements correlated with IVF clinical outcomes. In models adjusted for age, BMI, race/ethnicity, and smoking status, higher FF phytoestrogen concentrations were significantly associated with higher serum estradiol, enhanced probability of implantation, clinical pregnancy, and live birth. Moreover, higher urine phytoestrogen concentrations were significantly associated with improved oocyte maturation and fertilization potential and increased probability of clinical pregnancy and live birth. Finally, higher FF and urine phytoestrogen concentrations were associated with a higher probability of live birth from a given IVF cycle. Our results suggest that dietary phytoestrogens improved reproductive outcomes of women undergoing IVF treatment. However, additional prospective studies are needed to optimize the use of phytoestrogens to further enhance reproductive outcomes and/or protect against reproductive insults.

Is Frozen Embryo Transfer the New Norm in IVF?

Frozen embryo transfer is an established, highly successful technology in Assisted Reproductive Technologies. Its use as a part of a freeze only strategy is associated with a higher probability of live birth in high responders and a decrease incidence of ovarian hyperstimulation syndrome (OHSS). Its use in normal responders, maintains the probability of live birth compared to fresh embryo transfer and decreases the incidence of OHSS. Obstetric n neonatal outcomes in frozen as compared to fresh embryo transfer cycles are characterized by a decreased incidence of monozygotic twinning, of ectopic pregnancy, of small for gestational age babies, of premature labour, of antepartum hemorrhage and of perinatal mortality. On the other hand, an increased incidence of pregnancy induced hypertension, has been observed in frozen as compared to fresh embryo transfer cycles. This, however, appears to be associated with the absence of corpus luteum during endometrium preparation for embryo transfer, as is the case in frozen embryo transfer cycles using hormonal replacement. Overall, the increased efficacy and a safety present, if fresh embryo transfer following ovarian stimulation is avoided, redefine what should be the norm in modern in-vitro fertilization practice.

O-127 Higher probability of live birth after testosterone pretreatment in women with poor ovarian response undergoing IVF: a systematic review and meta-analysis

Abstract Study question Does testosterone pretreatment increase the probability of pregnancy in poor responders undergoing ovarian stimulation with gonadotrophin-releasing hormone (GnRH) analogues and gonadotrophins for in-vitro fertilization (IVF)? Summary answer Testosterone pretreatment increases clinical pregnancy and live birth rates in poor responders undergoing ovarian stimulation for IVF. What is known already Androgens have been shown to stimulate early stages of follicular growth, increase the number of primary, pre-antral and antral follicles as well as increase ovarian sensitivity to follicle stimulating hormone (FSH). Although androgen supplementation has been evaluated in several randomized controlled trials (RCTs) and meta-analyzed in six systematic reviews until today currently no solid conclusions can be drawn regarding its effectiveness. Study design, size, duration A literature search was performed until September 2021 aiming to identify RCTs evaluating testosterone pretreatment in poor responders. Outcome measures included achievement of pregnancy, total dose of gonadotrophins required, duration of stimulation, estradiol levels, endometrial thickness and number of follicles ≥17 mm on the day of triggering final oocyte maturation, number of cumulus–oocyte complexes (COCs) retrieved, embryos transferred, metaphase II (MII) and 2-pronuclei oocytes (2pn) and the proportion of patients having an embryo transfer (ET). Participants/materials, setting, methods Eight RCTs published between 2006 and 2021 were analyzed, including 760 women. Pretreatment with transdermal testosterone gel was performed in all studies with a dose ranging from 10 to 12.5 mg/day for 10 to 56 days. In dichotomous data, estimates were expressed as risk ratio (RR) with 95% confidence intervals (CIs), using the fixed or random effects method. In continuous data, differences were pooled across resulting in a weighted mean difference (WMD) with 95% CI. Main results and the role of chance Testosterone pretreatment was associated with a significantly higher live birth (RR: 2.07, 95%CI: 1.09 to 3.92) and clinical pregnancy rate (RR: 2.25, 95%CI: 1.54) in women with POR undergoing IVF, while there was also a significant increase in the number of COCs retrieved (WMD: +0.88, 95% CI: +0.22 to + 1.54). Significantly less days to complete ovarian stimulation (WMD: -0.81 days, 95% CI: -1.46 to −0.16), a lower total dose of gonadotrophins (WMD: -368.8 IUs, 95% CI: −612.4 to -125.2), a thicker endometrium on the day of triggering final oocyte maturation (WMD: +0.83 mm, 95% CI: +0.13 to + 1.53) and a lower cancellation rate due to poor ovarian response (RR: 0.37, 95%CI: 0.20 to 0.71) were observed. No significant differences were observed in estradiol levels (WMD: -8.12 pg/mL, 95% CI: -118.2 to + 101.96), in the numbers of follicles ≥17 mm on the day of triggering final oocyte maturation (WMD: +0.82, 95%CI: -0.11 to + 1.74), of MII oocytes (WMD: +0.50, 95% CI: -0.17 to + 1.17), of 2pn oocytes (WMD: +0.49, 95% CI: -0.11 to + 1.10), of embryos transferred (WMD: +0.21, 95%CI: -0.07 to + 0.49) and in the proportion of patients with ET (RR: 1.00, 95% CI: 0.96 to 1.04). Limitations, reasons for caution The definition of poor ovarian response varied among studies and a considerable heterogeneity regarding the type, dose and duration of testosterone pretreatment was present. Although the present study is currently the largest meta-analysis evaluating testosterone pretreatment, the total number of patients is still not large enough to draw solid conclusions. Wider implications of the findings The current study suggests that the probability of pregnancy is increased in poor responders pretreated with transdermal testosterone. This increase, in the absence of other proven beneficial interventions in these patients, justifies the conduction of further relevant RCTs. Trial registration number CRD42021262098

