2020 HIGHLIGHTS OF THE ANNUAL MEETING OF THE EUROPEAN SOCIETY OF HUMAN REPRODUCTION AND EMBRYOLOGY
Virtual Congress, 5th-8th July 2020
The purpose of this report is to capture highlights from the ESHRE 2020 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 2020 Post-ESHRE meeting. The development of this congress report has been financially supported by MERCK KGaA, however 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, or regarding 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.
GL-NONF-00570 August 2020 Sponsored by INTRODUCTION TO REPROFACTS Foreword
The year 2020 marks a new era in many fields of life and profession, and this is also true for reproductive medicine. For the first time since the inaugural meeting in Bonn in 1985, ESHREs annual get-to-together went exclusively virtual, providing a totally new experience for everyone involved, from presenter to audience to industry. While online lectures on-demand and ease of access to the presentations were convenient (and will likely stay), the inspiration gained from personal contact and the focus to the conference without distraction from routine business at home was certainly missed by many of the 12,520 online participants.
The COVID-19 crisis did, however, not impact the quantity or quality of the main scientific program, with 200+ peer-reviewed oral communications and more than 60 invited lectures. The wealth and breadth of information was as challenging as ever, so our REPROFACTs expert team once again shared the subspecialties among each other, sorted out ‘the wheat from the chaff’, and presented the essence of the ESHRE lectures in a one-day meeting in Mainz, Germany, on July 17, 2020.
This years REPROFACTS meeting marked the 10th anniversary of an initiative which started as a small ‘POST-ESHRE’ discussion forum and which grew, with Merck as a strong partner, into one of the largest reproductive medicine conferences within the German speaking countries. The COVID crisis also left its mark on the format of REPROFACTS, which was for the first time held as a hybrid-meeting, with online live streaming of the real event.
This report contains some of the key highlights from the REPROFACTS meeting 2020. Selection of topics was done by the REPROFACTS faculty, independently and neutrally, with a focus on clinically relevant novelties.
Watch Prof. Griesinger discuss the virtual ESHRE 2020 congress.
1 INTRODUCTION TO REPROFACTS Faculty members
Prof. Dr. med. habil. Dr. rer. nat. Jens Hirchenhain Jürgen M. Weiss Düsseldorf. Subspeciality: clinical Lucerne. Subspecialities: female infertility embryology and ovarian stimulation
Prof. Dr. med. Heribert Kentenich Prof. med. Ludwig Wildt Berlin. Subspecialities: safety and quality, Innsbruck. Subspeciality: endocrinology law and ethics, psychology
Priv.-Doz. Dr. rer. nat. Verena Prof. Dr. med. Michael von Wolff Nordhoff Münster. Subspecialities: basic science Bern. Subspecialities: fertility preservation, and reproductive genetics ovarian reserve, surgery
Dr. med. Maren Goeckenjan Prof. Dr. med. Michael Zitzmann Dresden. Subspecialities: endometrium, Münster. Subspeciality: andrology endometriosis, early pregnancy
2 CONTENTS
Andrology Low male testosterone 5
Negative impact of elevated DFI and HPV presence in sperm 7
Reproductive endocrinology
Efficacy and safety of linzagolix on HMB due to uterine fibroids 8
Relugolix for heavy menstrual bleeding due to uterine fibroids 10
Use of testosterone gel treatment in poor ovarian reserve in IVF-ICSI cycles 11
Early pregnancy
Pre-treatment with mifepristone to misoprostol in early pregnancy failure 13
Conception after early IVF pregnancy loss - should we wait? 15
Updated terminology for early pregnancy assessment 17
Fertility preservation and reproductive surgery
Live birth rate and utilization rate of eggs and embryos following FP 19
LH preserves the meiotic potential of oocytes exposed to chemotherapy 21
Septum resection versus expectant management in women with a septate uterus 22
3 CONTENTS
Clinical embryology
New evidence on mosaic developmental potential 24
Complex mosaic embryos after preimplantation genetic testing 26
Novel technologies for single-sperm vitrification 27
Intracytoplasmic sperm injection vs conventional IVF in couples with non-male factor infertility 29
Embryos excluding multinucleated cells during blastocyst formation increase their reproductive potential 31
Ovarian stimulation
Optimal GnRH antagonist protocol during ovarian stimulation 33
Comparing different progestin regimens for pituitary suppression 34
MPA as a pituitary suppressor instead of a GnRH antagonist during ovarian stimulation 36
Pituitary suppression is not necessary for blocking LH surge during luteal-phase stimulation 37
Natural cycle frozen-thawed embryo transfer 38
Safety & Outcomes
Nordic sibling study 39
Imprinting disorders in children born after ART 41
Major congenital malformations risk in children conceived after ICSI 43
Artificially prepared frozen cycles and increased risk of preeclampsia 44
Additional Video Highlights 46
4 Low male testosterone results in a substantial decrease of ANDROLOGY fresh live birth rates in couples with non-male factor infertility undergoing IVF, O-016
