European Society of Human Reproduction and Embryology

2019 HIGHLIGHTS OF THE ANNUAL MEETING OF THE EUROPEAN SOCIETY OF HUMAN REPRODUCTION AND EMBRYOLOGY

23rd-26th June 2019 Austria, Vienna

The purpose of this report is to capture highlights from the ESHRE 2019 congress. The REPROFACTS faculty has selected the studies presented in this report; putting study findings in perspective and extracting the practice points. The faculty members were independent in their choice of studies and their evaluation and this report is based on the REPROFACTS 2019 Post-ESHRE meeting. The development of this congress report has been financially supported by MERCK KGaA, whereas MERCK KGaA had no influence on the content and scientific opinions presented in the congress report do not necessarily represent the position of MERCK KGaA. MERCK KGaA is not responsible for the content of the report. Consequently, MERCK KGaA does not give any warranty, express or implied, regarding the scientific use of this report, orregarding any other particular use for any purpose, and MERCK KGaA therefore is not liable for any direct, indirect, incidental, or consequential damages related to the use of the information contained herein.

August 2019 GBPMLR/NONF/0819/0199 Sponsored by INTRODUCTION TO REPROFACTS This report containssome of the key highlightsfromthe REPROFACTS meeting2019. practice points.Thefaculty is totally independent intheir choice ofstudiesandtheir evaluation. of practicing cliniciansand embryologists, puttingstudyfindings inperspective and extracting the Frankfurt, Germany. TheREPROFACTS faculty presented their selection of studies to alarge audience Nine days after theconclusionofESHREmeeting, REPROFACTS meeting was held in conference. the background and finally selectingwhat theythinkrepresents the“must-know” content from the annual meeting,visitingthelectures,browsing the posters, speaking to the presenters, investigating Eight experts indifferent subspecialtiesshare among themthe whole scientific program of the from eachsubspecialty. For thatreason,theREPROFACTS initiative was founded in Germany in2011. not only understand thegeneral themes but to alsosingleout and focus onthe truly relevant news However, the wealth andbreadthofinformationcanmake it challengingfor individualdelegatesto program was trulypacked withinspiring content. counselling thepatient, to debates on the increasedincidenceof ICSI and freeze-all. The ESHRE 2019 The key themes ranged fromthe role of lutealphase support, male infertility and the importance of an additional789postersinelectronicformat. scientific program consisted of 234 peer-reviewed oral communicationsand63invited lectures, with in reproductive sciencefound a platformfor exchange and communicationatESHRE2019.Themain from 24to 26 June2019,attracting 12,003 delegates from130 countries. Allrelevant innovations event inthefieldof reproductive scienceand medicine. Thelatest Annual Meeting was heldinVienna, The Annual Meeting of ESHRE is considered by many to be theworld’s major and mostimportant Faculty members endometriosis, surgery endometriosis, surgery Vienna. Subspecialities: endometrium, Prof. Dr.med.KazemNouri and reproductivegenetics Münster. Subspecialities:basic science Nordhoff, Priv.-Doz. Dr.rer.nat.Verena law and ethics,psychology Berlin. Subspecialities: safety andquality, Prof. Dr.med.HeribertKentenich embryology Düsseldorf. Subspeciality: clinical Dr. rer.nat.JensHirchenhain

Münster. Subspeciality:andrology Prof. Dr.med.MichaelZitzmann ovarian reserve, early pregnancy Bern. Subspecialities:fertilitypreservation, Prof. Dr.med.MichaelvonWolff Prof. med.LudwigWildt and ovarian stimulation Lucerne. Subspecialities: female infertility Weiss Prof. Dr.med.habil.JürgenM. Innsbruck. Subspeciality: endocrinology

INTRODUCTION TO REPROFACTS CONTENTS Predicting lutealprogesterone levels Comparing biosimilartooriginator recombinant follitropinalfa Long vs classicalantagonistprotocol Freeze-all versus fresh embryo transfer Ovarian stimulation and infertility Endometriosis and the endometrium AMH asa driving force of PCOS Progesterone on theday ofembryo transfer Reproductive endocrinology Safety, psychology andcounselling Endometrial scratching after one failed IVF/ICSIcycle Linzagolix for endometriosis pain Frozen embryo transfer andmiscarriage rate GnRHa therapy before IVF AMH levels inadolescence and the presence of PCOS The long-termhealthof IVF-ICSI babies ART and risk ofcongenital heart defects Impact of the time interval betweenovulation triggering and oocyte injection Mobile appsand fertility IVF after caesareansection Andrology Fertility preservation Ovarian tumour risk afterART Clinical embryology De novo mutations affecting male infertility Blastocyst morphology and NIPGT-A accuracy ICSI versus conventional IVF Gene editing–past, present andfuture Outcomes from differentovarian tissuegrafting sites Oocyte aging Sperm morphologyasa marker ofnuclearquality and epigenetic status Impact of male factors on ICSIoutcomes

CONTENTS A large prospective trial in unselected population confirms that A large prospective trial in unselected population confirms that low serum progesterone on the day of embryo transfer impairs low serum progesterone on the day of embryo transfer impairs pregnancy outcome in artificial cycles, O-1731 pregnancy outcome in artificial cycles, O-1731

REPRODUCTIVE ENDOCRINOLOGY E. Labarta Demur et al E. Labarta Demur et al REPRODUCTIVE ENDOCRINOLOGY

Background blastocyst transfer after endometrial preparation After adjusting for the confounders age, body with 2x400mg vaginal progesterone. On the Artificial frozen-thawed embryo transfer cycle mass index (BMI), endometrial thickness, serum day of embryo transfer, the serum level of regimens often exclusively employ vaginal E2, number of embryos transferred and origin of progesterone was measured.1 progesterone for secretory transformation of the oocytes, low progesterone levels defined as <8.8 endometrium and for early pregnancy support.2 ng/mL remained a significant negative predictor Results for ongoing pregnancy (OR 0.39, 95% CI:0.28- In a previous publication, Elena Labarta et al 1 The mean serum progesterone level was 0.53, p=0.000). have already suggested that the serum levels of 12.0±5.8 ng/mL. Serum progesterone levels progesterone achieved by vaginal administration were associated with ongoing pregnancy in Key Findings may be insufficient for optimal outcomes for univariate analysis. Women with serum P levels a substantial proportion of oocyte donation This study adds to the existing concerns about <8.8 ng/mL (percentile 30) had a significantly recipients.3 only using vaginal progesterone for luteal phase lower ongoing pregnancy rate compared to support in the context of an anovulatory artificial 1 patients above this threshold. (Figure 1) cycle, where endometrial receptivity and early Watch Prof. Ludwig Wildt discuss measuring progesterone Study Summary in the luteal phase pregnancy completely rely on the exogenous The present prospective cohort study included progesterone source.3-6 1155 patients undergoing either autologous or heterologous frozen-thawed embryo transfers in artificial anovulatory cycles. All patients had a

60 58.0 Practice message

50 Artificial frozen-thawed embryo transfer cycles are highly vulnerable due to absence of a corpus luteum.3,6 Vaginal progesterone alone might not be sufficient in this scenario.3 39.8 40