Progestin-Primed Ovarian Stimulation Protocol for Patients With Endometrioma.

ObjectiveTo evaluate the pregnancy outcomes of progestin-primed ovarian stimulation (PPOS) protocol for patients with endometrioma underwent in vitro fertilization/intra-cytoplasmic sperm injection embryo transfer (IVF/ICSI-ET).DesignObservational retrospective cohort study.SettingUniversity affiliated reproductive center.Study Participants605 infertile patients with endometrioma underwent IVF/ICSI-ET from January 2016 to March 2021 were included in this study.MethodsMultivariable logistic regression analyses were conducted to determine the independent effect of controlled ovarian stimulation (COS) protocols on reproductive outcomes of first embryo transfer (ET) cycles. The live birth was primary outcome, the implantation rate, biochemical pregnancy, clinical pregnancy and ongoing pregnancy were secondary outcomes.ResultsCompared to PPOS protocol, the probability of implantation showed no significant difference with ultra-long gonadotrophin-releasing hormone agonist (GnRHa) protocol and gonadotrophin-releasing hormone antagonist (GnRHant) protocol (OR 1.7, 95% CI 0.9-3.1, OR 1.2, 95% CI 0.7-2.1, respectively). The PPOS protocol was correlated with a significantly lower biochemical pregnancy and clinical pregnancy than ultra-long GnRHa protocol in the multivariable logistic regression analysis (OR 2.3, 95% CI 1.1-4.9, OR 2.4, 95% CI 1.1-5.3, respectively). However, there was no significant difference in terms of biochemical pregnancy, clinical pregnancy and ongoing pregnancy between PPOS and GnRHant protocol (OR 1.4, 95% CI 0.7-2.7, OR 1.3, 95% CI 0.7-2.4, OR 1.1, 95% CI 0.6-2.3, respectively). In addition, compared to PPOS protocol, ultra-long GnRHa protocol and GnRHant protocol demonstrated no statistical difference in ongoing pregnancy (OR 2.0, 95% CI 0.9-4.5, OR 2.1, 95% CI 0.6-2.3, respectively). Notably, the ultra-long GnRHa protocol was associated with a significant higher probability of live birth than PPOS protocol both in crude analysis and multivariable logistic regression analysis (OR 2.6, 95% CI 1.3-5.1, OR 2.5, 95% CI 1.1-5.7, respectively). Nevertheless, no statistical difference was found in live birth between PPOS and GnRHant protocol either in crude analysis and multivariable logistic regression analysis (OR1.2, 95% CI 0.6-2.3, OR 1.2, 95% CI 0.6-2.5, respectively).ConclusionsBased on the reproductive outcomes of the first ET cycles in patients with endometrioma, PPOS protocol may associated with inferior reproductive outcomes in terms of biochemical pregnancy, clinical pregnancy and live birth than ultra-long GnRHa protocol. However, there was no significant difference in implantation rate, clinical pregnancy, ongoing pregnancy and live birth between PPOS and GnRHant protocol.