P. Drakopoulos et al.
Background
Sperm production is regulated via a complex and dynamic process that requires interaction of multiple hormones and testicular cell types. Testosterone is indispensable for sperm production; however, testosterone exerts it spermatogenetic action only within a network of endocrine and paracrine signals and tightly coordinated gene and protein expression programs within the testis. Little attention has so far been paid on the potential association of testosterone synthesis with fertility in case of normal sperm parameters. The necessity of routinely evaluating Watch Prof. Michael Zitzmann discuss the potential role of serum testosterone levels in male partner of testosterone as a functional marker for reduced fertility couples trying to conceive is also under dispute. potential.
Study
In a retrospective analysis (time period 2011 to No relevant difference in sperm parameters were 2018), conducted at the University of Brussels found in patients with low vs. normal testosterone Reproductive Medicine Center, 1,026 couples levels. However, the live birth rate was significantly undergoing a first IVF cycle for non-male factor reduced in the low testosterone group (13%; 95% subfertility were identified. Treatment course and CI, 8, 20) vs. normal testosterone group (23%; outcome of 136 couples (13.3%) with a male 95% CI, 21, 26). This finding remained after partner with a total serum testosterone of <264ng/ adjusting for male and female age, male smoking, dl (<9.2 nmol/L) were compared with couples with female BMI, number of oocytes and embryos, male partners above this threshold. This threshold cause of infertility and SHBG levels (adjusted OR, represents the recommended lower limit of the 0.35; 95% CI, 0.15, 0.79). Accordingly, both total normal total testosterone (TT) in healthy non- and free testosterone in serum were positively obese young men1. In a recent post-hoc analysis associated with live birth likelihood. of the AMIGOS RCT2, a decreased odds of live birth was observed in couples with unexplained infertility undergoing ovarian stimulation with letrozole, clomifen or FSH for timed intercourse or IUI, whose male partner was below 264ng/dl total testosterone (adjusted OR, 0.65; 95% CI, 0.38, 1.12). Only morning testosterone samples and men with no exogenous testosterone or other relevant medication were included in the Brussels study.
5 Low male testosterone results in a substantial decrease of fresh live birth rates in couples with non-male factor infertility ANDROLOGY undergoing IVF, O-016
P. Drakopoulos et al.
Univariate-analysis: live birth rate by male partner testosterone serum
40.0
30.0
20.0
10.0 Line Birth Rate (%) Rate Birth Line
0.0 Low Testosterone Normal Testosterone (<264 ng/dl) (≥264 ng/dl)
Comment
This study aimed at validating the post-hoc observation from the AMIGOS trial2 in the setting of IVF. In both studies, male factor (defined by sperm analysis) was excluded. Thus, the findings hint at a qualitative association of the endocrine and reproductive function of the testis.
Practice point
Testosterone administration is contra-indicated in the context of fertility treatment. Selective estrogen receptor modulators, gonadotropins and aromatase inhibitors can restore serum testosterone levels, however, the consequences of these pharmacological interventions for natural fertility or ART have not yet been fully clarified.
