Publications by authors named "Christos A Venetis"

46 Publications

Biosimilar recombinant follitropin alfa preparations versus the reference product (Gonal-F®) in couples undergoing assisted reproductive technology treatment: a systematic review and meta-analysis.

Reprod Biol Endocrinol 2021 Apr 2;19(1):51. Epub 2021 Apr 2.

Global Medical Affairs Fertility, Research and Development, Merck KGaA, F135/002, Darmstadt, 64293, Germany.

Background: Live birth has increasingly been identified as the standard clinical approach to measure the success of medically assisted reproduction (MAR). However, previous analyses comparing biosimilar preparations of follitropin alfa versus the reference product (GONAL-f®, Merck KGaA, Darmstadt, Germany or GONAL-f® RFF; EMD Serono, Inc., Rockland, MA), have had insufficient power to detect differences in clinically meaningful outcomes such as live birth.

Methods: Medline, Embase, the Cochrane Library, Web of Science and clinical trial registries were searched for randomised controlled trials (RCTs) and conference abstracts comparing biosimilar follitropin alfa versus the reference product in controlled ovarian stimulation (COS) cycles published before 31 October 2020. Only studies in humans and publications in English were included. Retrieved studies were screened independently by two authors based on titles and abstracts, and then by full text.

Inclusion Criteria: RCTs comparing follitropin alfa biosimilar preparations with the reference product in infertile patients of any age, with any type of infertility for any duration, undergoing COS for the purposes of MAR treatment (including frozen cycles). The primary outcome was live birth. Combined data for biosimilar preparations were analysed using a fixed-effects model.

Results: From 292 unique records identified, 17 studies were included in the systematic review, representing five unique RCTs that were included in the meta-analysis. Rates of live birth (RR = 0.83, 95% CI 0.71, 0.97; 4 RCTs, n = 1881, I = 0%), clinical pregnancy (RR = 0.82, 95% CI 0.72, 0.94; 4 RCTs, n = 2222, I = 0%) and ongoing pregnancy (RR = 0.81, 95% CI 0.68, 0.96; 4 RCTs, n = 1232, I = 0%) were significantly lower with biosimilar preparations versus the reference product. Rates of cumulative live birth and cumulative clinical pregnancy were also significantly lower with biosimilars versus the reference product. There was high risk of publication bias.

Conclusions: This meta-analysis included data from RCTs evaluating the efficacy and safety of the biosimilar follitropin alfa preparations and demonstrated lower probability of live birth and pregnancy (ongoing and clinical) in couples treated with biosimilar preparations compared with the reference product. This study provides more insight into the differences between biosimilar r-hFSH preparations and the reference product than previously reported.

Trial Registration: Registration number: CRD42019121992 .
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http://dx.doi.org/10.1186/s12958-021-00727-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017804PMC
April 2021

Female age is associated with the optimal number of oocytes to maximize fresh live birth rates: an analysis of 256,643 fresh ART cycles.

Reprod Biomed Online 2021 Mar 24;42(3):669-678. Epub 2020 Nov 24.

National Perinatal Epidemiology and Statistics Unit, School of Women's and Children's Health and Centre for Big Data Research in Health, Level 1, AGSM Building (G27), UNSW Medicine, Sydney NSW 2052; The George Institute for Global Health, University of New South Wales, Sydney NSW, Australia. Electronic address:

Research Question: What is the optimal number of oocytes retrieved at which maximum live birth rate is observed after fresh autologous assisted reproductive technology (ART) cycles for women of different ages?

Design: Retrospective cohort study of all fresh autologous ART aspiration cycles (n = 256,643) undertaken in Australia and New Zealand between 2009 and 2015. Primary outcome measure was live birth rate (LBR) (delivery of at least one liveborn baby at 20 weeks' gestation or over per fresh aspiration cycle). Cycles were grouped according to female age (<30, 30-34, 35-49, 40-44 and ≥45 years) and ovarian response (one to three, four to nine, 10-14, 15-19, 20-25 and ≥25 oocytes). Secondary outcome was incidence of ovarian hyperstimulation syndrome (OHSS) requiring hospitalization.

Results: At different oocyte yields, LBR per fresh aspiration cycle peaked and then declined at, depending on female age: <30 years: six to 11 oocytes (LBR 31-34%); 30-34 years: 11-16 oocytes (LBR 29-30%); 35-39 years: nine to 17 oocytes (LBR 21-24%); and 40-44 years: 15-17 oocytes (LBR 11-12%). The incidence of OHSS increased significantly with the number of oocytes retrieved, from 1.2% with 15 oocytes retrieved to 9.3% with 30 or more oocytes retrieved (P < 0.001).

Conclusion: The optimal number of oocytes at which maximum LBR was observed in a fresh aspiration cycle was highly dependent on age. Because of the observational nature of the results, a cause-effect relationship between the number of oocytes retrieved and LBR should not be assumed; evidence from well-designed randomized control trials is required before clinical advice can be suggested.
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http://dx.doi.org/10.1016/j.rbmo.2020.11.010DOI Listing
March 2021

Is there an optimal number of oocytes retrieved at which live birth rates or cumulative live birth rates per aspiration are maximized after ART? A systematic review.

Reprod Biomed Online 2021 Jan 22;42(1):83-104. Epub 2020 Oct 22.

National Perinatal Epidemiology and Statistics Unit, School of Women and Children's Health and Centre for Big Data Research in Health, UNSW Medicine, Level 2, AGSM Building (G27), UNSW Australia, UNSW Sydney NSW 2052, Sydney NSW, Australia; School of Women's and Children's Health, UNSW Medicine, Sydney NSW, Australia; IVFAustralia, Sydney NSW, Australia. Electronic address:

The association between the number of oocytes retrieved and fresh live birth rate (LBR) or cumulative LBR (CLBR), and whether an optimal number of oocytes are retrieved when LBR or CLBR are maximized, are highly relevant clinical questions; however published results are conflicting. A systematic review of all eligible studies (n = 16) published until January 2020 on MEDLINE, Embase, Scopus, CINAHL and Web of Science was conducted. Five studies evaluated only LBR from fresh cycles, five studies evaluated only CLBR from stimulated cycles and six evaluated both. A marked difference was observed between the oocyte yields at which LBR and CLBR were reportedly maximized in the individual studies. On the basis of nine studies, the optimal number of oocytes at which fresh LBR seems to be maximized is proposed to be between 12 and 18 oocytes (15 oocytes was the most common suggestion). On the other hand, CLBR continues to increase with the number of oocytes retrieved. This is the first systematic review on the topic, and it suggests that the retrieval of 12-18 oocytes is associated with maximal fresh LBR, whereas a continuing positive association is present between the number of oocytes retrieved and CLBR.
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http://dx.doi.org/10.1016/j.rbmo.2020.10.008DOI Listing
January 2021

Endometrial injury before IVF: light at the end of the tunnel or false hope?

Hum Reprod 2021 Jan;36(1):1-2

Centre for Big Data Research in Health, UNSW Medicine, Kensington Campus, Sydney, Australia.

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http://dx.doi.org/10.1093/humrep/deaa295DOI Listing
January 2021

Association between body mass index and oocyte maturation in patients triggered with GnRH agonist who are at high risk for severe ovarian hyperstimulation syndrome: an observational cohort study.

Reprod Biomed Online 2020 Jan 15;40(1):168-175. Epub 2019 Oct 15.

Unit of Human Reproduction, 1st Department of OB/Gyn, Medical school, Aristotle University, Thessaloniki, 7 Ventiri Street, Athens 11528, Greece.