POSC152 Cost-Effectiveness Analysis of Follitropin ALFA Product (GONAL-F) Compared to Its Biosimilars Based on Meta-Analysis of Randomized Controlled Trials

A recent meta-analysis based on data from Randomized Controlled Trails (RCTs) demonstrated higher probability of live birth (LB) and pregnancy (ongoing) in couples treated with the reference follitropin alfa product (GONAL-f) compared with biosimilar follitropin alfa preparations (Chua et al, 2021). It is not known to which extent this better clinical outcome is associated with improved cost-effectiveness. The objective of this study is to perform a Cost-Effectiveness Analysis (CEA), using clinical outcomes from the published meta-analysis.

The effects of oocyte donor and recipient body mass index on live birth rates and pregnancy outcomes following assisted reproduction

ObjectiveTo investigate the effects of oocyte donor and recipient body mass index (BMI) on outcomes of vitrified donor oocyte assisted reproductive technology (ART).DesignRetrospective cohort study.SettingPrivate fertility center.Patient(s)A total of 338 oocyte donors and 932 recipients who underwent 1,651 embryo transfer cycles in 2008–2015.Intervention(s)Multivariable log binomial regression models with cluster-weighted generalized estimating equations were used to estimate the adjusted risk ratios.Main Outcome Measure(s)Live birth, defined as the delivery of at least one live-born infant, including all embryo transfer cycles. Secondary outcomes included birth weight and gestational length only among singleton live births.ResultsThe mean ± SD body mass indexes (BMIs) of donors and recipients were 22.6 ± 2.5 kg/m2 and 24.6 ± 4.8 kg/m2, respectively. There were no significant associations between donor BMI and probability of live birth. Recipients with BMI ≥35 kg/m2 had a significantly higher probability of live birth compared with normal-weight recipients. Among singleton live births, recipients with BMI <18.5 kg/m2 had a lower risk whereas women with BMI ≥35 kg/m2 had a higher risk of delivery in an earlier gestational week compared with normal weight women. Recipients with a BMI ≥35 kg/m2 also had a higher risk of having a low birth weight infant compared with normal-weight women.ConclusionsIn the setting of vitrified donor oocyte ART, recipient BMI was positively associated with probability of live birth but negatively associated with gestational length and birth weight among singleton births.

The effect of donor and recipient race on outcomes of assisted reproduction

A growing literature suggests that minority races, particularly Black women, have a lower probability of live birth and higher risk of perinatal complications after autologous assisted reproductive technology. However, questions still remain as to whether these racial disparities have arisen because of associations between race and oocyte/embryo quality, the uterine environment, or a combination of the two. Oocyte donation assisted reproductive technology represents a unique approach to examine this question. This study aimed to evaluate the associations between the race of female oocyte donors and recipients and live birth rates following vitrified donor oocyte assisted reproductive technologies. This was a retrospective study conducted at a single, private fertility clinic that included 327 oocyte donors and 899 recipients who underwent 1601 embryo transfer cycles (2008-2015). Self-reported race of the donor and recipient were abstracted from medical records. Live birth was defined as the delivery of at least 1 live-born neonate. We used multivariable cluster weighted generalized estimating equations with binomial distribution and log link function to estimate the adjusted risk ratios of live birth, adjusting for donor age and body mass index, recipient age and body mass index, tubal and uterine factor infertility, and year of oocyte retrieval. The racial profile of our donors and recipients were similar: 73% white, 13% Black, 4% Hispanic, 8% Asian, and 2% other. Women who received oocytes from Hispanic donors had a significantly higher probability of live birth (adjusted risk ratio, 1.20; 95% confidence interval, 1.05-1.36) than women who received oocytes from white donors. Among Hispanic recipients, however, there was no significant difference in probability of live birth compared with white recipients (adjusted risk ratio, 1.07; 95% confidence interval, 0.90-1.26). Embryo transfer cycles using oocytes from Black donors (adjusted risk ratio, 0.86; 95% confidence interval, 0.72-1.03) and Black recipients (adjusted risk ratio, 0.84; 95% confidence interval, 0.71-0.99) had a lower probability of live birth than white donors and white recipients, respectively. There were no significant differences in the probability of live birth among Hispanic, Asian, and other race recipients compared with white recipients. Black female recipients had a lower probability of live birth following assisted reproductive technology, even when using vitrified oocytes from healthy donors. Female recipients who used vitrified oocytes from Hispanic donors had a higher probability of live birth regardless of their own race.