6 Negative impact of elevated DNA fragmentation index (DFI) ANDROLOGY and human Papillomavirus (HPV) presence in sperm on the outcome of intra-uterine insemination (IUI), O-017
C. Depuydt et al.
Background Comment
Human Papillomavirus (HPV) are sexually This study corroborates the hypothesis further transmitted DNA viruses with high prevalence. that HPV infection does play a role in human The association of HPV infection and fertility in the fertility. However, infected men may infect their male1 and female2 have remained inconclusive so partners and the impairment of fertility may differ far. The head of spermatozoa carry syndecan-I, between males and females. Furthermore, socio- a transmembrane protein also used by the HI- economic status and immune status may play a virus (HIV) to enter cells. HPV virions can bind role in acquiring and resolving a HPV infection. to syndecan I, potentially inducing DNA damage Such interactions impose significant difficulties in the sperm and infecting the oocyte leading to when deciphering the impact of HPV on fertility. embryonic arrest after fertilization with an infected spermatozoon.
Study Summary
In a prospective, multi-center study, 161 men undergoing 209 IUI cycles were examined. HPV DNA of 18 different subspecies was analyzed by PCR and the amount of DNA damage was quantified by the sperm chromatin structure assay (DNA fragmentation index, DFI).
15% of the sperm samples used for IUI were positive for one of the HPV subtypes tested, in 10% of sperm samples a high-risk HPV subtype was detected. The DFI was higher in infected vs. non-infected samples (29% vs. 20%, p=0.01). A cut-off of 26% DFI was identified as a strong Watch Prof. Michael Zitzmann discuss available data and the impact of HPV infections on the impairment of fertility. predictor of pregnancy, e.g. all pregnancies in this cohort originated from sperm samples below this threshold. No pregnancy was achieved in the 31 IUIs with sperm tested positive for HPV.
Practice point
Routine fertility work-up of the male still does not require testing for HPV.
7 ESHRE 2020-Clinical science award for oral presentation
Efficacy and safety of linzagolix on heavy menstrual bleeding (HMB) due to uterine fibroids (UF): Results from a placebo- ENDOCRINOLOGY controlled, randomized, Phase 3 trial, O-027
H. Taylor et al.
Background Study
Sex steroid withdrawal via GnRH-analogue In a phase III, double-blind, placebo-controlled, administration mitigates heavy menstrual multicenter RCT (PRIMROSE2 study), women with bleeding. While full suppression of sex steroids uterine fibroids and >80ml menstrual blood loss induced by GnRH-analogues is highly effective, per cycle received 100mg or 200mg daily linzagolix bone mineral density and overall quality of life with or without hormonal add-back (estradiol are negatively affected. Therefore, hormone add- 1mg/NETA 0.5mg) for 52 weeks. Menstrual blood back therapy is necessary. Linzagolix is a novel, loss was significantly reduced in all linzagolix non-peptide, orally active gonadotropin-releasing treated patients, as was uterine volume and pain. hormone antagonist that reduces circulating serum Median estradiol levels were below 20pg/ml in the sex steroid levels in a dose-dependent manner. 200mg without add-back therapy, but were 20- A dose-dependent, only partial suppression of 60pg/ml in all other groups. Bone mineral density estradiol could make the need for add-back loss was most pronounced in the 200mg group redundant, while still achieving good bleeding without add-back therapy. control. Recently, the use of Linzagolix within a phase IIb trial for the treatment of endometriosis- associated pain was reported1. In this trial, no hormone add-back was given. Both pain and bone mineral density were reduced in a dose-dependent fashion within 24 weeks of treatment.
100
81
75 71 63
% 50 34
25 12
0 Placebo Linzagolix Linzagolix Linzagolix Linzagolix 100mg 100mg + ABT 200mg 200mg + ABT
Figure 1: Proportion of women achieving amenorrhoea at the end of linzagolix vs. placebo treatment (p<0.0125) (ABT = add-back therapy)
8 Efficacy and safety of linzagolix on heavy menstrual bleeding (HMB) due to uterine fibroids (UF): Results from a placebo- ENDOCRINOLOGY controlled, randomized, Phase 3 trial, O-027
H. Taylor et al.
1
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Placebo Linzagolix Linzagolix Linzagolix Linzagolix 100mg 100mg + ABT 200mg 200mg + ABT
Figure 2: Mean percentage change in lumbar spine bone mineral density under linzagolix vs. placebo treatment.