Research Question: Is body-mass index (BMI) associated with oocyte maturation in women at high risk for developing severe ovarian hyperstimulation syndrome (OHSS) who are triggered with gonadotrophin releasing hormone (GnRH) agonist?

Design: Prospective observational cohort study. A total of 113 patients at high risk for severe OHSS (presence of at least 19 follicles ≥11 mm) pre-treated with gonadotrophin releasing hormone (GnRH) antagonists and recombinant FSH were administered 0.2 mg triptorelin to trigger final oocyte maturation. Patients were classified in two groups depending on their BMI: ΒΜΙ less than 25 kg/m (n = 72) and ΒΜΙ 25 kg/m or over (n = 41). Baseline, ovarian stimulation and embryological characteristics, as well as luteal-phase hormone profiles, were compared in patients classified into the two BMI groups. The main outcome measure was the number of mature oocytes.

Results: A significantly higher number of mature (metaphase II) oocytes (19 [18-21] versus 16 [13-20], P = 0.029) was present in women with BMI less than 25 kg/m compared with those with BMI 25 kg/m or greater. The number of retrieved oocytes, the number of fertilized oocytes, oocyte retrieval, maturation and fertilization rates were similar in the two groups. A significantly higher dose of recombinant FSH was required for patients with BMI 25 kg/m or greater compared with patients with BMI less than 25 kg/m (1875 [1650-2150] IU versus 1650 [1600-1750] IU, P = 0.003) and the two groups displayed different luteal phase hormonal profiles.

Conclusions: Among women at high risk for developing severe OHSS who are triggered with a standard dose (0.2 mg) of the GnRH agonist triptorelin, women with BMI 25 kg/m or greater had significantly fewer mature oocytes, required a higher total dose of recombinant FSH compared with women with BMI less than 25 kg/m.
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http://dx.doi.org/10.1016/j.rbmo.2019.10.006DOI Listing
January 2020

Is there an association between oocyte number and embryo quality? A systematic review and meta-analysis.

Reprod Biomed Online 2019 Nov 3;39(5):751-763. Epub 2019 Jul 3.

Merck KGaA, Darmstadt, Germany.

This systematic review and meta-analysis determined the association between aspirated after ovarian stimulation and top/good quality embryos obtained in women undergoing ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI). MEDLINE, EMBASE, Scopus, CINAHL and Web of Science were searched for English-language publications on top/good-quality embryos at cleavage (day 2/3) and/or blastocyst (day 5/6) developmental stages, up to 18 November 2017. Twenty-eight studies (three prospective and 25 retrospective) reporting data on 291,752 assisted reproductive technology (ART) cycles were considered eligible. We confirmed a strong positive association between oocytes retrieved and top/good-quality day 2/3 embryos (weighted correlation coefficient [r] = 0.791), day 5/6 embryos (r = 0.901), metaphase II oocytes (r = 0.988), oocytes exhibiting two pronuclei (r = 0.987) and euploid embryos (r = 0.851); P < 0.001 for all correlations (evaluated in subsets of the 17 studies). Data from 5657 cycles showed that the group with the most oocytes aspirated had the most top/good-quality day 2/3 embryos (pooled standardized mean differences (high [>15] versus low [<4] 1.91, 95% confidence interval [CI] 1.05-2.77, P < 0.0001; high versus medium [4-15] 1.15, 95% CI 0.74-1.55, P < 0.0001; medium versus low 1.41, 95% CI 0.79-2.03, P < 0.0001). Individual participant meta-analysis would enable accurate determination of these associations and other outcomes.
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http://dx.doi.org/10.1016/j.rbmo.2019.06.013DOI Listing
November 2019

Fine-tuning blastocyst selection based on morphology: a multicentre analysis of 2461 single blastocyst transfers.

Reprod Biomed Online 2019 Oct 22;39(4):588-598. Epub 2019 Jun 22.

IVF Australia, Sydney NSW, Australia; Centre for Big Data Research in Health and School of Women's and Children's Health, UNSW NSW, Australia.

Research Question: Which blastocyst morphology parameter is associated with live birth after controlling for female age and endometrial receptivity?

Design: Retrospective study including fresh single blastocyst transfers (n = 2461) where the value of serum progesterone on day of human chorionic gonadotrophin trigger (PdHCG) was available. Generalized estimating equation regression models evaluated the independent effects of developmental stage (DevSt), inner cell mass (ICM) and trophectoderm grade on live birth rates while controlling for the confounding effects of female age and PdHCG.

Results: DevSt was strongly associated with the probability of live birth (P < 0.0001) independently of female age (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.87-0.91) and PdHCG (OR 0.80, 95% CI 0.74-0.87). For full blastocysts, expanded blastocysts and hatching blastocysts, addition of ICM and trophectoderm grading in the multivariable analysis suggested that besides female age (OR 0.92, 95% CI 0.90-0.94) and PdHCG (OR 0.80, 95% CI 0.73-0.87), only DevSt (P = 0.001) and trophectoderm quality (P = 0.004) were independent predictors of live birth, while the predictive capacity of ICM was no longer significant. The mean probability of live birth was highest for AA blastocysts (35.0%), followed by BA blastocysts (31.2%) and AB blastocysts (27.7%).

Conclusion: This large study analyses for the first time the independent role of blastocyst morphology in predicting live birth while controlling for female age and PdHCG. Its findings suggest that DevSt and then trophectoderm grade are stronger predictors of live birth over ICM grade when selecting a single blastocyst for transfer.
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http://dx.doi.org/10.1016/j.rbmo.2019.06.008DOI Listing
October 2019

The number of oocytes associated with maximum cumulative live birth rates per aspiration depends on female age: a population study of 221 221 treatment cycles.

Hum Reprod 2019 09;34(9):1778-1787

National Perinatal Epidemiology and Statistics Unit, School of Women's and Children's Health and Centre for Big Data Research in Health, UNSW Medicine, Sydney NSW Australia.

Study Question: What is the number of oocytes where the maximum cumulative live birth rate per aspiration (CLBR) is observed during ART in women of different ages?

Summary Answer: The maximum CLBR was observed when around 25 oocytes were retrieved in women between 18-35 years of age, around 9 oocytes in women more than 45 years of age and continued to increase beyond 30 oocytes in women between 36-44 years of age.

What Is Known Already: The live birth rate per fresh or frozen/thaw embryo transfer (FET) procedure has traditionally been the main measure of ART success. However, with the introduction of highly efficient embryo cryopreservation methods, CLBR encompassing live delivery outcomes from the fresh and all subsequent FET following a single ovarian stimulation and oocyte collection is increasingly viewed as a more meaningful measure of treatment success. There is evidence suggesting that larger oocyte yields are associated with increased likelihood of cumulative live birth per aspiration. Whether this association is the same across female ages has not yet been properly investigated.

Study Design, Size, Duration: This is a large retrospective population-based cohort study using data from the Australian and New Zealand Assisted Reproduction Database (ANZARD). ANZARD contains information from all ART treatment cycles carried out in all fertility centres in Australia and New Zealand. Overall, 221 221 autologous oocyte aspiration cycles carried out between January 2009 to December 2015 were included in the analysis.

Participants/materials, Setting, Methods: Cumulative live birth per aspiration was defined as at least one liveborn baby at ≥20 weeks gestation resulting from an ART aspiration cycle, including all fresh and FET resulting from the associated ovarian stimulation, until one live birth occurred or all embryos were used. Cycles where no oocytes were retrieved were excluded from analysis as there is no possibility of live birth. Analyses of data were performed using generalized estimating equations to account for the clustered nature of data (multiple cycles undertaken by a woman). Univariate and multivariable regression analysis was performed to identify and adjust for factors known to independently affect cumulative live birth per aspiration. An interaction term between female age and the number of oocytes retrieved was included to assess whether the age of the women was associated with a different optimal number of oocytes to achieve at least one live birth from an aspiration cycle (i.e. the effect-modifying role of female age). The likelihood of cumulative live birth per aspiration was calculated as odds ratios (ORs) with 95% CI.