Associations Between Preconception Plasma Fatty Acids and Pregnancy Outcomes.

Although fatty acids are involved in critical reproductive processes, the relationship between specific fatty acids and fertility is uncertain. We investigated the relationship between preconception plasma fatty acids and pregnancy outcomes. We included 1,228 women attempting pregnancy with one to two previous pregnancy losses from the EAGeR trial (2007-2011). Plasma fatty acids were measured at baseline. We used log-binomial regression to assess associations between fatty acids and pregnancy, pregnancy loss, and live birth, adjusting for age, race, smoking, BMI, physical activity, income, parity, treatment arm, and cholesterol. Although total saturated fatty acids (SFAs) were not associated with pregnancy outcomes, 14:0 (myristic acid; relative risk [RR] = 1.10, 95% confidence interval [CI] = 1.02, 1.19, per 0.1% increase) and 20:0 (arachidic acid; RR = 1.05, 95% CI = 1.01, 1.08, per 0.1% increase) were positively associated with live birth. Findings suggested a positive association between total monounsaturated fatty acids (MUFAs) and pregnancy and live birth and an inverse association with loss. Total polyunsaturated fatty acids (PUFAs) were associated with lower probability of pregnancy (RR = 0.97, 95% CI = 0.95, 1.00) and live birth (RR = 0.96, 95% CI = 0.94, 0.99), and increased risk of loss (RR = 1.10, 95% CI = 1.00, 1.20), per 1% increase. Trans fatty acids and n-3 fatty acids were not associated with pregnancy outcomes. Preconception total plasma MUFAs were positively associated with pregnancy and live birth. PUFAs were inversely associated with pregnancy outcomes. Specific SFAs were associated with a higher probability of live birth. Our results suggest that fatty acids may influence pregnancy outcomes.

The Deferred Embryo Transfer Strategy Seems Not to be a Good Option After Repeated IVF/ICSI Cycle Failures

The aim of this study was to assess whether a deferred frozen-thawed embryo transfer (Def-ET) offers any benefits compared to a fresh ET strategy in women who have had 2 or more consecutive in vitro fertilization (IVF)/intracytoplasmic injection (ICSI) cycle failures. An observational cohort study in a tertiary referral care center including 416 cycles from women with a previous history of 2 or more consecutive IVF/ICSI failures cycles. Both Def-ET and fresh ET strategies were compared using univariate and multivariate logistic regression models. The main outcome measured was the cumulative live birth rate (CLBR). A total of 416 cycles were included in the analysis: 197 in the fresh ET group and 219 in the Def-ET group. The CLBR was not significantly different between the fresh and Def-ET groups (58/197 [29.4%] and 57/219 [26.0%], respectively, P = .437). In addition, after the first ET, there was no significant difference in the live birth rate between the fresh ET and Def-ET groups (50/197 [25.4%] vs 44/219 [20.1%], respectively). Multivariate logistic regression analysis indicated that compared to the fresh strategy, the Def-ET strategy was not associated with a higher probability of live birth. In cases with 2 or more consecutive prior IVF/ICSI cycle failures, a Def-ET strategy did not result in better ART outcomes than a fresh ET strategy.