Ongoing Pregnancy Rate (%) Ongoing Pregnancy Rate 10

0 <8.8 ng/mL ≥8.8 ng/mL Serum progesterone levels

RR 0.69, CI: 0.59-0.79, p<0.0001

Figure 1: Ongoing pregnancy rate at different levels of serum progesterone1 REPRODUCTIVE ENDOCRINOLOGY been demonstrated in humans. hormone (GnRH)neurons by AMH,hasnot yet via central stimulationof gonadotropin-releasing association of AMHwith LH levels, hypothetically compared to the controls. high or low serum AMH levels inPCOSwomen metabolic and ultrasound variables related to performed to identify which clinical, hormonal, non-PCOS controls. Adiscriminant analysis was Rotterdam criteria)werecomparedwith 137 PCOS patients(diagnosedaccordingtothe In this retrospective mono-centricstudy, 639 Study Summary of androgenviathecacellstimulation. (LH) levels, whichmay contributeto an excess often have high serumluteinizinghormone Polycystic ovary syndrome (PCOS) patients Background independently from insulin-resistance,O-009 Antimüllerian Hormoneasadrivingforce of PCOS, follicle numbers in thepolycystic ovary. Müllerian hormone(AMH) serum levels and is alsohighcorrelationbetween elevated Anti- G. Robin rather thana“metabolic phenotype”. PCOS patientswith high AMHappear to show moreof an“ovarian phenotype” Practice message et al

1 1 1 There There 1 The The hyperandrogenic anovulation). an AMHdependentphenotype of PCOS(e.g. effect of AMH on LHsecretion which drives These observations hint atastimulatory Key Findings increases anddecreasesinmany variables. In PCOSpatients,higher AMH was related to with age and number of follicles. In the control patients, AMH was only associated Results (Figure 1) in PCOSpatients Figure 1: Variables associated with higher AMH Increasing > oligo-anovulation hyperandrogen of androgens serum levels serum serum levels numbers follicle follicle of LH

1 1

1 plasma insulin plasma insulin circumference

incidence of incidence of serum FSH 1 (I) levels obesity waist BMI

Decreasing > Decreasing patients. Patients underwent: This prospective cohortstudyassessed 432 Study Summary progesterone or dydrogesterone. introduced to the market, such as subcutaneous luteal phasesupport have been testedand more and moreinterest.New compounds for The lutealphase of the fresh IVF cycle is eliciting luteal phaseofan IVF cycle. subsequent serumprogesteronelevels inthe of ovarian progesteroneproductionand As yet, little isknownaboutotherdeterminants amount of circulating progesterone. corpora lutea isa strong determinant of the total under debate. It is assumed that the number of cycle aftercontrolled ovarian stimulation,isstill luteal phaseofa fresh invitrofertilization (IVF) The optimalserum progesterone level in the Background O-177 in IVF patients - A prospective study of 432 IVF/ICSI cycles, Luteal serum progesteronelevels cannot be predicted potentially, fetal health. pregnancy course, maternal healthand, not only a determinant of success, but also corpus luteum function isnow considered L. Thomsen etal • • • • vaginal progesterone Identical lutealphase support regimens using Fresh embryo transfer oocyte maturation hCG or GnRH-agonist triggering of final GnRH-agonist or GnRH-antagonist protocol Controlled ovarian stimulation inalong 1 5,6

1 3,4 Also, the 2 assessed by linearregression modelling: following predictorsof progesterone levels were progesterone levels weremeasured. The Two to threedays after oocyte retrieval, serum form ofimpairmentcorpusluteum function. speculate thatsomepatientssufferfrom cannot reliablybe done. Theauthors therefore and treatmentcharacteristics, respectively, predicting the serum progesterone from patient in serum levels between patients. In other words, explain only approximately 50%ofthevariation It was found that allfactorstaken togethercould Key Findings Numberof final follicles Type of gonadotropin Total gonadotropin dose Smoking Duration ofstimulation Protocol type The dayof progesterone assessment Type of ovulation trigger BMI Age

1 1

REPRODUCTIVE ENDOCRINOLOGY

Long-term gonadotrophin-releasing hormone agonist (GnRHa) Anti-Müllerian hormone levels in adolescence in relation to therapy before in vitro fertilisation (IVF) for improving fertility long-term follow up for presence of polycystic ovary syndrome, outcomes in women with endometriosis: a Cochrane systematic THE ENDOMETRIUM O-0101 review and meta-analysis, O-2081 ENDOMETRIOSIS AND

M. Caanen et al E. Georgiou et al REPRODUCTIVE ENDOCRINOLOGY

Background morphology (PCOM) compared with regular Background There was no difference in miscarriage cycling girls (Figure 1).1 rate, multiple pregnancy rate or number of Diagnostic criteria for polycystic ovary syndrome The 2013 ESHRE guideline on the management embryos (PCOS) must not be applied to adolescents as In the follow-up study, 11.9% of females were of women with endometriosis states that irregular cycles are frequent, clinical signs of diagnosed with PCOS. These women had higher clinicians can prescribe GnRH-analogues for There was a lack of data on adverse events hyperandrogenism are difficult to classify and AMH in adolescence as compared to women a period of 3 to 6 months prior to assisted such as ectopic pregnancy rate or fetal there is lack of normal references for ovarian without PCOS (4.7 vs. 3.6 μg/L, p=0.051). reproduction in order to increase pregnancy rates abnormalities 2 morphology.2 (Figure 1) The same phenomenon was observed in infertile women with endometriosis. for adults with oligomenorrhea.1 It was noted that the quality of the evidence Study Summary Study Summary was not consistently high and there was Serum AMH measured in adolescence was a poor heterogeneity in studies and outcomes.1 Between 1990 and 1997, adolescents with predictor of PCOS in adulthood, especially given A Cochrane systematic review and meta- 1 analysis summarized seven randomized studies, menstrual irregularities were included in this the incidence of oligomenorrhea in adolescence. Key Findings Dutch long-term follow-up study. 271 stored incorporating 496 women, on the effects of a adolescent serum samples were available from In the words of Caanen and colleagues: “Given minimal treatment period of three months with The available evidence indicates a small benefit 1 this cohort.1 Anti-Müllerian hormone (AMH) adolescent oligomenorrhea, using high AMH GnRH-agonists prior to IVF/ICSI. for pregnancy rate of GnRH-agonist treatment 1 was now measured and information on current as factor to predict adult PCOS or adult oligo- prior to IVF/ICSI. 1 menstrual cycle pattern and presence of PCOS amenorrhea was of no value”. Results 1 features in the grown up females was collected. 1 Key Findings It was found that:

Results This unique long-term follow-up project Clinical pregnancy rate (RR 1.31, 95% CI confirmed the association of AMH measured 1.05 to 1.64) and mean number of oocytes It was found that AMH levels at adolescence in adolescence with the development of signs (MD 1.09, 95% CI 0.32 to 1.86) were were already significantly higher in girls who of PCOS. However, serum AMH measured in increased after GnRH-agonist treatment had oligo-amenorrhea or polycystic ovarian adolescence is not a clinically useful predictor of Live birth rate was only reported in one PCOS in the adult.1 small study and thus no robust conclusion is 6 5.5 currently possible 5.2 5 4.7

4 3.6 3.1 3.1 Practice message 3

AMH (µg/L) Subfertile patients with endometriosis should be counselled about the available evidence. 2