Main Results And The Role Of Chance: The median number of oocytes retrieved was 7 (interquartile range, 4-12) and median age of patients was 36 (interquartile range, 33-40). The overall CLBR was 32.2%. The results from the multivariable regression analysis showedthat the number of oocytes retrieved remained a significant predictor (P < 0.001) of cumulative live birth per aspiration after adjusting for female age, parity and cycle count. Compared to the reference group of 10-14 oocytes retrieved, the adjusted odds for cumulative live birth per aspiration increased with the number of oocytes retrieved: 1-3 oocytes, 0.21 (95% CI, 0.20-0.22); 4-9 oocytes, 0.56 (95% CI, 0.55-0.58); 15-19 oocytes, 1.38 (95% CI, 1.34-1.43); 20-24 oocytes, 1.75 (95% CI, 1.67-1.84); and 2.10 (95% CI, 1.96-2.25) with more than 25 oocytes. After stratifying by female age group, the rate of increase in CLBR per additional oocyte retrieved was lower in the older age groups, indicating that higher oocyte yields were more beneficial in younger women. CLBR of patients in the <30 years and 30-34 years age groups appeared to reach a plateau (with only minimal increase in CLBR per additional oocyte retrieved) after retrieval of 25 oocytes at 73% and 72%, respectively, while CLBR of patients in the 35-39 years and 40-44 years age groups continued to increase with higher oocyte yields, reaching 68% and 40%, respectively, when 30 or more oocytes were retrieved. CLBR of patients aged 45 years and above remained consistently below 5%. Findings suggest that the number of oocytes retrieved where CLBR appears to be maximized is around 25 in women between 18-35 years, more than 30 in women between 36-44 years and around 9 in women 45 years and older. However, results for women aged 45 years and older may not be as robust due to the relatively small sample size available in this age group.

Limitations, Reasons For Caution: As with all large retrospective database studies, there are potential confounders that cannot be accounted for. Despite the current study being based on complete ascertainment of ART cycles across two countries, ovarian stimulation protocols, oocyte quality parameters and a number of important patient characteristics are not collected by ANZARD. Additionally, a small number of cycles were available for women over 45 years yielding more than 15 oocytes, making these estimates unreliable.

Wider Implications Of The Findings: The results from this study demonstrate that the number of oocytes retrieved where the maximum CLBR is observed during ART is dependent on female age. This provides information for clinicians and patients to understand the modifying effect of age on the number of oocytes retrieved and the likelihood of success with ART.

Study Funding/competing Interest(s): No external funding was used for this study. The Fertility Society of Australia funds the National Perinatal Epidemiology and Statistics Unit to manage ANZARD and conduct national reporting of ART in Australia and New Zealand. Associate Professor Georgina Chambers (G.C.) is employed by the University of New South Wales (UNSW) and is director of the National Perinatal Epidemiology and Statistics Unit at UNSW. G.C. was also a paid member of the Australian governments Medicare Benefits Scheme taskforce on assisted reproductive technologies in 2017.
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http://dx.doi.org/10.1093/humrep/dez100DOI Listing
September 2019

A Review of Second- and Third-line Infertility Treatments and Supporting Evidence in Women with Polycystic Ovary Syndrome.

Med Sci (Basel) 2019 Jun 26;7(7). Epub 2019 Jun 26.

University of New South Wales, High St. Kensington, Sydney, NSW 2052, Australia.

In clomiphene-citrate-resistant anovulatory women with polycystic ovary syndrome (PCOS) and no other infertility factors, either metformin combined with clomiphene citrate or gonadotrophins could be used as a second-line pharmacological therapy, although gonadotrophins are more effective. Gonadotrophins could also be used as a second-line pharmacological therapy in anovulatory women with PCOS and clomiphene-citrate-failure. Laparoscopic ovarian surgery can also be used as a second-line therapy for ovulation induction in anovulatory women with clomiphene-citrate-resistant PCOS and no other infertility factors. The usefulness of letrozole as a second-line pharmacological treatment for ovulation induction in clomiphene-citrate-resistant women with PCOS requires further research. In terms of improving fertility, both pharmacological anti-obesity agents and bariatric surgery should be considered an experimental therapy in anovulatory women with PCOS and no other infertility factors. Where first- or second-line ovulation induction therapies have failed, in vitro fertilization (IVF)/ intracytoplasmic sperm injection (ICSI) could be offered as a third-line therapy in women with PCOS in the absence of an absolute indication for IVF/ICSI. For women with PCOS undergoing IVF/ICSI treatment, the gonadotropin-releasing hormone (GnRH) antagonist protocol is preferred and an elective frozen embryo transfer strategy could be considered. In assisted conception units with sufficient expertise, in-vitro maturation (IVM) of oocytes could be offered to women with PCOS.
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http://dx.doi.org/10.3390/medsci7070075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681353PMC
June 2019

Is more better? A higher oocyte yield is independently associated with more day-3 euploid embryos after ICSI.

Hum Reprod 2019 Jan;34(1):79-83

School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.

Study Question: Is the number of oocytes retrieved after ovarian stimulation for ICSI independently associated with the number of day-3 euploid embryos (EE)?

Summary Answer: A larger oocyte yield is independently associated with more day-3 EE, although the expected benefit decreases significantly with advancing age.

What Is Known Already: Although traditionally ovarian stimulation aims at collecting more than one oocyte in order to increase the chance of pregnancy, there is evidence suggesting that excessive ovarian response leads to lower live birth rates. Whether a larger oocyte yield after ovarian stimulation is associated with the genetic composition of the resulting embryos and therefore with their reproductive potential is still largely unknown.

Study Design, Size, Duration: This is a multi-centered retrospective cohort study analyzing 724 cycles of preimplantation genetic testing for aneuploidy (PGT-A) cycles using day-3 biopsy and array-comparative genomic hybridization between March 2011 and December 2016 in three laboratories.

Participants/materials, Setting, Methods: The primary outcome measure was the number of EE on day-3. Statistical analysis was performed using the generalized estimating equations (GEE) framework and multivariate regression models to control for the clustered nature of the data while adjusting for potential confounders.

Main Results And The Role Of Chance: A multivariate regression GEE model including all significant population and stimulation characteristics as covariates as well as an interaction term between female age and number of oocytes revealed that the number of oocytes retrieved was still positively associated with the number of EE (coeff: +0.40, 95% CI: 0.24-0.56). The interaction term was highly significant (coeff: -0.01, P < 0.001) indicating an effect modifying role of female age on the association of oocytes retrieved with the number of EE. The number of oocytes retrieved was also positively associated with cumulative live birth rates (odds ratio: 1.07, 95% CI: 1.03-1.12).

Limitations, Reasons For Caution: This study is retrospective and the presence of residual unknown bias cannot be excluded. Furthermore, the population analyzed in this study might not be completely representative of the general population undergoing ICSI.

Wider Implications Of The Findings: These results provide an explanatory mechanism for the recently published positive association between the number of oocytes retrieved and cumulative live birth rates.

Study Funding/competing Interest(s): CAV is supported by a NHMRC Early Career Fellowship (GNT1147154)/ No competing interests to declare.
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http://dx.doi.org/10.1093/humrep/dey342DOI Listing
January 2019

Trying to define the optimal progesterone elevation cut-off in fresh in vitro fertilization cycles: time to evolve our way of thinking.