Dietary patterns and outcomes of assisted reproduction

There is growing acceptance that nutrition may be related to fertility and specifically to assisted reproductive technologies success in women; however, there is still no specific dietary guidance. The objective of the study was to evaluate the relationship between pretreatment adherence to various dietary patterns and outcomes of assisted reproductive technologies. We followed up 357 women enrolled in the prospective Environment and Reproductive Health (EARTH) study, who underwent 608 assisted reproductive technologies cycles (2007-2017). Using a validated food frequency questionnaire completed prior to treatment, we assessed adherence to the Mediterranean diet, the alternate Healthy Eating Index 2010, the Fertility Diet (developed based on risk factors for anovulatory infertility), and a profertility diet we developed based on factors previously related to assisted reproductive technologies outcomes (higher intake of supplemental folic acid, vitamin B12, vitamin D, low- rather than high-pesticide residue produce, whole grains, dairy, soy foods, and seafood rather than other meats). Higher adherence to the alternate Healthy Eating Index 2010 and Fertility Diet was not related to live birth following assisted reproductive technologies. Women in the second through the fourth quartiles of Mediterranean diet adherence had significantly higher probability of live birth (0.44, 95% confidence interval, 0.39-0.49) compared with women in the first quartile (0.31, 95% confidence interval, 0.25-0.39); however, there was no additional benefit of adherence to the Mediterranean diet above the second quartile. Increased adherence to the profertility diet was linearly associated with assisted reproductive technologies outcomes. The adjusted odds (95% confidence interval) of implantation, clinical pregnancy, and live birth were higher by 47% (21%, 77%), 43% (19%, 72%), and 53% (26%, 85%), respectively, per SD increase. The adjusted difference in the proportion of cycles resulting in live birth for women in the fourth vs first quartile of adherence to the profertility diet was 0.28 (95% confidence interval, 0.16-0.38). While the profertility diet was not related to estradiol levels, oocyte counts, or endometrial thickness, it was inversely associated with clinical pregnancy loss (odds ratio, 0.69, 95% confidence interval, 0.53-0.90 per SD increase). Higher pretreatment adherence to the profertility diet was associated with an increased probability of live birth among women undergoing assisted reproductive technologies. Commonly recommended dietary advice such as adhering to the Mediterranean diet may not provide the most appropriate guidance for women undergoing infertility treatment in the United States.

Higher probability of live-birth in high, but not normal, responders after first frozen-embryo transfer in a freeze-only cycle strategy compared to fresh-embryo transfer: a meta-analysis.