PCOM No PCOM Adult PCOS Normal cycle No adult PCOS Oligomenorrhea

Figure 1: Girls with oligomenorrhea, PCOM and who later develop PCOS have higher serum AMH levels in adolescence than normal controls.1

Artificial cycle for frozen embryo transfer is associated with Artificial cycle for frozen embryo transfer is associated with increased miscarriage rate compared to natural/stimulated increased miscarriage rate compared to natural/stimulated THE ENDOMETRIUM THE ENDOMETRIUM ENDOMETRIOSIS AND cycle: a large multicenter cohort study (14,421 cycles), O-0211 cycle: a large multicenter cohort study (14,421 cycles), O-0211 ENDOMETRIOSIS AND

L. Vinsonneau et al L. Vinsonneau et al

Background Study Summary After adjustment for available confounders, Key Findings including maternal age and previous miscarriage, Incidence of frozen-thawed embryo transfers This multicentric retrospective study evaluated This study adds to the growing body of evidence the artificial cycle was associated with a (FET) is increasing due to the use of freeze 14,421 FET cycles, corresponding to 3,844 evidence that the suppression of ovulation and significantly higher risk of miscarriage.1 (Table 2) all cycles for patients at risk of developing pregnancies.1 (Table 1) the lack of a corpus luteum in early pregnancy ovarian hyperstimulation syndrome (OHSS) and Accordingly, the live birth rate (LBR) was lower in associated with artificial cycles may be Results 3 undergoing preimplantation genetic diagnosis artificial cycles.1 associated with decreased efficacy. 2 (PGD). Frozen-thawed embryos may be The artificial cycle was most frequently used transferred in a natural cycle (with or without Further data discussed at the ESHRE meeting overall (56.6% of all cycles) and more often used indicated that the lack of a corpus luteum may hCG triggering and luteal phase support), an in women with a history of ovulatory disorder 1 also be associated with changes in the maternal anovulatory artificial cycle or a stimulated cycle. 1 and previous pregnancy. 40 cardiovascular system with implications for To date, there is no consensus on the optimal 36.50 1,4-6 protocol for efficacy, maternal safety or fetal The miscarriage rate was highest in the artificial 35 preeclampsia and long-term fetal health. 1 safety. cycle and lowest in the stimulated cycle. (Figure 1) 30 25.60 25 23.60

15 Table 1: The number of pregnancies associated with each protocol1 Miscarriage rate (%) rate Miscarriage 10

5 Protocol Number of women Pregnancies 0 Artificial cycle Natural cycle Stimulated cycle Artificial cycle 8139 2214 Protocol Natural cycle 3126 812 Figure 1: The miscarriage rate associated with Stimulated cycle 3156 818 each endometrial preparation protocol1

Total 14421 3844

Practice message Table 2: A comparison of miscarriage rate between protocols following multivariate regression1

Use of natural or stimulated ovulatory FET cycles may be preferential to an artificial FET cycle. OR 95% CI P value

Artificial vs natural cycle 1.63 [1.35-1.97] P<0.0001

Artificial vs stimulated cycle 1.87 [1.55-2.26] P<0.0001

Linzagolix for treating endometriosis-associated pain: efficacy Linzagolix for treating endometriosis-associated pain: efficacy and safety results from a randomized, placebo-controlled, and safety results from a randomized, placebo-controlled, THE ENDOMETRIUM THE ENDOMETRIUM ENDOMETRIOSIS AND multinational, phase 2b dose-ranging trial, O-1411 multinational, phase 2b dose-ranging trial, O-1411 ENDOMETRIOSIS AND

E. Bestel et al E. Bestel et al

Background Results Key Findings 80 Sex steroid withdrawal via GnRH-analogue Compared to placebo, doses ≥75 mg resulted Linzagolix is the third orally active GnRH- 70 administration is an established therapy for in a significant increase in patients reaching the 61.5 antagonist tested for endometriosis therapy (p=0.003) 56.4 56.3 1 1 endometriosis-associated pain. Low levels of primary endpoint. (Figure 1) 60 (p=0.039) (p=0.034) following the large trial on Elagolix in 2017 and 49.5 2,4 estrogen and progesterone induced by GnRH- (p=0.155) ASP1707. Orally active GnRH-antagonists analogues can affect bone mineral density and A similar pattern of results was seen for 50 may form the treatment standard of the future. overall quality of life.2,3 Linzagolix is a novel, dysmenorrhea and non-menstrual pelvic pain. A 75mg dose of oral Linzagolix will be tested 40 39.8 non-peptide orally active gonadotropin-releasing The effects were maintained or increased at 24 in a larger phase III trial. Also, the impact of

1 Patients % hormone antagonist that reduces circulating weeks. 30 estrogen/progestogen add-back to Linzagolix serum sex steroid levels.1 treatment still needs to be established.1 Median E2 levels changed from 35 to 47pg/mL 20 with a 75mg dose and from 12.5 to 13 pg/mL Study Summary with a 200 mg dose.1 10 In this phase II study, women with 0 Changes in bone mineral density from baseline endometriosis-associated pain received oral Placebo 50 75 100 200 to week 24 were reported for doses 75-200mg.1 Linzagolix once daily in doses of 50, 75, 100 Dose (mg) (Table 1) or 200 mg taken for 24 weeks. The primary endpoint was the proportion of subjects reporting a ≥30% reduction in pelvic pain over 28 days Figure 1: Proportion of patients reporting a 1 assessed on a Verbal Rating Scale.1 ≥30% reduction in pelvic pain over 28 days

Table 1: BMD changes for lumbar spine from baseline to week 241

Practice message Mean percent (95% CI) Dose P-value BMD change Linzagolix has been shown to reduce endometriosis related pain however this must be confirmed in larger trials. 50 0.137% (-0.83, +1.11) P=0.777

75 -0.798% (-1.57, -0.03) P=0.042

100 -1.365% (-2.14, -0.59) P<0.001

200 -2.602% (-3.56, -1.65) P<0.001 ENDOMETRIOSIS AND THE ENDOMETRIUM O-023 cycle: results of a randomized controlledtrial (SCRaTCH trial), Endometrial scratching in women after onefailed IVF/ICSI Figure 1: LBR outcomes fromthe SCRaTCH trial 942 participantswithone failed intracytoplasmic In the multicenter, non-blinded SCRaTCH trial, Study Summary patients undergoing invitrofertilization(IVF). endometrial scratching improves live birthrate in (RCTs) have beenconflictingas towhether Data frompastrandomized controlledtrials Background rate (LBR). scratching had no significant effect on live birth The PIP trial suggestedthat endometrial population. procedure andinsufficient homogeneity of the for a lackof standardization of the scratching presented at the 2018ESHRE annual meeting. The PIP trial involved 1,364 participants and was N.E. van Hoogenhuijze LBR (%) 10 15 20 0 5 1