Comment
This study identified two linzagolix doses for the treatment of uterine fibroids: 100mg without add-back therapy for potential longer-term usage and the highly effective 200mg dose necessitating add-back, a regimen which is still most likely better suitable for shorter treatment courses.
Practice point
Currently available oral GnRH-antagonists in Gynecology are Relugolix2 and Elagolix3,4, licensed for the treatment of fibroids in Japan (Relumina©, Takeda) and endometriosis in the U.S. (Orilissa©, AbbVie). ASP17075 is another oral GnRH-antagonist that is still under development for endometriosis, but not yet clinically available.
9 Relugolix combination therapy improves hemoglobin levels in anemic women with heavy menstrual bleeding due to uterine ENDOCRINOLOGY fibroids: results from the LIBERTY Phase 3 program, O-023
Venturella et al.
Background
35 Relugolix is an orally active non-peptide GnRH- antagonist recently licensed for use in women 30 with symptomatic fibroids. Two phase III trials P<0.0001 have recently been conducted (LIBERTY 11 and 25 23 LIBERTY 22) in a total of 770 women with heavy menstrual bleeding and fibroids. Both trials were 20 randomized, double-blind, placebo-controlled % 15 RCTs, and in both trials, 24 weeks of oral daily relugolix 40 mg co-administered with 1mg E2 and 10 0.5mg NETA vs. 12 weeks of daily oral relugolix 6.4 40 mg alone followed by 12 weeks of daily oral 5 relugolix 40 mg co-administered with the same add-back vs 24 weeks of placebo was compared. 0 Placebo Relugolix (n 257) (n 254)
Study Figure 1: Percentage change in hemoglobin concentration from baseline to week 24 in the pooled data from LIBERTY 1 A pooled analysis of LIBERTY 1 and LIBERTY 2 was and 2. conducted. The results of an analysis of a subset of women with fibroids and heavy menstrual bleeding Comment and with hemoglobin ≤ 10.5 g/dL at baseline were reported. The outcome of primary interest was This study shows that the reduction in menstrual the proportion of patients who had a (clinically blood loss, one of the key outcome parameters of meaningful) increase of ≥2 g/dL hemoglobin from the phase III trial program, also translates into a baseline. This increase in hemoglobin levels was meaningful increase in serum hemoglobin levels observed more often in the Relugolix arms (55.7%) in women with low levels at screening. Another compared with the placebo arms (11.7%; p< sub-analyses of LIBERTY trial program data 0.0001). Similarly, the mean percentage increase presented at ESHRE 20203 reported significantly in hemoglobin concentration was greater in the reduced patient-reported distress from common pooled Relugolix-CT arms (23.0%) compared with uterine fibroid symptoms and improved physical the placebo arms (6.4%; p <0.0001). and social activities vs placebo.
Practice point
Relugolix is currently licensed for the treatment of fibroids only in Japan (Relumina©,Takeda).
10 A prospective study of testosterone gel treatment in poor ENDOCRINOLOGY ovarian reserve in IVF-ICSI cycles, O-198
Singh & Singh
Background Study
Testosterone treatment has been investigated Fifty-two patients fulfilling the “Bologna criteria” for women with diminished ovarian reserve of poor ovarian response (age ≥40 years and/or undergoing ART. Proposed mechanisms of action AFC <5-7 or AMH <0.5 ng/ml and/or a previous include the facilitation of the transition of follicles IVF cycle with low response) were randomly from the quiescent to the growing pool, thereby treated with either placebo (lubricant) or with increasing the number of pre-antral and antral 12.5mg trans-dermal testosterone gel once daily. follicles and an augmentation of the expression Previous ovarian surgery, BMI ≥30kg/m2 and of FSH receptors in granulosa cells, potentially endometriosis grade III-IV were key exclusion enhancing the ovarian responsiveness to ovarian criteria. All patients received pre-treatment stimulation. A number of RCTs (included in a for 28 days with estradiol valerate 2mg and number of systematic reviews are available1,2) norethindrone 5mg for 21 days. On the 6th day investigated the effect of testosterone pre- of pre-treatment, patients in the verum group treatment before ovarian stimulation in poor applied once daily 12.5mg testogel on the inner responder women. However, the evidence is thigh and continued for 21 days. All patients overall inconclusive, all single RCTs are too small underwent ovarian stimulation with rFSH 225 IU to allow conclusions on the pregnancy or live birth in a GnRH-antagonist protocol. Key findings were rate and the risk of bias in most studies is high3. that the mean number of mature oocytes and the mean number of good quality embryos was higher in the testosterone pre-treated patients.