Fertil Steril 2018 09;110(4):634-635

School of Medicine, Aristole University of Thessaloniki, Thessaloniki, Greece.

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http://dx.doi.org/10.1016/j.fertnstert.2018.06.006DOI Listing
September 2018

GnRH antagonists vs. long GnRH agonists in IVF: significant flaws in a meta-analysis lead to invalid conclusions.

Hum Reprod Update 2018 Mar;24(2):242-243

Women's and Children's Health, UNSW Medicine, University of New South Wales, Royal Hospital for Women, Level 1, Barker Str, Randwick NSW 2031, Australia.

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http://dx.doi.org/10.1093/humupd/dmx037DOI Listing
March 2018

Blastocyst utilization rates after continuous culture in two commercial single-step media: a prospective randomized study with sibling oocytes.

J Assist Reprod Genet 2017 Oct 17;34(10):1377-1383. Epub 2017 Jul 17.

Eugonia Assisted Reproduction Unit, 7 Ventiri Street, 11528, Athens, Greece.

Purpose: The aim of this study is to determine whether blastocyst utilization rates are different after continuous culture in two different commercial single-step media.

Methods: This is a paired randomized controlled trial with sibling oocytes conducted in infertility patients, aged ≤40 years with ≥10 oocytes retrieved assigned to blastocyst culture and transfer. Retrieved oocytes were randomly allocated to continuous culture in either Sage one-step medium (Origio) or Continuous Single Culture (CSC) medium (Irvine Scientific) without medium renewal up to day 5 post oocyte retrieval. Main outcome measure was the proportion of embryos suitable for clinical use (utilization rate).

Results: A total of 502 oocytes from 33 women were randomly allocated to continuous culture in either Sage one-step medium (n = 250) or CSC medium (n = 252). Fertilization was performed by either in vitro fertilization or intracytoplasmic sperm injection, and embryo transfers were performed on day 5. Two patients had all blastocysts frozen due to the occurrence of severe ovarian hyperstimulation syndrome. Fertilization and cleavage rates, as well as embryo quality on day 3, were similar in the two media. Blastocyst utilization rates (%, 95% CI) [55.4% (46.4-64.1) vs 54.7% (44.9-64.6), p = 0.717], blastocyst formation rates [53.6% (44.6-62.5) vs 51.9 (42.2-61.6), p = 0.755], and proportion of good quality blastocysts [36.8% (28.1-45.4) vs 36.1% (27.2-45.0), p = 0.850] were similar in Sage one-step and CSC media, respectively.

Conclusions: Continuous culture of embryos in Sage one-step and CSC media is associated with similar blastocyst development and utilization rates. Both single-step media appear to provide adequate support during in vitro preimplantation embryo development. Whether these observations are also valid for other continuous single medium protocols remains to be determined.

Clinical Trial Registration Number: NCT02302638.
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http://dx.doi.org/10.1007/s10815-017-0997-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633582PMC
October 2017

What is the best predictor of severe ovarian hyperstimulation syndrome in IVF? A cohort study.

J Assist Reprod Genet 2017 Oct 14;34(10):1341-1351. Epub 2017 Jul 14.

Fertility Clinic, Department of Obstetrics and Gynecology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium.

Purpose: The purpose of the present study is to study what is the best predictor of severe ovarian hyperstimulation syndrome (OHSS) in IVF.

Methods: This is a retrospective analysis of all consecutive IVF/intracytoplasmic injection cycles performed during a 5-year period (2009-2014) in a single university fertility centre. All fresh IVF cycles where ovarian stimulation was performed with gonadotrophins and GnRH agonists or antagonists and triggering of final oocyte maturation was induced with the administration of urinary or recombinant hCG were analyzed (2982 patients undergoing 5493 cycles). Because some patients contributed more than one cycle, the analysis of the data was performed with the use of generalized estimating equation (GEE).

Results: Severe OHSS was diagnosed in 20 cycles (0.36%, 95% CI 0.20-0.52). The number of follicles ≥10 mm on the day of triggering final oocyte maturation represents the best predictor of severe OHSS in IVF cycles. The cutoff in the number of follicles ≥10 mm with the best capacity to discriminate between women that will and will not develop severe OHSS was ≥15.

Conclusion: The presence of more than 15 follicles ≥10 mm on the day of triggering final oocyte maturation represents the best predictor of severe OHSS in IVF cycles.
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http://dx.doi.org/10.1007/s10815-017-0990-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633577PMC
October 2017

Anti-Müllerian hormone kinetics in pregnancy and post-partum: a systematic review.

Reprod Biomed Online 2017 May 24;34(5):522-533. Epub 2017 Feb 24.

School of Women's and Children's Health, UNSW Medicine, University of New South Wales, New South Wales, Australia.

The aim of this systematic review is to critically appraise the available evidence regarding the kinetics of anti-Müllerian hormone (AMH) during pregnancy and post-partum. A systematic literature search was conducted in MEDLINE, Embase, CENTRAL, Scopus and Web of Science on 14 December 2015, aiming to identify studies providing data on the serum concentration of AMH in women at various stages of gestation and post-partum. There was a total of 1719 participants across eight studies. Seven out of the eight studies reported a decline in serum AMH concentration with advancing gestational age. Further, all four of the studies that evaluated pre- and post-delivery AMH concentrations found that it increased in the post-partum period. This review demonstrated an association between reduced maternal serum AMH concentrations and advancing gestational age, with a subsequent post-partum increase in concentration. These findings suggest that AMH measurements in pregnant women, especially at later stages of pregnancy, should not be used to assess ovarian reserve. Additionally, further longitudinal research would be beneficial, to elucidate the pathophysiological mechanism through which this decline in serum AMH concentration is observed during pregnancy.
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http://dx.doi.org/10.1016/j.rbmo.2017.02.005DOI Listing
May 2017

Inter-observer and intra-observer agreement between embryologists during selection of a single Day 5 embryo for transfer: a multicenter study.

Hum Reprod 2017 02 28;32(2):307-314. Epub 2016 Dec 28.

IVFAustralia, Sydney, NSW, Australia.

Study Question: What is the inter-observer and intra-observer agreement between embryologists when selecting a single Day 5 embryo for transfer?

Summary Answer: The inter-observer and intra-observer agreement between embryologists when selecting a single Day 5 embryo for transfer was generally good, although not optimal, even among experienced embryologists.

What Is Known Already: Previous research on the morphological assessment of early stage (two pronuclei to Day 3) embryos has shown varying levels of inter-observer and intra-observer agreement. However, single blastocyst transfer is now becoming increasingly popular and there are no published data that assess inter-observer and intra-observer agreement when selecting a single embryo for Day 5 transfer.

Study Design, Size, Duration: This was a prospective study involving 10 embryologists working at five different IVF clinics within a single organization between July 2013 and November 2015.

Participants/materials, Setting, Methods: The top 10 embryologists were selected based on their yearly Quality Assurance Program scores for blastocyst grading and were asked to morphologically grade all Day 5 embryos and choose a single embryo for transfer in a survey of 100 cases using 2D images. A total of 1000 decisions were therefore assessed. For each case, Day 5 images were shown, followed by a Day 3 and Day 5 image of the same embryo. Subgroup analyses were also performed based on the following characteristics of embryologists: the level of clinical embryology experience in the laboratory; amount of research experience; number of days per week spent grading embryos. The agreement between these embryologists and the one that scored the embryos on the actual day of transfer was also evaluated. Inter-observer and intra-observer variability was assessed using the kappa coefficient to evaluate the extent of agreement.