Does the outcome of the comparison of live birth rates between the first frozen embryo transfer (ET) (in a freeze-only cycles strategy, i.e. frozen ET group) and a fresh embryo transfer (fresh ET group) differ considering the type of ovarian response? Α significantly higher probability of live birth is present in high, but not normal, responders, after the first frozen ET in a freeze-only cycle strategy as compared to a fresh ET. It has been hypothesised that freezing all good embryos in a fresh in-vitro fertilisation (IVF) cycle and deferring embryo transfer in subsequent cycles may provide a more physiological endometrial environment for embryo implantation when compared to a fresh ET. However, currently, three relevant meta-analyses have been published with conflicting results, while none of them has taken into consideration the type of ovarian response. Recently, the publication of additional, large relevant randomised controlled trials (RCTs) in patients with different types of ovarian response makes possible the comparative evaluation of the first frozen ET (in a freeze-only cycle strategy) versus fresh ET, considering the type of ovarian response. A systematic review and meta-analysis was performed aiming to identify RCTs comparing the first frozen ET (in a freeze-only cycle strategy) to a fresh ET. The main outcome was live birth, while secondary outcomes included ongoing pregnancy, clinical pregnancy, moderate/severe ovarian hyperstimulation syndrome (OHSS) and miscarriage. We identified eight eligible RCTs, including 5265 patients, which evaluated the first frozen ET in a freeze-only cycle strategy versus a fresh ET either in high responders (n = 4) or in normal responders (n = 4). No relevant RCTs were present in poor responders. Meta-analysis of weighted data using fixed and random effects model was performed. Results are reported as relative risk (RR) with 95% confidence interval (CI). Eligible RCTs were published between 2011 and 2018. Four RCTs (n = 3255 patients) compared the first frozen ET (in a freeze-only cycle strategy) to a fresh ET in normal responders and four RCTs (n = 2010 patients) did the comparison in high responders. In high responders, a significantly higher probability of live birth was observed in the frozen ET group when compared with the fresh ET group (RR: 1.18, 95% CI: 1.06-1.31; fixed effects model; heterogeneity: I2 = 0%; three studies; n = 3398 patients). However the probability of live birth was not significantly different between the frozen ET group and the fresh ET group in normal responders (RR: 1.13, 95% CI: 0.90-1.41; random effects model; heterogeneity: I2 = 77%; three studies; n = 1608 patients). The risk of moderate/severe OHSS was significantly lower in the frozen ET group when compared with the fresh ET group both in high (RR: 0.19, 95% CI: 0.10-0.37; fixed effects model; heterogeneity: not applicable; a single study; n = 1508 patients) and normal responders (RR: 0.39, 95% CI: 0.19-0.80; fixed effects model; heterogeneity: I2 = 0%; two studies; n = 2939 patients). Considerable heterogeneity was present among the studies, regarding ovarian stimulation protocols and the triggering signal used for inducing final oocyte maturation as well as the cryopreservation methods, while the quality of evidence was poor for the live birth rate in high responders. Moreover, the analysis did not apply a standard for determining 'high' or 'normal' responders since the type of ovarian response followed the characterisation of populations as reported by the authors of the eligible studies. A freeze-only cycle strategy should be the preferred option in high responders since it enhances the probability of live birth, while reducing the chance of moderate/severe OHSS. In normal responders, the same strategy could be applied, in the interest of patient safety or clinic convenience, without compromising the chances of live birth. No external funding was used and there were no competing interests. PROSPERO registration number: CRD42018099389.

Intake of protein-rich foods in relation to outcomes of infertility treatment with assisted reproductive technologies

Some dietary factors have been linked to outcomes of infertility treatment with assisted reproductive technology (ART), but the role of intake of meats and other protein-rich foods remains unclear. The aim of this manuscript was to study the relation between preconception intake of meat and other protein-rich foods and outcomes of infertility treatment with ART. A total of 351 women enrolled in a prospective cohort at the Massachusetts General Hospital Fertility Center and underwent 598 ART cycles for infertility treatment. Meat intake was assessed with a validated food-frequency questionnaire, and ART outcomes were abstracted from electronic medical records. We estimated the associations between intake of protein-rich foods (meats, eggs, beans, nuts, and soy) and the outcome of live birth per initiated cycle using generalized linear mixed models. The average total meat intake was 1.2 servings/d, with most coming from poultry (35%), fish (25%), processed meat (22%), and red meat (17%). Fish intake was positively related to the proportion of cycles resulting in live birth. The multivariable-adjusted probabilities of live birth for women in increasing quartiles of fish intake were 34.2% (95% CI: 26.5%, 42.9%), 38.4% (95% CI: 30.3%, 47.3%), 44.7% (95% CI: 36.3%, 53.4%), and 47.7% (95% CI: 38.3%, 57.3%), respectively (P-trend=0.04). In the estimated substitution analyses, the ORs of live birth associated with increasing fish intake by 2 servings/wk were 1.54 (95% CI: 1.14, 2.07) when fish replaced any other meat, 1.50 (95% CI: 1.13, 1.98) when fish replaced any other protein-rich food, and 1.64 (95% CI: 1.14, 2.35) when fish replaced processed meat. Fish consumption is related to a higher probability of live birth following infertility treatment with ART. This trial was registered at clinicaltrials.gov as NCT00011713.

Serum omega-3 fatty acids and treatment outcomes among women undergoing assisted reproduction.