Parameter Testosterone pre-treatment Placebo pre-treatment P value
FSH dose (IU) 2506±278 3108±346 < 0.0001
Antagonist (days) 4.5±0.4 5.6±1.4 0.0003
Number of mature follicles on 5.0±1.4 3.1±1.7 < 0.0001 day of hCG
Number of mature oocytes 3.12±1.14 1.27±1.03 < 0.0001
Grade I and II embryos 2.3±1.08 0.39±0.48 < 0.0001
Clinical pregnancy rate 15% (4/26) 4% (1/26) 0.0096
Figure 1: Key findings of the testosterone pre-treatment trial.
11 A prospective study of testosterone gel treatment in poor ENDOCRINOLOGY ovarian reserve in IVF-ICSI cycles, O-198
Singh & Singh
Comment
The ESHRE guideline on ovarian stimulation (2020) states that the use of testosterone before ovarian stimulation is probably not recommended for poor responders3 since there is currently inconsistent evidence that adjuvant testosterone pre-treatment before ovarian stimulation improves ovarian response in terms of number of oocytes retrieved and clinical outcomes. The study of Singh et al. is unlikely to change this conclusion, as the study received criticism at the ESHRE meeting as being too small in sample size, lacking the measurement of actual serum testosterone levels in the patients, not being prospectively registered and several methodological aspects remaining unclear. Another randomized clinical trial4 presented at the ESHRE meeting found no impact of either ~60 days or ~14 days of 12.5mg transdermal testosterone pre-treatment on oocyte numbers in poor response patients.
Practice point
The results from the “T-Transport Trial”5, started in 2015, in which 400 poor ovarian response patients undergoing IVF will be randomized to 0.55g transdermal testosterone per day or placebo for 65 days will hopefully clarify the place of androgen pre-treatment for poor responders.
12 Results of a highly significant, prematurely halted Dutch multicenter randomized double-blinded placebo-controlled study of pretreatment with mifepristone to misoprostol in early EARLY PREGNANCY pregnancy failure (triple m), O-300
C. Hamel et al.
Background
Early pregnancy failure is common, often necessitating pharmacological or surgical intervention. While D&C is highly effective, it is invasive, requires anesthesia and is associated with significant risks, most importantly the risk of injury to the uterine lining. A randomized trial published in NEJM in 20181 on 300 women with pregnancy failure reported that pharmacological treatment with mifepristone followed by misoprostol resulted in a higher likelihood of successful management of first-trimester pregnancy loss than treatment with misoprostol alone. A Cochrane systematic review, however, concluded in 20192 that Mifepristone did not appear to further hasten miscarriage when added to a misoprostol regimen and that a single small study (46 women) reported that mifepristone alone was more effective than placebo.
Study
A multi-center, prospective, two-armed, randomized, double-blinded and placebo-controlled study included women with confirmed early pregnancy failure (6–14 weeks), managed expectantly for at least 1 week, and then randomized to pre-treatment with oral mifepristone (600 mg) or oral placebo. In both arms, mifepristone treatment was followed by oral misoprostol, started 36–48 h later consisting of two doses 400 μg (4 hours apart), repeated after 24 hours if no tissue was lost. The primary outcome was complete evacuation six weeks after treatment. The Data Safety Board stopped the trial after 50% recruitment (344 subjects) according to a pre-defined rule, since successful treatment, need for uterine aspiration and risk profile were strongly in favor of mifepristone. Serious adverse events occurred in 24 vs. 55 subjects in the mifepristone vs. placebo group (p=0.0005). It was also found that mifepristone treatment was more cost-effective.