Main Results And The Role Of Chance: This study showed that all 10 embryologists agreed on the embryo chosen for transfer in 50 out of 100 cases. In 93 out of 100 cases, at least 6 out of the 10 embryologists agreed. The inter-observer and intra-observer agreement among embryologists when selecting a single Day 5 embryo for transfer was generally good as assessed by the kappa scores (kappa = 0.734, 95% CI: 0.665-0.791 and 0.759, 95% CI: 0.622-0.833, respectively). The subgroup analyses did not substantially alter the inter-observer and intra-observer agreement among embryologists. The agreement when Day 3 images were included alongside Day 5 images of the same embryos resulted in a change of mind at least three times by each embryologist (on average for <10% of cases) and resulted in a small decrease in inter-observer and intra-observer agreement between embryologists (kappa = 0.676, 95% CI: 0.617-0.724 and 0.752, 95% CI: 0.656-808, respectively).The assessment of the inter-observer agreement with regard to morphological grading of Day 5 embryos showed only a fair-to-moderate agreement, which was observed across all subgroup analyses. The highest overall kappa coefficient was seen for the grading of the developmental stage of an embryo (0.513; 95% CI: 0.492-0.538). The findings were similar when the individual embryologists were compared with the embryologist who made the morphological assessments of the available embryos on the actual day of transfer.

Limitations, Reasons For Caution: All embryologists had already completed their training and were working under one organization with similar policies between the five clinics. Therefore, the inter-observer agreement might not be as high between embryologists working in clinics with different policies or with different levels of training.

Wider Implications Of The Findings: The generally good, although not optimal uniformity between participating embryologists when selecting a Day 5 embryo for transfer, as well as, the surprisingly low agreement when morphologically grading Day 5 embryos could be improved, potentially resulting in increased pregnancy rates. Future studies need to be directed toward technologies that can help achieve this.

Study Funding/competing Interests: None declared.

Trial Registration Number: Not applicable.
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http://dx.doi.org/10.1093/humrep/dew330DOI Listing
February 2017

Exaggerations and Caveats in Press Releases and Health-Related Science News.

PLoS One 2016 15;11(12):e0168217. Epub 2016 Dec 15.

Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, United Kingdom.

Background: Exaggerated or simplistic news is often blamed for adversely influencing public health. However, recent findings suggested many exaggerations were already present in university press releases, which scientists approve. Surprisingly, these exaggerations were not associated with more news coverage. Here we test whether these two controversial results also arise in press releases from prominent science and medical journals. We then investigate the influence of mitigating caveats in press releases, to test assumptions that caveats harm news interest or are ignored.

Methods And Findings: Using quantitative content analysis, we analyzed press releases (N = 534) on biomedical and health-related science issued by leading peer-reviewed journals. We similarly analysed the associated peer-reviewed papers (N = 534) and news stories (N = 582). Main outcome measures were advice to readers and causal statements drawn from correlational research. Exaggerations in press releases predicted exaggerations in news (odds ratios 2.4 and 10.9, 95% CIs 1.3 to 4.5 and 3.9 to 30.1) but were not associated with increased news coverage, consistent with previous findings. Combining datasets from universities and journals (996 press releases, 1250 news), we found that when caveats appeared in press releases there was no reduction in journalistic uptake, but there was a clear increase in caveats in news (odds ratios 9.6 and 9.5 for caveats for advice and causal claims, CIs 4.1 to 24.3 and 6.0 to 15.2). The main study limitation is its retrospective correlational nature.

Conclusions: For health and science news directly inspired by press releases, the main source of both exaggerations and caveats appears to be the press release itself. However we find no evidence that exaggerations increase, or caveats decrease, the likelihood of news coverage. These findings should be encouraging for press officers and scientists who wish to minimise exaggeration and include caveats in their press releases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168217PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5158314PMC
July 2017

Does oocyte donation compared with autologous oocyte IVF pregnancies have a higher risk of preeclampsia?

Reprod Biomed Online 2017 Jan 14;34(1):11-18. Epub 2016 Oct 14.

Fertility Clinic, Department of Obstetrics and Gynecology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.

The aim of this study was to evaluate whether pregnancies resulting from oocyte donation have a higher risk of preeclampsia compared with pregnancies after IVF using autologous oocytes. Propensity score matching on maternal age and parity was carried out on a one to one basis, and a total of 144 singleton pregnancies resulting in delivery beyond 22 gestational weeks, achieved by oocyte donation, were compared with 144 pregnancies achieved through IVF and intracytoplasmic sperm injection with the use of autologous oocytes. All pregnancies were achieved after fresh embryo transfer. Obstetric and neonatal outcomes were compared for each pregnancy. Singleton pregnancies after oocyte donation were associated with a significantly higher risk for preeclampsia (OR 2.4, CI 1.02 to 5.8; P = 0.046), as well as for pregnancy-induced hypertension (OR 5.3, CI 1.1 to 25.2; P = 0.036), and caesarean delivery (OR 2.3, CI 1.4 to 3.7; P = 0.001) compared with pregnancies using autologous oocytes.
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http://dx.doi.org/10.1016/j.rbmo.2016.10.002DOI Listing
January 2017

Basal serum progesterone and history of elevated progesterone on the day of hCG administration are significant predictors of late follicular progesterone elevation in GnRH antagonist IVF cycles.

Hum Reprod 2016 08 14;31(8):1859-65. Epub 2016 Jun 14.

Eugovia ART Unit, Athens, Greece.

Study Question: Are there any baseline predictors of progesterone elevation (PE) on the day of human chorionic gonadotrophin (hCG) which are not associated with the intensity of ovarian stimulation in women undergoing in vitro fertilization (IVF) using follicle stimulating hormone (FSH) and gonadotrophin-releasing hormone (GnRH) antagonists?

Summary Answer: Basal (Day 2 of the menstrual cycle) serum progesterone concentration and history of PE are baseline variables that can predict the occurrence of PE on the day of hCG independently of the intensity of ovarian stimulation.

What Is Known Already: PE on the day of hCG is associated with the magnitude of the ovarian response to stimulation. For this reason, it has been hypothesized that milder ovarian stimulation might reduce the probability of PE. However, given the fact that the number of oocytes retrieved is associated with the probability of live birth, such a strategy should be considered only in patients that are at high risk of PE on the day of hCG.

Study Design, Size, Duration: This is a retrospective analysis of a cohort of fresh IVF/ICSI cycles (n = 1702) performed in a single IVF centre during the period 2001-2015.

Participants/materials, Setting, Methods: Patients in whom ovarian stimulation was performed with FSH and GnRH antagonists and with basal FSH <14.0 mIU/ml, progesterone (P) ≤1.6 ng/ml and estradiol (E2) ≤80 pg/ml on the same day (prior to the initiation of stimulation) were considered eligible. PE was defined as serum progesterone concentration >1.5 ng/ml. Pre-stimulation characteristics of patients and basal hormonal profile were assessed for their ability to predict the occurrence of PE after ovarian stimulation through generalized estimating equation univariable and multivariable regression analyses, controlling for the effect of ovarian stimulation. Furthermore, a secondary analysis in a subset of patients with multiple IVF cycles explored whether the occurrence of PE in one of the previous cycles included in this study is associated with a significantly higher occurrence of PE elevation in subsequent cycles.

Main Results And The Role Of Chance: Univariable regression analyses showed that female age (OR: 0.97; 95% CI: 0.94-0.99), basal FSH (OR: 0.85; 95% CI: 0.79-0.92) and basal P (OR: 4.20; 95% CI: 2.47-7.12) were baseline variables that could significantly predict PE on the day of hCG. When these variables were entered in the same model as covariates, only basal FSH (OR: 0.86; 95% CI: 0.80-0.94) and basal P (OR: 3.83; 95% CI: 2.24-6.56) could still predict the occurrence of PE. Basal P (OR: 6.30; 95% CI: 3.35-11.82) was the only variable that could significantly predict the occurrence of PE on the day of hCG after adjusting for the intensity of ovarian stimulation. The secondary analysis revealed that history of PE on the day of hCG in a previous cycle was also strongly associated with an increased risk of PE in a subsequent cycle.