Are serum polyunsaturated fatty acids (PUFA) concentrations, including omega-3 (ω3-PUFA) and omega-6 (ω6-PUFA), related to ART outcomes? Serum levels of long-chain ω3-PUFA were positively associated with probability of live birth among women undergoing ART. Intake of ω3-PUFA improves oocyte and embryo quality in animal and human studies. However, a recent cohort study found no relation between circulating ω3-PUFA levels and pregnancy rates after ART. This analysis included a random sample of 100 women from a prospective cohort study (EARTH) at the Massachusetts General Hospital Fertility Center who underwent 136 ART cycles within one year of blood collection. Serum fatty acids (expressed as percentage of total fatty acids) were measured by gas chromatography in samples taken between Days 3 and 9 of a stimulated cycle. Primary outcomes included the probability of implantation, clinical pregnancy and live birth per initiated cycle. Cluster-weighted generalized estimating equation (GEE) models were used to analyze the association of total and specific PUFAs with ART outcomes adjusting for age, body mass index, smoking status, physical activity, use of multivitamins and history of live birth. The median [25th, 75th percentile] serum level of ω3-PUFA was 4.7% [3.8%, 5.8%] of total fatty acids. Higher levels of serum long-chain ω3-PUFA were associated with higher probability of clinical pregnancy and live birth. Specifically, after multivariable adjustment, the probability of clinical pregnancy and live birth increased by 8% (4%, 11%) and 8% (95% CI: 1%, 16%), respectively, for every 1% increase in serum long-chain ω3-PUFA levels. Intake of long-chain ω3-PUFA was also associated with a higher probability of life birth in these women, with RR of 2.37 (95% CI: 1.02, 5.51) when replacing 1% energy of long-chain ω3-PUFA for 1% energy of saturated fatty acids. Serum ω6-PUFA, ratios of ω6 and ω3-PUFA, and total PUFA were not associated with ART outcomes. The generalizability of the findings to populations not undergoing infertility treatment may be limited. The use of a single measurement of serum fatty acids to characterize exposure may lead to potential misclassification during follow up. Serum ω3-PUFA are considered biomarkers of dietary intake. The association of higher serum long chain ω3-PUFA levels with improved ART outcomes suggests that increased intake of these fats be may be beneficial for women undergoing infertility treatment with ART. NIH grants R01-ES009718 from the National Institute of Environmental Health Sciences, P30-DK046200 and T32-DK007703-16 from the National Institute of Diabetes and Digestive and Kidney Diseases, and L50-HD085359 from the National Institute of Child Health and Human Development, and the Early Life Nutrition Fund from Danone Nutricia US. Dr Rueda is involved in a patent 9,295,662, methods for enhancing, improving, or increasing fertility or reproductive function (http://patents.com/us-9295662.html). This patent, however, does not lead to financial gain for Dr Rueda, or for Massachusetts General Hospital. Dr Rueda does not own any part of the company nor does he have any equity in any fertility related company. As Dr Rueda is not a physician, he does not evaluate patients or prescribe medications. All other coauthors have no conflicts of interest to declare.

Maternal physical and sedentary activities in relation to reproductive outcomes following IVF

Physical activity could benefit reproductive function through its ability to regulate energy balance and improve insulin sensitivity, but its association with IVF outcomes remains unclear. The aim of this study was to evaluate whether pre-treatment physical and sedentary activity is associated with outcomes of IVF. The Environment and Reproductive Health Study is an ongoing prospective cohort study that enrols subfertile couples at Massachusetts General Hospital Fertility Center. Time spent in physical and sedentary activities in the year before IVF treatment is self-reported using a validated questionnaire. This analysis included 273 women who underwent 427 IVF cycles. Women engaged in a median of 2.8 h per week of moderate-to-vigorous activities. Time spent in moderate-to-vigorous physical activities and total metabolic equivalent task hours before IVF were not associated with probability of implantation, clinical pregnancy or live birth. Of the specific physical activities, only greater time spent in aerobics, rowing, and on the ski or stair machine was associated with higher probability of live birth. Time spent in total and specific sedentary activities were not associated with clinical outcomes of IVF. Physical activity is unlikely to have a deleterious effect on IVF success and certain forms of vigorous activity may be beneficial.