3 2 However, thePIPtrialwas criticized et al Scratch 18.9 LBR = live birth rate per first embryo transfer RR 1.35,95%CI: 1.01-1.81, p=0.043 2 3

luteal phase,priorto ovarian stimulation. using anendometrial biopsy catheter in the mid- Participants underwent endometrialscratching sperm injection (ICSI)/IVF cycle wererecruited. of scratching. the available evidence is not consistently infavor with endometrialscratching in the SCRaTCH trial, Despite asmall non-significant increase in LBR Key Findings cycle was analyzed. (Figures 1and 2) was not present whenthe cumulative LBR per scratching inthe fresh IVFcycle but this effect The LBR was increasedfollowing endometrial Results No scratch 14.0 1,2 1 1

Figure 2: Cumulative LBR outcomesfromthe SCRaTCH trial O-023 cycle: results of a randomized controlledtrial (SCRaTCH trial), Endometrial scratching in women after onefailed IVF/ICSI Cumulative LBR (%) N.E. van Hoogenhuijze Scratching may notimprove pregnancy outcomes for women with failed IVF cycles. Practice message 10 15 20 25 0 5 1

cumulative LBR =live birthrate per firstembryo transfer and et al Scratch 23.6 RR 1.14,95%CI: 0.9O-1.46, p=0.271 subsequent frozen-thawed cycles No scratch 20.8 4

ENDOMETRIOSIS AND THE ENDOMETRIUM OVARIAN STIMULATION AND INFERTILITY treatment. or withdrawal bleeding after sexsteroid pre- on the occurrenceof spontaneous menstruation protocol isthat the initiationof stimulation relies A major drawback of the GnRH-antagonist protocol. may stillusethe long luteal GnRH-agonist achieving comparable pregnancy outcome, O-237 efficiently downregulate LHduring ovarian stimulation for IVF Single lutealuse of long-acting GnRH-antagonist Degarelix can Long-Antagonist protocol versus Classical-day-6 Antagonist. 113 womenreceived either: In a small, randomized proof-of-concept study, Study Summary friendliness andsafety. vitro fertilization (IVF), because of its patient stimulation regimen in women undergoingin from cycle day 5 or 6hasbecomeawidelyused with daily 0.25mgantagonist administration The GnRH-antagonist multiple dose protocol Background rates. blastocyst numbers, respectively, and pregnancy no difference was observed for oocyteand in the long luteal antagonist protocol, while The duration of stimulation was slightlylonger Results E. Papanikolaou etal • • the stimulation cycle regimen withfirstadministration onday 6of a multi-dose,0.25mgGnRH-antagonist stimulation cycle, or Degarelix in the lutealphasepreceding the 0.5ml of the long-acting GnRH-antagonist 1

3 Thisisonereasonwhy many centers 2,3

1 future studies. including side-effects, needto be addressed in help incycle scheduling but a numberofissues, A long luteal GnRH-antagonist protocol may Key Findings day 6insteadof daily0.25mgGnRH-antagonist. use ofa single doseof0.1mlDegarelix on cycle report from Najdecki etalwhichevaluated the This years’ ESHRE meeting saw another trial Degarelix administration. successfully performed inallpatients after Remarkably, GnRH-agonist triggering was 1 1 1 1

live birth. surrogate primaryoutcomes for pregnancy and on an abbreviated approval procedure with follitropin alfa have enteredthemarket based alfa, lostitspatentprotection, biosimilars to After one oftheoriginatorcompounds, follitropin cells forpharmaceuticaluse. glycoprotein expressed inChinesehamster ovary Follicle stimulatinghormone(FSH)isacomplex Background undergoing IVF/ICSI,O-238 versus OriginatorRecombinant Follitropin Alfa inwomen A systematicreview and meta-analysis comparingBiosimilar study. studies respectively, and Ovaleap inthethird preparations were Bemfola and Afolia intwo three randomized controlled trials.Thebiosimilar A systematicreview and meta-analysis reviewed Study Summary Table 1:Clinicaloutcomesusingbiosimilarscompared with theoriginator preparation S. Longobardi etal 1 OHSS (moderate tosevere) 3,4

Clinical pregnancyrate Clinical outcome Live birthrate 2

1 investigations. efficacy outcome.This finding warrants further difference for live birth rate, theprimary authors indicated astatistically significant studies on biosimilars to follitropin alfa,the After meta-analyzing these small sized individual Key Findings (OHSS) was observed. difference inovarian hyperstimulation syndrome significantly lowerwhenusingbiosimilars.No live birth rate andclinicalpregnancy rate was Compared withthe originator preparation, the Results statistically andclinicallyhomogenous. 1.30 (0.83-2.70) 0.83 (0.71-0.96) 0.82 (0.70-0.97) RR (95%CI) 1 1 (Table 1) Thetrialswere 1 1

OVARIAN STIMULATION AND INFERTILITY

Freeze-all versus fresh embryo transfer in ART: A multicentre Freeze-all versus fresh embryo transfer in ART: A multicentre AND INFERTILITY AND INFERTILITY 1 1 OVARIAN STIMULATION randomised controlled trial in normo-ovulatory women, O-069 randomised controlled trial in normo-ovulatory women, O-069 OVARIAN STIMULATION

S. Stormlund et al S. Stormlund et al

Background • GnRH agonist trigger and single vitrified- In the fresh embryo transfer group, 25 warmed blastocyst transfer in a subsequent participants were converted to freeze-all due A number of large randomized controlled trials natural cycle, or to risk of ovarian hyperstimulation syndrome (RCTs) comparing fresh vs. frozen embryo (OHSS). One case of OHSS with hospital transfer have been published in the last four • hCG trigger and single blastocyst transfer in admission occurred in the fresh transfer group.1 years.2-5 the fresh cycle

1 Key Findings A recent systematic review and meta-analysis All participants were normo-ovulatory. of the available RCTs reported a significantly The findings of this RCT do not support general higher probability of live birth in high, but not Results utilization of a freeze-all approach in normo- normal responders, after the first frozen embryo The ongoing pregnancy rate (OPR) per ovulatory women but rather a freeze-all for transfer (ET) in a freeze-only cycle strategy when randomized patient after the first potential distinct patients, such as hyper-responders 6 compared to a fresh ET. blastocyst transfer was comparable in the freeze- or those where an impairment of endometrial Watch Prof. Jurgen Weiss discuss whether 1 receptivity is suspected.1 Study Summary all group and the fresh transfer group. (Figure 1) freeze-all is appropriate for all

In a multicenter, randomized trial conducted in OPR per embryo transfer (only including patients Denmark, Sweden and Spain, 460 women were who had a transfer) was also comparable in the allocated 1:1 to either undertake:1 freeze-all group compared with the fresh embryo transfer group.1 (Figure 2)

40 40 Practice message 36.8 36.1 35 35 Normoresponder patients should not routinely defer fresh embryo transfer. 30 28.8 30 26.1

25 25

20 20

15 15

10 10 Ongoing Pregnancy Rate (%) Ongoing Pregnancy Rate Ongoing Pregnancy Rate (%) Rate Pregnancy Ongoing 5 5

0 0 Fresh Frozen Fresh Frozen Embryo transfer Embryo transfer OR 0.88, 95% CI 0.58-1.34; p=0.54 OR 0.97, 95% CI 0.62-1.52; p=0.89

Figure 1: Ongoing pregnancy rate (OPR) per Figure 2: Ongoing pregnancy rate (OPR) patient1 per embryo transfer1