Limitations, Reasons For Caution: This is a retrospective analysis and although the effect of the most important confounders was controlled for in the multivariable analysis, the presence of residual bias cannot be excluded.

Wider Implications Of The Findings: The findings of this study might help clinicians identify patients at high risk for late follicular PE and alter the management of their cycle.

Study Funding/competing Interests: None.

Trial Registration Number: Not applicable.
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http://dx.doi.org/10.1093/humrep/dew141DOI Listing
August 2016

Propofol versus thiopental sodium as anaesthetic agents for oocyte retrieval: a randomized controlled trial.

Reprod Biomed Online 2015 Dec 4;31(6):752-9. Epub 2015 Sep 4.

Unit for Human Reproduction, 1st Department of Obstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki, Greece.

Clinical outcomes of IVF cycles using propofol or thiopental sodium as anaesthetic agents for oocyte retrieval were compared. The primary outcome measure was fertilization rate per patient. One hundred and eighty patients undergoing ovarian stimulation with gonadotrophins and gonadotrophin-releasing hormone antagonists for IVF were randomized to receive either propofol (n = 90) or thiopental sodium (n = 90). No significant differences in baseline characteristics were present between the two groups. Overall fertilization rates were similar between propofol and thiopental sodium groups, respectively: median (IQR): 54.8 (29.2) versus 54.6 (29.7); fertilization rates for intracytoplasmic sperm injection only: median (IQR): 70 (50) versus 75 (50), respectively. For secondary outcome measures, time under anaesthesia was significantly increased in the thiopental sodium group: median (IQR): 12(5) versus 10 (4.5) min, P = 0.019 compared with the propofol group. Number of cumulus oocyte complexes retrieved [median (IQR): 7.1 (6.3) versus 6.5 (5.6)] did not differ significantly between the two groups. A non-significant difference in live birth rates per randomized patient of +4.4% (95% CI: -5.7 to +14.6) in favour of propofol was observed. Use of propofol compared with thiopental sodium for general anaesthesia during oocyte retrieval results in similar fertilization rates and IVF outcomes.
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http://dx.doi.org/10.1016/j.rbmo.2015.08.013DOI Listing
December 2015

Reply: Modified natural cycles for poor responders: addressing misconceptions and fallacies.

Hum Reprod 2016 Jan 27;31(1):222-3. Epub 2015 Oct 27.

Department of Women's and Children's Health, St George Hospital, School of Women's and Children's Health, University of New South Wales, Kogarah, NSW 2217, Australia.

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http://dx.doi.org/10.1093/humrep/dev262DOI Listing
January 2016

Is the time interval between HCG administration and oocyte retrieval associated with oocyte retrieval rate?

Reprod Biomed Online 2015 Nov 13;31(5):625-32. Epub 2015 Aug 13.

Unit for Human Reproduction, 1st Department of Obstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.

The aim of this study was to evaluate whether prolongation of the time interval between HCG administration and oocyte retrieval, from 36 h to 38 h, affects oocyte retrieval rate in women undergoing ovarian stimulation with gonadotrophins and GnRH antagonists for IVF. One hundred and fifty-six normo-ovulatory women were randomized to have oocyte retrieval performed 36 h (n = 78) or 38 h (n = 78) following HCG administration. Oocyte retrieval rate was defined as number of cumulus-oocyte-complex (COC) retrieved/follicle ≥ 11 mm present on day of HCG administration. No significant differences were observed between the groups regarding baseline characteristics. Moreover, no significant difference was observed between the groups regarding oocyte retrieval rate (difference: + 1.2%, 95% CI for difference between medians: -4.5 to +12.1). The median (95% CI for the median) was not significantly different between the groups regarding number of cumulus-oocyte-complexes (COCs) retrieved: 5.5 (5.0-7.0) versus 6.0 (5.0-6.2), respectively, and fertilization rates: 57.7% (50.0-66.7) versus 50.0% (44.8-65.5), respectively. Live birth rates were similar between the groups (20.5% versus 16.7%, RD: + 3.8%, 95% CI: -8.5 to +16.1, respectively). Prolongation of time interval between HCG administration and oocyte retrieval from 36 h to 38 h does not affect oocyte retrieval rate.
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http://dx.doi.org/10.1016/j.rbmo.2015.08.005DOI Listing
November 2015

Live birth rates after modified natural cycle compared with high-dose FSH stimulation using GnRH antagonists in poor responders.

Hum Reprod 2015 Oct 25;30(10):2321-30. Epub 2015 Aug 25.

Unit for Human Reproduction, 1st Department of Obstetrics & Gynaecology, Papageorgiou General Hospital, Medical School, Aristotle University of Thessaloniki, Ring Road, Nea Efkarpia, Thessaloniki 56429, Greece

Study Question: Do live birth rates differ between modified natural cycles (MNCs) and cycles using high-dose follicle stimulating hormone (HDFSH) with gonadotrophin-releasing hormone (GnRH) antagonist in poor responder patients?

Summary Answer: Live birth rates are significantly higher in MNC compared with HDFSH GnRH antagonist cycles in poor responder patients.

What Is Known Already: Previous data on the efficiency of MNC in poor responders are very limited and suggest that MNC in vitro fertilization (IVF) does not offer a realistic solution for parenthood in these patients, since live birth rates are disappointingly low. To date, no studies exist comparing MNC with HDFSH stimulation protocols in poor responders.

Study Design, Size, Duration: The present retrospective study included 161 MNCs (106 women in the MNC group) and 164 HDFSH antagonist cycles (136 women in the HDFSH group) performed between January 2008 and December 2013 at Eugonia Assisted Reproduction Unit. The patients included in the study had to fulfill the Bologna criteria for the definition of poor ovarian response.

Participants/materials, Setting, Methods: Irrespective of their age, poor responder patients should have a diminished ovarian reserve as shown by low antral follicle count (≤5) and increased basal FSH (>12 IU/l), and one or more previous failed IVF cycles in which ≤3 oocytes were retrieved using a high gonadotrophin dose. Analysis was performed by adjusting for the non-independence of the data.

Main Results And The Role Of Chance: The probability of live birth was significantly higher in the MNC when compared with the HDFSH group (OR: 4.01, 95% CI: 1.14-14.09), after adjusting for basal FSH, female age and cause of infertility, variables which were shown to be associated with the probability of live birth in univariable analysis. MNCs were characterized by significantly lower total gonadotrophin dose (490.0 ± 35.2 IU versus 2826.1 ± 93.4 IU, P < 0.001), lower estradiol concentrations (237.5 ± 12.3 pg/ml versus 487.3 ± 29.8 pg/ml, P < 0.001), fewer follicles present on the day of hCG (1.9 ± 0.1 versus 3.2 ± 0.2, P < 0.001), fewer oocytes retrieved (1.1 ± 0.01 versus 2.4 ± 0.1, P < 0.001), fewer oocytes fertilized (0.7 ± 0.1 versus 1.4 ± 0.1, P < 0.001), fewer embryos transferred (0.7 ± 0.1 versus 1.4 ± 0.1, P < 0.001), fewer good-quality embryos available (0.5 ± 0.1 versus 0.8 ± 0.1, P < 0.001) and fewer good-quality embryos transferred (0.5 ± 0.05 versus 0.8 ± 0.1, P < 0.001) compared with the HDFSH group. However, the proportion of cycles with at least one good-quality embryo transferred per started cycle was similar between the two groups compared (62.5, 95% CI: 52.7-72.3 versus 62.7, 95% CI: 53.0-72.5, respectively).