Maternal whole grain intake and outcomes of in vitro fertilization

To evaluate the relationship between pretreatment intake of whole grains and outcomes of IVF. Prospective cohort study. Academic medical center. A total of 273 women who collectively underwent 438 IVF cycles. Whole grain intake was assessed with a validated food frequency questionnaire at enrollment. Intermediate and clinical end points of IVF were abstracted from medical records. Women had a median whole grain intake of 34.2g per day (∼1.2 servings/day). Higher pretreatment whole grain intake was associated with higher probability of implantation and live birth. The adjusted percentage of cycles resulting in live birth for women in the highest quartile of whole grain intake (>52.4g/day) was 53% (95% confidence interval [CI] 41%, 65%) compared with 35% (95% CI 25%, 46%) for women in the lowest quartile (<21.4g/day). This association was largely driven by intake of bran as opposed to germ. When intermediate end points of IVF were examined, only endometrial thickness on the day of ET was associated with whole grain intake. A 28-g per day (∼1 serving/day) increase in whole grain intake was associated with a 0.4-mm (95% CI 0.1, 0.7mm) increase in endometrial thickness. Higher pretreatment whole grain intake was related to higher probability of live birth among women undergoing IVF. The higher probability of live birth may result from increased endometrial thickness on the day of ET and improved embryo receptivity manifested in a higher probability of implantation.

Cost of fertility treatment and live birth outcome in women of different ages and BMI.

What is the impact of different age and BMI groups on total investigation and treatment costs in women attending a secondary/tertiary care fertility clinic? Women in their early to mid-30s and women with normal BMI had higher cumulative investigation and treatment costs, but also higher probability of live birth. Female age and BMI have been used as criteria for rationing publically funded fertility treatments. Population-based data on the costs of investigating and treating infertility are lacking. A retrospective cohort study of 2463 women was conducted in a single secondary/tertiary care fertility clinic in Aberdeen, Scotland from 1998 to 2008. Participants included all women living in a defined geographical area referred from primary care to a specialized fertility clinic over an 11-year period. Women were followed up for 5 years or until live birth if this occurred sooner. Mean discounted cumulative National Health Service costs (expressed in 2010/2011 GBP) of fertility investigations, treatments (including all types of assisted reproduction), and pregnancy (including delivery episode) and neonatal admissions were calculated and summarized by age (≤ 30, 31-35, 36-40, >40 years) and BMI groupings (<18.50, 18.50-24.99 (normal BMI), 25.00-29.99, 30.00-34.99, ≥ 35.00 kg/m(2)). Further multivariate modelling was carried out to estimate the impact of age and BMI on investigation and treatment costs and live birth outcome, adjusting for covariates predictive of the treatment pathway and live birth. Of the 2463 women referred, 1258 (51.1%) had a live birth within 5 years, with 694 (55.1%) of these being natural conceptions. The live birth rate was highest among women in the youngest age group (64.3%), and lowest in those aged >40 years (13.4%). Overall live birth rates were generally lower in women with BMI >30 kg/m(2). The total costs of investigations were generally highest among women younger than 30 years (£491 in those with normal BMI), whilst treatment costs tended to be higher in 31-35 year olds (£1,840 in those with normal BMI). Multivariate modelling predicted a cost increase associated with treatment which was highest among women in the lowest BMI group (across all ages), and also highest among women aged 31-35 years. The increase in the predicted probability of live birth with exposure to treatment was consistent across age and BMI categories (∼ 10%), except in the oldest age group where a slightly smaller increase in the probability of live birth was observed. The ratio of increased costs to the increased probability of live birth in women who were treated increased markedly in women over the age of 40 years, but tended to fall as BMI increased within all age groups. Our results, based on retrospective observational data from a single centre, have limited generalizability and are not free from clinician and clinic selection bias which can influence the choice of treatments as well as their costs. Spontaneous live birth rates were particularly high in younger women with unexplained infertility, suggesting that expectant management is a reasonable option in this group. The policy of not over-investigating older women and offering early treatment where appropriate still incurred the highest costs per additional live birth associated with treatment, owing to the lower probability of treatment success. The increased additional cost for each live birth associated with treatment for women with decreasing BMI across all age groups, suggests that it may be possible to identify a more targeted approach to treatment. This study was partly funded by an NHS endowment grant (Grant Number 12/48) and D.J.M. by a Chief Scientist Office Postdoctoral Fellowship (Ref PDF/12/06). There are no conflicts of interest to declare.