Treatment factors and the risk of specific congenital heart Treatment factors and the risk of specific congenital heart AND COUNSELLING AND COUNSELLING SAFETY, PSYCHOLOGY defects, O-0631 defects, O-0631 SAFETY, PSYCHOLOGY

M. Davies et al M. Davies et al

Background All associations were identified as positive Table 1: Estimated risks for congenital heart defects1 in direction, meaning that the authors only Assisted reproductive techniques are associated observed increases in risk. The distribution of with an increased risk of birth defects.2 In births multiple increased risks with ART is unlikely to be Defect (subgroup) aOR 95% CI from assisted reproductive technology (ART), random.1 congenital heart defects are more common than Any cardiac defect (IVF & ICSI combined) 1.42 1.13-1.80 natural births, with an estimated incidence of Key Findings 0.8% after natural conception and 1.6% after Congenital Aorta Valve Stenosis (IVF & ICSI combined) 3.20 1.26-8.11 A RT. 1 Techniques of ART, including ovarian stimulation, are associated with an increased risk of serious Patent Ductus Arteriosus (IVF & ICSI combined) 1.88 1.18-3.00 Study Summary cardiac defects.1

In this registry-based cohort study, all deliveries The subgroup findings on distinct medications Patent Ductus Arteriosus (only fresh IVF) 2.69 1.32-5.48 (n=302,811) and terminations of pregnancy in and culture media from this study need South Australia from January 1986 to December corroboration from further epidemiological Patent Ductus Arteriosus (only frozen ICSI) 4.59 1.84-11.44 2002 were linked to all cycles of ART (6,163 research. births) for the same period.1 Of note, a history of infertility without ART Coarctation Of Aorta (only if ovulation induction with clomiphene) 5.90 1.05-33.11 The registry included information on births is also associated with an increased risk for and terminations of pregnancy. These were organ malformations, as has been shown in Patent Ductus Arteriosus (Culture medium X, IVF) 5.56 1.31-23.53 linked to all cycles of ART and to all congenital previous studies.3,4 Mechanistic studies are now anomalies (defined using ICD-9 British Paediatric also needed for a better understanding of the Endocardial Cushion Defects (spontaneous conception after ART) 4.06 1.43-11.50 th Association codes) notified up to the 5 birthday. underlying pathways and for finding ways to Logistic regression was used to investigate Cardiac Septal Closure Anomalies decrease exposure by treatment. 1.90 1.12-3.23 associations between parental factors, treatment (history of “infertility” but no IVF) modality and the presence of congenital heart defects.1 Atrial Septal Defect (history of “infertility” but no IVF) 3.65 1.88-7.12

Results Patent Ductus Arteriosus (history of “infertility” but no IVF) 3.09 1.26-7.56 Multiple comparisons including drug administration and culture media revealed:1 aOR= adjusted odds ratio; 95% CI = 95% confidence interval (Table 1)

• Increased risk for Patent Ductus Arteriosus was associated with fresh in vitro fertilization Practice message (IVF) cycles and frozen intracytoplasmic sperm injection (ICSI) cycles Counselling patients on the risks associated with ART must include counselling specifically on • Clomiphene citrate treatment for ovulation the risk increase of congenital heart defects. induction was associated with Coarctation Of Aorta • One culture medium was associated with an increased risk of Patent Ductus Arteriosus for both fresh IVF and ICSI SAFETY, PSYCHOLOGY AND COUNSELLING national registries, O-091 Alarming findings when using administrative databases and C. Bergh Watch Prof. HeribertKentenich discussresearchonthelong-termhealth effects of ART 1 technology, O-183 Long-term riskof ovarian tumoursafter assistedreproductive cancers. fully consistent, especially for invasive ovarian (ART) in follow-up studies, but results are not associated with assisted reproductive technology risk increases for ovarian tumorshave been Netherlands. historical cohortwithprospective follow-up inthe The OMEGAstudywas based on a nationwide Study Summary ovarian physiology. stimulation and oocyteretrieval alter normal Manipulation of pituitary function, ovarian Background National Cancer Registry data was linked with: group) between1980 and 2001. subfertility treatments otherthanART (non-ART IVF centersand9,969womenwhounderwent between 1983 and 2001in one of the12 Dutch received ovarian stimulation for ART (ART group) This cohort included 30,636 women who M. Spaanet al • • performance and lifestyle factors Updated informationonreproductive The initialmedicalrecords on ART treatment study found no increasedriskfor invasive cancers after ART. ovarian cancer lateron.Patients shouldbe counselled that this recent large epidemiological Patients undergoing ovarian stimulation and oocyte pick-up may be worried about developing Practice message 3 4

2 Sofar, no alarming 1 1 1 data (>25 years) was examined. numbers ofcycles or when long-termfollow-up The riskwas also not increased with higher subfertile subjectsnotundergoingART. because of the use of an internal control group of size and theprospective follow-up, butalso valid datanot only because of the large sample The OMEGAstudyprovides robust and externally Key Findings respectively (HR1.03, 95% CI:0.70-1.52). vs. 35/10,000 in ART and non-ART subjects found, with an estimated incidence of 36/10,000 increased riskof invasive ovarian cancers was After a median follow-up of 22 years, no Results regression analysis. explored by multi-variable time-dependentCox Associations with ovarian cancer risk were 1 1 1 1

SAFETY, PSYCHOLOGY AND COUNSELLING

A systematic review and meta-synthesis of mobile device Oocyte quality during reproductive aging: Are the chromosomal AND COUNSELLING SAFETY, PSYCHOLOGY fertility applications: More than a glitch in the matrix!, O-1011 abnormalities the only problem?, O-0531 FERTILITY PRESERVATION

S. Costa and A. Yazdani S. Ledda and D. Bebbere

Background Key Findings Many women trying to conceive use fertility and Fertility and cycle applications are often cycle tracking apps to track their cycle.1 Between unreliable.1 2015 and 2019, the number of fertility apps has increased by 47%. However, the validity of mobile device fertility apps has not been systematically evaluated to date.1

Study Summary iTunes and Google Play were systematically searched for iOs and Android applications (paid and free, restricted to English). 381 applications were included, reviewed and scored independently by several researchers based on a predetermined matrix.1

Results Watch Prof. Kazem Nouri discuss the role of mobile Less than 10% of applications cited published applications in fertility literature or professional guidelines. A significant number of applications made unrealistic and unsubstantiated claims with respect to efficacy, while development, functionality, ownership, and store ranking were often not transparent.1 Watch Prof. Verena Nordhoff discuss oocyte aging and the role of chromosomal abnormalities

Practice message

Patients should be advised to exercise caution when using fertility apps. Adverse/ reproductive outcomes of reduced pregnancy and live Adverse/ reproductive outcomes of reduced pregnancy and live birth rates after In Vitro Fertilization in women with previous birth rates after In Vitro Fertilization in women with previous caesarean section: a retrospective cohort study, O-3011 caesarean section: a retrospective cohort study, O-3011 FERTILITY PRESERVATION FERTILITY PRESERVATION