Limitations, Reasons For Caution: This is a retrospective comparison between MNC and HDFSH GnRH antagonist protocols in a large group of poor responder patients according to the Bologna criteria. Although the two groups compared were not imbalanced for all basic characteristics and multivariate analysis were performed to adjust for all known confounders, it cannot be excluded that non-apparent sources of bias might still be present. Future randomized controlled trials are necessary to verify the present findings.

Wider Implications Of The Findings: Both MNC and HDFSH antagonist protocols offer very low chances of live birth in poor responder patients who fulfill the Bologna criteria. However, MNC-IVF is a more patient-friendly approach, with a higher probability of live birth compared with the HDFSH antagonist protocol. In this respect, the current data might be of help in counseling such patients, who do not wish to undergo oocyte donation, prior to abandoning treatment altogether and/or proceeding to adoption.

Study Funding/competing Interests: No funding was obtained. C.A.V. reports personal fees and non-financial support from Merck, Sharp and Dome, personal fees and non-financial support from Merck Serono, personal fees and non-financial support from IPSEN Hellas S.A. outside the submitted work. B.C.T. reports grants from Merck Serono, grants from Merck Sharp & Dohme, personal fees from IBSA, personal fees from Merck Sharp & Dohme and personal fees from Ovascience outside the submitted work .
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http://dx.doi.org/10.1093/humrep/dev198DOI Listing
October 2015

Morphokinetic parameters using time-lapse technology and day 5 embryo quality: a prospective cohort study.

J Assist Reprod Genet 2015 Jul 15;32(7):1151-60. Epub 2015 Jul 15.

IVF Australia Western Sydney, Level 2, 20-22 Mons Road, Westmead, NSW, 2145, Australia,

Purpose: The aims of this prospective study were to evaluate whether time-lapse parameters can aid in the prediction of day 5 embryo quality and also to assess their discriminatory capacity.

Methods: In this prospective cohort study, we used time-lapse technology to record specific timings of key events for 380 day 5 blastocysts (originating from 108 patients). Generalized estimating equation regression models were used to evaluate the capacity of these markers to identify a top-quality blastocyst. Multivariable regression models were also constructed, aiming to identify the model with the highest capacity to predict a top-quality blastocyst. The discriminatory capacity of single predictors or composite models was assessed with the use of receiver operating characteristic (ROC) analyses.

Results: Eight significant predictive parameters of a top-quality blastocyst were identified: s3, t6, t7, t8, tM, tSB, tB and tEB. A ROC analysis of the identified parameters found s3 (area under the curve--AUC 0.585, 95 % CI 0.534-0.635) to have the best individual discriminatory capacity to predict a top-quality blastocyst prior to embryo compaction. The parameter tEB (AUC 0.727, 95 % CI 0.675-0.775) was the best predictor regardless of embryo stage. A model containing s3, t8 and tEB showed a slightly increased discriminatory capacity for top-quality blastocyst prediction (AUC 0.748, 95 % CI 0.697-0.794).

Conclusions: The identified morphokinetic parameters and their cutoffs, albeit of limited clinical value, add to the increasing knowledge concerning the potential predictive markers of a top-quality blastocyst. Additional evidence is necessary before validated time-lapse parameters can be used for embryo selection in IVF laboratories.
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http://dx.doi.org/10.1007/s10815-015-0534-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531856PMC
July 2015

To pill or not to pill in GnRH-antagonist cycles: the answer is in the data already!

Reprod Biomed Online 2015 Jul 9;31(1):6-8. Epub 2015 Apr 9.

Unit for Human Reproduction, 1st Department of Obstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.

The planning of IVF treatment by scheduling menstruation and hence initiation of ovarian stimulation using sex-steroid pre-treatment is commonly used. Pooling data from six randomized-controlled trials encompassing 1343 patients, with and without combined oral contraceptive pill pre-treatment, suggests that the ongoing pregnancy rate per randomized woman is significantly lower in patients with oral contraceptive pill pre-treatment (relative risk [RR]: 0.80, 95% confidence interval [CI]: 0.66-0.97; rate difference [RD]: -5%, 95% CI: -10% to -1%; fixed effects model). This finding remains remarkably robust in multiple sensitivity analyses: exclusion of a study on poor responders, exclusion of the three smallest studies or exclusion of studies with a pill-free interval of less than 5 days, results in RR of 0.78 (95% CI: 0.64-0.94), 0.80 (95% CI: 0.65-0.98) and 0.79, (95% CI: 0.64-0.99), respectively. Furthermore, the finding of a significant reduction in ongoing pregnancy rate is not inconsistent with other evidence from the literature. The potential benefit of using oral contraceptive pill pre-treatment for cycle planning should therefore be balanced against its detrimental effect. Further randomized studies should test whether an effect similar to the one observed after combined oral contraceptive pill usage exists after other sex steroid pre-treatment regimens.
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http://dx.doi.org/10.1016/j.rbmo.2015.04.001DOI Listing
July 2015

Estimating the net effect of progesterone elevation on the day of hCG on live birth rates after IVF: a cohort analysis of 3296 IVF cycles.

Hum Reprod 2015 Mar 12;30(3):684-91. Epub 2015 Jan 12.

Eugonia - IVF Unit, Athens, Greece.

Study Question: What is the proper way of assessing the effect of progesterone elevation (PE) on the day of hCG on live birth in women undergoing fresh embryo transfer after in vitro fertilization (IVF) using GnRH analogues and gonadotrophins?

Summary Answer: This study indicates that a multivariable approach, where the effect of the most important confounders is controlled for, can lead to markedly different results regarding the association between PE on the day of hCG and live birth rates after IVF when compared with the bivariate analysis that has been typically used in the relevant literature up to date.

What Is Known Already: PE on the day of hCG is associated with decreased pregnancy rates in fresh IVF cycles. Evidence for this comes from observational studies that mostly failed to control for potential confounders.

Study Design, Size, Duration: This is a retrospective analysis of a cohort of fresh IVF/intracytoplasmic sperm injection cycles (n = 3296) performed in a single IVF centre during the period 2001-2013.

Participants/materials, Setting, Methods: Patients in whom ovarian stimulation was performed with gonadotrophins and GnRH analogues. Natural cycles and cycles where stimulation involved the administration of clomiphene were excluded. In order to reflect routine clinical practice, no other exclusion criteria were imposed on this dataset. The primary outcome measure for this study was live birth defined as the delivery of a live infant after 24 weeks of gestation. We compared the association between PE on the day of hCG (defined as P > 1.5 ng/ml) and live birth rates calculated by simple bivariate analyses with that derived from multivariable logistic regression. The multivariable analysis controlled for female age, number of oocytes retrieved, number of embryos transferred, developmental stage of embryos at transfer (cleavage versus blastocyst), whether at least one good-quality embryo was transferred, the woman's body mass index, the total dose of FSH administered during ovarian stimulation and the type of GnRH analogues used (agonists versus antagonists) during ovarian stimulation. In addition, an interaction analysis was performed in order to assess whether the ovarian response (<6, 6-18, >18 oocytes) has a moderating effect on the association of PE on the day of hCG with live birth rates after IVF.

Main Results And The Role Of Chance: Live birth rates were not significantly different between cycles with and those without PE when a bivariate analysis was performed [odds ratio (OR): 0.78, 95% confidence interval (CI): 0.56-1.09]. However, when a multivariable analysis was performed, controlling for the effect of the aforementioned confounders, live birth rates (OR: 0.68, 95% CI: 0.48-0.97) were significantly decreased in the group with PE on the day of hCG. The number of oocytes retrieved was the most potent confounder, causing a 29.4% reduction in the OR for live birth between the two groups compared. Furthermore, a moderating effect of ovarian response on the association between PE and live birth rates was not supported in the present analysis since no interaction was detected between PE and the type of ovarian response (<6, 6-18, >18 oocytes).

Limitations, Reasons For Caution: This is a retrospective analysis of data collected during a 12-year period, and although the effect of the most important confounders was controlled for in the multivariable analysis, the presence of residual bias cannot be excluded.

Wider Implications Of The Findings: This analysis highlights the need for a multivariable approach when researchers or clinicians aim to evaluate the impact of PE on pregnancy rates in their own clinical setting. Failure to do so might explain why many past studies have failed to identify the detrimental effect of PE in fresh IVF cycles.

Study Funding/competing Interests: None.
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http://dx.doi.org/10.1093/humrep/deu362DOI Listing
March 2015

The association between exaggeration in health related science news and academic press releases: retrospective observational study.

BMJ 2014 Dec 9;349:g7015. Epub 2014 Dec 9.

Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff CF10 3AT, UK School of Psychology, Cardiff University, UK

Objective: To identify the source (press releases or news) of distortions, exaggerations, or changes to the main conclusions drawn from research that could potentially influence a reader's health related behaviour.

Design: Retrospective quantitative content analysis.

Setting: Journal articles, press releases, and related news, with accompanying simulations.

Sample: Press releases (n = 462) on biomedical and health related science issued by 20 leading UK universities in 2011, alongside their associated peer reviewed research papers and news stories (n = 668).

Main Outcome Measures: Advice to readers to change behaviour, causal statements drawn from correlational research, and inference to humans from animal research that went beyond those in the associated peer reviewed papers.

Results: 40% (95% confidence interval 33% to 46%) of the press releases contained exaggerated advice, 33% (26% to 40%) contained exaggerated causal claims, and 36% (28% to 46%) contained exaggerated inference to humans from animal research. When press releases contained such exaggeration, 58% (95% confidence interval 48% to 68%), 81% (70% to 93%), and 86% (77% to 95%) of news stories, respectively, contained similar exaggeration, compared with exaggeration rates of 17% (10% to 24%), 18% (9% to 27%), and 10% (0% to 19%) in news when the press releases were not exaggerated. Odds ratios for each category of analysis were 6.5 (95% confidence interval 3.5 to 12), 20 (7.6 to 51), and 56 (15 to 211). At the same time, there was little evidence that exaggeration in press releases increased the uptake of news.

Conclusions: Exaggeration in news is strongly associated with exaggeration in press releases. Improving the accuracy of academic press releases could represent a key opportunity for reducing misleading health related news.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262123PMC
http://dx.doi.org/10.1136/bmj.g7015DOI Listing
December 2014

Clinical implications of congenital uterine anomalies: a meta-analysis of comparative studies.

Reprod Biomed Online 2014 Dec 21;29(6):665-83. Epub 2014 Sep 21.

First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece; European Academy for Gynecological Surgery, Scientific project on Female Genital Tract Congenital Anomalies, Diestsevest 43/0001, 3000 Leuven, Belgium.

The clinical implications of congenital uterine anomalies (CUA), and the benefits of hysteroscopic resection of a uterine septum, were evaluated. Studies comparing reproductive and obstetric outcome of patients with and without CUA and of patients who had and had not undergone hysteroscopic resection of a uterine septum, were evaluated. Meta-analysis of studies indicated that the pregnancy rate was decreased in women with CUA (RR 0.85, 95% CI 0.73 to 1.00; marginally significant finding, P = 0.05). The spontaneous abortion rate was increased in women with CUA (RR 1.68, 95% CI 1.31 to 2.15). Preterm delivery rates (RR 2.21, 95% CI 1.59 to 3.08), malpresentation at delivery (RR 4.75, 95% CI 3.29 to 6.84), low birth weight (RR 1.93, 95% CI 1.50 to 2.49) and perinatal mortality rates (RR 2.43, 95% CI 1.34 to 4.42) were significantly higher in women with CUA. Hysteroscopic removal of a septum was associated with a reduced probability of spontaneous abortion (RR 0.37, 95% CI 0.25 to 0.55) compared with untreated women. Presence of CUA might be associated with a detrimental effect on the probability of pregnancy achievement, spontaneous abortion and obstetric outcome. Hysteroscopic removal of a septum may reduce the probability of a spontaneous abortion.
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http://dx.doi.org/10.1016/j.rbmo.2014.09.006DOI Listing
December 2014

Is assessment of anti-Müllerian hormone and/or antral follicle count useful in the prediction of ovarian response in expected normal responders treated with a fixed dose of recombinant FSH and GnRH antagonists? A prospective observational study.

Gynecol Endocrinol 2014 Nov 3;30(11):817-21. Epub 2014 Jul 3.

Unit for Human Reproduction, 1st Dept. of OB/Gyn, Medical School, Aristotle University of Thessaloniki , Greece .

The purpose of this prospective observational study was to evaluate whether the assessment of AMH and AFC is useful in the prediction of ovarian response in expected normal responders treated with a fixed dose of recombinant FSH (rec-FSH) and GnRH antagonists. A base model including age and basal FSH as independent predictors of COCs could explain 15% of the variance observed in the number of COCs retrieved (p = 0.002). The addition of AFC did not increase significantly the predictive ability of the above model, whereas the addition of AMH increased the performance of the base model by 13% (p < 0.001). Logistic regression analysis showed that only when AMH was added to the base model, including age and FSH, its predictive capacity for high ovarian response was statistically significant (F-test: p = 0.001; c-statistic: 0.80, 95% CI: 0.70-0.88), but this was not the case for poor ovarian response. In conclusion, the addition of AMH, but not of AFC, to a model including female age and basal FSH, is useful in the prediction of ovarian response in expected normal responders treated with a fixed dose of recombinant FSH and GnRH antagonists.
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http://dx.doi.org/10.3109/09513590.2014.938624DOI Listing
November 2014

The Bologna criteria for poor ovarian response: the good, the bad and the way forward.

Hum Reprod 2014 Sep 7;29(9):1839-41. Epub 2014 Jun 7.

Women's & Children's Health, St George Hospital, 2nd Level - Prichard Wing, Gray Street, Kogarah P.C. 2217, NSW, Australia School of Women's & Children's Health, Faculty of Medicine, University of New South Wales, Australia

The management of poor ovarian response (POR) remains one of the most significant challenges of in vitro fertilization. Numerous interventions have been proposed, yet few have been shown to be beneficial. The most important problem in evaluating the available evidence has been the lack of a standardized definition of POR. The Bologna criteria for POR have been recently introduced to provide a framework allowing future research in this field to be performed on a relatively homogenous population. However, it has been suggested that the population described by the Bologna criteria might not be sufficiently homogenous and for this reason stratified randomization should be used in relevant randomized controlled trials (RCTs). Stratified randomization, besides its advantages, also has important shortcomings and for this reason it should be used only when there is clear evidence mandating such a design. Currently, there is insufficient data to support such practice in RCTs performed on the population described by the Bologna criteria for POR. Until such evidence becomes available, the scientific community should aim at evaluating interventions for POR according to the Bologna criteria in RCTs of sufficient sample size, with proper allocation concealment and masking.
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http://dx.doi.org/10.1093/humrep/deu138DOI Listing
September 2014