J. Vissers et al J. Vissers et al

Background Study Summary Results Caesarean section (CS) is the most common This retrospective cohort study included all It was found that live birth rates were surgery performed around the world.2 The rates women who underwent an in vitro fertilization significantly lower in women after a CS. (Table of delivery by CS are rising on a global scale (IVF) or intracytoplasmic sperm injection 1) The rate of difficult transfers was higher in the with ART associated with greater odds of CS (ICSI) cycle at a single academic center in CS group (9.3% vs. 1.0%).1 compared with fertile women.3,4 the Netherlands between 2006 and 2016 with one previous delivery (1317 women total, 334 Key Findings Sequelae of CS include niches (scar defects), women with a previous caesarean section, 983 2 As the quality and number of embryos bleeding disorders and obstetrical complications. women with a previous vaginal delivery).1 It has previously been reported that non-IVF transferred was similar between the groups, patients who underwent a CS had a 9% lower Only the first fresh embryo transfer was this study suggests that a CS scar may have an subsequent pregnancy rate [RR 0.91, 95% CI considered for the analyses.1 impact specifically on implantation, since in an Watch as Prof. Michael von Wolff shares key insights on (0.87, 0.95)] and 11% lower birth rate [RR 0.89, IVF population confounding from alterations of caesarean section and future fertility 95% CI (0.87, 0.92)] compared with patients Multivariable logistic regression analyses sperm transport or tubal function cannot play a who had delivered vaginally.5 were performed with adjustment for possible major role.1 confounders (age, BMI, smoking, indication for However, the available study results are not IVF/ICSI, uterine pathology, endometrioses, completely consistent.6 It has been suggested duration of infertility) to study the association of that a woman’s clinical and social circumstances a previous CS on the outcome of the subsequent play larger roles for future fertility than the IVF cycle.1 surgical procedure itself.6

Table 1: Estimated impact on IVF treatment outcome of a previous cesarean section7 Practice message

Previous CS Previous VD aOR (95% CI) Elective caesarean sections should be discouraged if a woman intends to have further children n=334 n=983 via IVF.

Clinical Pregnancy rate (%) 25.7 33.8 0.76 (0.56-0.90)

Miscarriage rate (%) 22.1 16.9 1.40 (0.78-2.51)

Extra-uterine pregnancy rate 0 0.2 -- (%)

Live birth rate (%) 15.9 23.3 0.63 (0.45-0.87)

CS = cesarean section; VD = vaginal delivery; OR= odds ratio; 95% CI = 95% confidence interval Outcomes from heterotopic and orthotopic grafting of human 1 1 cryopreserved ovarian tissue, O-135 Gene editing – past, present and future, O-002 CLINICAL EMBRYOLOGY FERTILITY PRESERVATION

D. Gook et al B. Davies

Background Results Approximately 120 live births from autologous Similar outcomes were observed with both graft re-transplantation of cryopreserved ovarian sites including:1 (Table 1) tissue have been reported to date.1 The optimal site for grafting is still under debate. • Number of oocytes recovered • Number of mature oocytes Study Summary • Proportion of fertilized oocytes which In this retrospective cohort study, 18 women cleaved on day 2 with previously cryopreserved ovarian tissue, had Overall, the number and quality of oocytes from autografts into a pelvic peritoneal pocket close to the abdominal site were similar to the oocytes the ovary or an abdominal pocket.1 from the pelvic sites.1 After resumption of cycling, these women Key Findings received ovarian stimulation and transvaginal or transabdominal oocyte retrieval.1 This study suggests that the previous notion of a benefit of the ‘ovarian niche’ for the autografted tissue may be incorrect.2

Table 1: Outcomes from ovarian grafting1

Oocyte retrieval Mature oocytes Embryos developed failure (%) retrieved (%) on day 2 (%) Watch Prof. Verena Nordhoff explain the role of gene editing and what we can expect in future

Abdominal site 29.8 66.7 88.9

Pelvic site 33.3 63.5 86.5 ICSI does not offer any benefit over conventional IVF across ICSI does not offer any benefit over conventional IVF across different ovarian response categories: a European multicenter different ovarian response categories: a European multicenter 1 1 CLINICAL EMBRYOLOGY analysis, O-228 analysis, O-228 CLINICAL EMBRYOLOGY

P. Drakopoulos et al P. Drakopoulos et al

Background Only one cycle, the first per patient, was included fertilization rate 61 ± 23% vs. 60 ± 27% in case of GnRH-antagonist stimulation and in p=0.90) and this was the case for all ovarian On a global scale, intracytoplasmic sperm case of a normal sperm analysis (as per 5th response subgroups.1 injection (ICSI) is increasingly being used to edition of the WHO manual).5 inseminate oocytes instead of in vitro fertilization The total number of transferred and 1 (IVF). The underlying assumption for the Patients were divided into 4 groups based on cryopreserved embryos per number of fertilized preferential use of ICSI is that it provides a their ovarian response: oocytes was also similar between groups, better chance of fertilization, which would be irrespective of the ovarian response category.1 especially appropriate in case of low ovarian • Group 1: poor responders (1-3 oocytes) (Figure 1) The type of insemination was also not response where only a few oocytes are • Group 2: suboptimal responders (4-9 a predictor of live birth or cumulative live birth in 1 1 available. oocytes) a multi-variable regression analysis. A Cochrane review identified a single randomised • Group 3: normal responders (10-15 oocytes) Key Findings controlled trial (RCT) comparing IVF vs. ICSI for Watch Prof. Jens Hirchenhain share key insights into whether • Group 4: high responders (>15 oocytes)1 ICSI should be used in place of conventional IVF the treatment of non-male factor infertility.2 The The outcome of this study indicated that ICSI RCT showed no benefit of ICSI in case of normal does not yield higher fertilization or pregnancy Results sperm parameters.3 However, the effect of using rates than in vitro fertilization in case of non- ICSI in different ovarian response categories has 4891 patients were analyzed, of whom 4227 male infertility. This suggests that ICSI may not been sufficiently evaluated. underwent ICSI and 664 underwent IVF. The function only as a normalizer of fertilization in ratio of ICSI:IVF was similar across the response case of sperm impairment. Limits of the study 1 Study Summary categories. relate to the retrospective, non-randomized design and the rather low number of IVF cases This study was a retrospective analysis of data The mean fertilization rate was not different when split by ovarian response.1 collected in 15 centres between 2009 and 2014.1 between the ICSI and IVF group (overall Another retrospective study presented at the ESHRE annual meeting on the same topic by 80 Lattes Altamirano et al claimed that ICSI in non- 66.6 66.6 66.6 male factor cases performs worse than IVF in 70 63.6 62.5 53.3 61.0 61.0 60.0 terms of pregnancy and live birth rate, even in 60 55.7 poor responders.1

30 Practice message Fertilization rate (%) rate Fertilization 20 ICSI Patients with low response do not appear to benefit from the use of ICSI instead of IVF, where 10 there are normal sperm parameters. IVF 0 Total Poor response Suboptimal Normal High response

*Fertilization rate defined as number of 2PN oocytes divided by the number of oocyte-cumulus complexes

Figure 1: Fertilization rate* in non-male factor ICSI and IVF cases by ovarian response category4 Time interval between ovulation triggering and oocyte injection: Time interval between ovulation triggering and oocyte injection: 1 1 CLINICAL EMBRYOLOGY does it affect the clinical outcome?, O-233 does it affect the clinical outcome?, O-233 CLINICAL EMBRYOLOGY

L. Vandenberghe et al L. Vandenberghe et al

Background Results * The time interval between human chorionic It was found that the time interval was not 40 36.5 gonadotropin (hCG) injection for inducing final associated with clinical pregnancy rates (range 34.7 34.0 34.2 34.6 33.8 oocyte maturation and oocyte injection by 21.9%-36.5%; p=0.286) or live birth rates 35 intracytoplasmic sperm injection (ICSI) can be (range 15.6%-27.9%; p=0.263), after adjusting 30 split into:1 for potential confounders.1 27.9 26.6 26.1 26.1 25.3 24.7 25 • The time from hCG injection to oocyte pick- There was a tendency towards lower live birth 21.9 up (35-36 hours) rate in the <36h cases as compared to 38h

after OPU. A period of ≥41h post-injection was % 20 • The post pick-up waiting period before not associated with a difference in outcome 15.6 denudation and injection (1-3 hours) compared to injection at 38h.1 (Figure 1) 15 Little is known if variation in these time spans 1 are associated with outcome. Key Findings 10 The optimal time window for ICSI is less Study Summary 5 stringent than previously thought, which may be This retrospective cohort study analyzed 8,889 reassuring to busy centers.1 0 ICSI cycles performed between 2010 and 2015 <36h 36h 37h 38h 39h 40h >41h in a single center. Seven time interval categories CPR LBR were defined: <36h, 36h, 37h, 38h, 39h, 40h and ≥41h.1 * adjusted OR for live birth in the <36h group vs. reference group 38-39h: 0.522, 95% CI: 0.247-1.104; P=0.075 The <36h was only the case if the hCG to oocyte pick-up (OPU) time was <36hours and when ICSI was performed immediately after OPU. Figure 1: Clinical pregnancy rate (CPR) and live birth rate (LBR) Otherwise, the center routine was to perform stratified by time interval between hCG injection and ICSI2 OPU after 36h and the variation observed originated predominantly from the post-pick up period.1

Practice message

When oocyte retrieval is performed 36h after hCG, there is leeway of several hours for the laboratory to perform ICSI. Assessment of the impact of blastocyst morphology on the Assessment of the impact of blastocyst morphology on the accuracy of non-invasive preimplantation genetic testing accuracy of non-invasive preimplantation genetic testing (NIPGT-A) utilizing culture-conditioned embryo culture medium (NIPGT-A) utilizing culture-conditioned embryo culture medium 1 1 CLINICAL EMBRYOLOGY combined with blastocoel fluid, O-201 combined with blastocoel fluid, O-201 CLINICAL EMBRYOLOGY

S. Madjunkova et al S. Madjunkova et al

Background Results Table 1: Cell-free DNA amount and fragment size from blastocoel and embryo culture medium5 Cell-free DNA has been found in blastocoelic fluid It was found that WGA-DNA was detected in all and embryo culture medium.2,3 These fluids have 71 NIPGT-A and 71 TE samples.1 WGA-DNA WGA-DNA DNA fragment 1 been used for non-invasive genetic testing. WGA positive ng/μl ng/μl size The difference in DNA amount was lower for good (range) (mean± SD) (mean± SD) The cell-free DNA is likely to be nuclear by origin, quality blastocysts as compared to moderate/low stemming from apoptotic or necrotic cellular quality blastocyts, but the difference was small NIPGT-A 1 35/35 5.1 – 30.0 13.9 ± 0.9 747 ± 43 bp events. However, it may also include extra- and statistically not significant. (Figure 1) Good quality blastocyst chromosomal mitochondrial DNA.3 In addition, no difference in DNA fragment length 1 NIPGT-A Low/moderate It has been postulated that cell-free DNA present was found. 36/36 6.3 – 36.0 15.7 ± 1.0 737 ± 27 bp in the blastocoel cavity of human embryos quality blastocyst positively correlates with embryonic morphology.4 63/71 (88.7%) NIPGT-A samples and 70/71 Therefore, lower quality blastocysts may have a (98.6%) of the TE samples were informative, 1 TE biopsy 71/71 25.0 – 46.0 31.3 ± 1.2 -- higher rate of apoptosis and as result, a higher while concordance for ploidy was 100%. quantity of cell-free DNA. Key Findings WGA= whole genome amplification; NIPGT-A = Non-invasive preimplantation genetic testing- aneuploidy; TE = trophectoderm Study Summary This study did not provide evidence that cell-free In this prospective study, 21 patients underwent DNA from culture medium and blastocoelic fluid preimplantation genetic testing for aneuploidies can serve as a proxy for embryo quality. Culture (PGT-A) with trophectoderm biopsy of fresh medium combined with blastocoelic fluid has the 1 blastocysts.1 potential for use with NIPGT-A.

From these blastocysts, the following non- As a side observation, the authors found it invasive preimplantation genetic testing for unlikely that cell apoptosis would be the only aneuploidies (NIPGT-A) samples were collected:1 mechanism leading to cell-free DNA given the large size of the DNA fragments observed • Culture medium (apoptotic fragments are typically only ~180bp).6 Therefore, non-apoptosis related active or • Blastocoelic fluid (after pulse-laser collapse) passive forms of DNA release are likely to play a 35 good quality blastocysts and 36 moderate/ role. low quality blastocysts were available. Whole genome amplification (WGA) was performed on the fluid samples, DNA quantity measured and PGS-NGS was completed using VeriSeq™. The corresponding trophectoderm (TE) samples served as controls.1 ANDROLOGY De novo mutations affecting maleinfertility, O-161 J. Veltman Watch Prof. Michael Zitzmann discuss therole of de novo mutations in male infertility 1 intracytoplasmic sperm injection(ICSI). available forinvitrofertilization(IVF)or as advanced maternalageoroocytenumbers model can reduce some of the confounding, such assessed. semen quality on recipients’ ICSIoutcomeswas of paternal age, ejaculatory abstinence and Using a general mixed model,the impact and May 2017, wereanalyzed. sharing donation program between January 2015 recipient ICSIcycles, participating in an egg- 321 oocyterecipientsundergoing427 oocyte center, 268vitrifiedoocytedonorICSI cycles and In this retrospective studyfrom a private IVF Study Summary oocytes fromolder women. For example, sperm fromolder men often meet to confounding factors from the female side. reproductive technology (ART) isdifficult, due sperm parameters on theoutcomeof assisted Analyzing theisolatedimpactofmale factors and Background injection (ICSI) in an egg-sharing donation program, O-017 semen quality on the outcomes of intracytoplasmic sperm Impact of paternal age, ejaculatory abstinence length and A. Setti discouraged to ‘accumulate sperm’ by ejaculatory abstinence before undergoing ART treatment. Frequent ejaculation is potentially associatedwithbetteroutcomes. Patients should be Practice message et al 1 2 The oocyte donation Theoocytedonation 1 2 at ESHRE 2019 by Horta infertility undergoing IVF/ICSI presented in anotherstudy on coupleswithidiopathic outcomes ofICSI.Thiswas also reported association between paternalageandimmediate This study usedan elegant model to find an Key Findings significant negative association with: It was found that paternal age hadastatistically Results (especially normalembryonic development). associated with negative laboratory parameters sperm count. Ejaculatory abstinence was also development) werespermcountand totalmotile parameters (fertilization rate, embryo Positive confounders for embryological >51 years. ICSI population, when the male partner age was reduced to approximately 30%inanoverall IVF/ estimated that clinical pregnancyrate was • • • • • odds of pregnancy odds of pregnancy high quality blastocyst development blastocyst development rate cleavage rate fertilization rate 1

et al. 1 Morrisetal 1 1

ANDROLOGY ANDROLOGY absence of vacuoles. integrity of spermmightdifferby presence or levels. associated withlow chromatin condensation In alive human sperm, vacuoles have been condensation. during spermatogenesis to allow chromatin spermatozoon is needed. of oocytes where identifying the most competent most frequent method for in vitroinsemination Intracytoplasmic sperm injection (ICSI) is the Background and epigeneticstatus: implications for oocyteinjection,O-181 Human spermmorphologyas a marker of itsnuclearquality are clinicallyused for that purpose, including: Various techniques have been tested in trials and sperm vacuoles. origin, location,andclinical consequences of not been clarified relatingtotheprevalence, morphology examination, several questions have Decades after the introduction of spermorganelle M. Bendayan • • • • annexin V agent identification annexin V agent identification polarized lightmicroscopy hyaluronic binding sperm injection intracytoplasmic morphologicallyselected 1 Histones are replaced by protamines Histones arereplaced by protamines et al 4 It was postulatedthatthenuclear 3

2 deconvolution microscopy. spermatozoa were studied by three-dimensional Next, theepigeneticprofiles of 4000alive sample were selectedunderhigh-magnification: 200 alive normal spermatozoa from each sperm differing sperm profiles were studied. From those, Sperm samplesfrom 20 infertile patientswith Study Summary at theone-cellscale: development, were assessed by immunostaining spermatozoa andas potentiallyimpliedinembryo Epigenetic marks, known to bepresent on human • •

of head-area) 100 with a vacuole (occupying >15% 100 withoutvacuole H4k20me2 H3K27me3 H3K9me3 H3K9me2 H3K9me1 H3K4me3 H3K4me2 H3K4me1 1

1 1 It was foundthat: Results and epigeneticstatus: implications for oocyteinjection, O-181 Human spermmorphologyas a marker of itsnuclearquality embryo development. to spermatids, which may negatively affect spermatozoa have an immature chromatinclosest These epigenetic profiles suggestthat vacuolated M. Bendayan • • H3K27me3 thanvacuolated spermatozoa higher degreesof protamination and spermatozoa with no vacuole presented H3K4me3 than spermatozoa withno vacuole more pronetoretaininghistone H3 and spermatozoa with vacuoles were significantly et al 1 1

an epigenetic signature. free spaces.Accordingly, vacuoles appear to have – filled theseareas, described untilnow as DNA H3K9me1 (allrelated toDNA decondensation) basement of vacuoles while H3,H3K4me3 and showed thatprotamine was located at the 3D visualizationof vacuolated spermatozoa still needs to be defined. The biologicaland clinical relevance of this finding is linked to epigenetic marks. morphological characteristic of alive spermatozoa This studywas the first todemonstratea that Key Findings 1 1 1

ANDROLOGY REFERENCES 2. 1. AMH levels inadolescence and the presence ofPCOS 6. 5. 4. 3. 2. 1. 6. 5. 4. 3. 2. 1. Progesterone ontheday of embryo transfer Reproductive endocrinology Predicting luteal progesterone levels 1. AMH as a driving force of PCOS 2015;136(6):1154 LP-1165. doi: https://doi.org/10.1542/peds.2015-1430 Rosenfield RL.The Diagnosis of Polycystic Ovary Syndrome inAdolescents. Pediatrics. Supplement_1.1 Embryology. Hum Reprod. 2019;34(Supplement_1):i1-i543.doi:https://doi.org/10.1093/humrep/34. Abstracts of the 35th Annual Meeting of theEuropeanSociety of Human Reproduction and fertnstert.2014.12.120 an analysis of 231,815 cycles of in vitro fertilization. Fertil Steril. 2015;103(4):931-938.e2. doi: Baker VL,BrownMB, Luke B, Conrad KP. Association of number of retrieved oocytes with live birthrate and birth weight: HYPERTENSIONAHA.118.12046 Maternal Vascular Health in Early Pregnancy. Hypertension. 2019;73(3):680-690.doi: Frauke von V-H, Purnima N,Seda STE, etal. Absent or Excessive Corpus LuteumNumber Is Associated WithAltered org/10.1371/journal.pone.0151388 in IVF: An Individual Patient Data Meta-Analysis of thePhaseIIITrials. PLoS One. 2016;11(3):e0151388. Doblinger J, ComettiB, Trevisan S, Griesinger G.Subcutaneous Progesterone IsEffective and Safe for Luteal Phase Support humrep/dey306 phase supportin IVF: a randomized clinical trial. Hum Reprod. 2018;33(12):2212-2221. doi: Griesinger G, Blockeel C,Sukhikh GT, et al. Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal during early pregnancy. HumReprod. 2014;29(11):2393-2401. doi:https://doi.org/10.1093/humrep/deu223 Järvelä IY, Pelkonen S, Uimari O, etal.Controlled ovarian hyperstimulation leads to high progesterone and estradiol levels 2019;34(Supplement_1):i1-i543. doi: Abstracts of the 35th Annual Meeting of theEuropeanSociety of Human Reproduction and Embryology. Hum Reprod. during early pregnancy. HumReprod. 2014;29(11):2393-2401. doi:https://doi.org/10.1093/humrep/deu223 Järvelä IY, Pelkonen S, Uimari O, etal.Controlled ovarian hyperstimulation leads to high progesterone and estradiol levels org/10.1016/j.rbmo.2018.11.026 embryo transfers withhormonallypreparedendometrium.Reprod Biomed Online. 2019;38(3):472-480.doi: Cédrin-Durnerin I,Isnard T, Mahdjoub S, et al. Serum progesterone concentration and live birthrate in frozen-thawed doi: cryopreserved embryo transfer cycles and related reproductive outcomes. Reprod Biomed Online. 2018;37(5):641-647. Alsbjerg B, Thomsen L, Elbaek HO, etal. Progesteronelevels onpregnancy test day after hormone replacement therapy- prospective study. HumReprod. 2017;32(12):2437-2442. doi:https://doi.org/10.1093/humrep/dex316 associated with a diminished ongoingpregnancyrate in oocyte donation cycles after artificial endometrialpreparation:a Labarta E, Mariani G,Holtmann N, Celada P, Remohí J, Bosch E. Low serum progesterone on the day of embryo transfer is preparation and timing.HumReprod. 2017;32(11):2234-2242. doi:https://doi.org/10.1093/humrep/dex285 Mackens S, Santos-Ribeiro S, van deVijver A, et al. Frozen embryo transfer: a review on the optimal endometrial 2019;34(Supplement_1):i1-i543. doi: Abstracts of the 35th Annual Meeting of theEuropeanSociety of Human Reproduction and Embryology. Hum Reprod. 2019;34(Supplement_1):i1-i543. doi: Abstracts of the 35th Annual Meeting of theEuropeanSociety of Human Reproduction and Embryology. Hum Reprod. https://doi.org/10.1016/j.rbmo.2018.08.022

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