13 Results of a highly significant, prematurely halted Dutch multicenter randomized double-blinded placebo-controlled study of pretreatment with mifepristone to misoprostol in early pregnancy failure (triple m), O-300 EARLY PREGNANCY
C. Hamel et al.
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80 75
60 59 % 50 48
30 25
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0 successful evacuation adverse successful evacuation adverse treatment (D&C) events treatment (D&C) events (medical) (medical)
Mifepristone Misoprostol Placebo Misoprostol
Figure 1: Main outcomes of the >triple m< trial on mifegyne followed by misoprostol vs. misoprostol alone for managing early pregnancy failure.
Comment
This trial corroborates the NEJM trial1 findings from 2018 and provides good evidence for the effectiveness and safety of mifepristone for managing early pregnancy failure. A slightly higher incidence of patient reported adverse events occurred in the mifepristone group (mostly nausea, dizziness and diarrhea), which must be taken into account when counseling patients.
Practice point
Use of Mifepristone may not be available for managing early pregnancy failure in some countries.
14 Conception after early IVF pregnancy loss - should we wait? EARLY PREGNANCY O-256
M. Sharon-Weiner et al.
Background
The effect of the inter-pregnancy interval (IPI) on the course and outcome of a subsequent pregnancy has received considerable attention in obstetrical literature. A short IPI (<6 months) appears to be associated with increased risks for preterm birth, small-for-gestational age and infant death1,2. However, a recent systematic review indicated that a short interpregnancy interval after a miscarriage was found to be associated with a reduced miscarriage risk (RR 0.82, 95% CI 0.78, 0.86) and reduced preterm delivery risk (RR 0.79 95% CI 0.75, 0.83).3
Study
A retrospective cohort study included 289 women who experienced first trimester IVF pregnancy loss who reinitiated IVF treatment. The type of miscarriage (spontaneous, medical, surgical), the interval between miscarriage and subsequent treatment and the outcome of the subsequent IVF cycle were analyzed by multi-variable modelling. It was found that the interval did not impact the chance of clinical pregnancy, while the type of miscarriage did: compared to biochemical pregnancy, the odds ratio in a multi-variable analysis for achieving pregnancy after a spontaneous miscarriage was 0.7 (P=0.5), 0.3 (P=0.002) for a pregnancy after a medical termination, and OR=0.3 (P=0.001) for a pregnancy following surgical termination.
15 Conception after early IVF pregnancy loss- Should we wait? O-256 EARLY PREGNANCY
M. Sharon-Weiner et al.
Comment
Previous studies have already shown that an IPI of less than 6 months following miscarriage is not associated with adverse outcomes in the next pregnancy. This present study added further to this knowledge by investigating the IPI specifically in the setting of IVF. In an ideal world, patients would be randomized to different IPIs following pregnancy failure, but such a study will be difficult to be performed, therefore we can only resort to observational data.
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0 Biochemical Spontaneous Pharmacological Surgical pregnancy miscarriage intervention intervention
Figure 1: Clinical pregnancy rate by type of pregnancy failure in the previous IVF cycle.
Practice point
Women who desire to continue IVF treatment after early pregnancy failure can be encouraged to do so. This is especially relevant for advanced age women, where time may play a crucial role.
16 EARLY PREGNANCY Updated terminology for early pregnancy assessment, O-046
D. Jurkovic
Background
Sonography in early pregnancy is performed to • An ectopic pregnancy which contained confirm the location of the pregnancy (eutopic vs. an embryo/foetus with evidence of heart ectopic), to establish the viability of the conceptus pulsations should be described as a live ectopic and to assess the risk to maternal health posed pregnancy. by ectopic pregnancy. The Special Interest Group “Implantation and early pregnancy (SIG-IEP)” of • Ectopic pregnancies should be classified as the ESHRE underwent a formal 9-step procedure uterine or extrauterine. Previous classification for creating a new recommendation document of ectopic pregnancies as tubal and non-tubal on the criteria for the diagnosis of pregnancy should be abandoned. location and differentiation between normally and abnormally sited pregnancies. • All uterine ectopics (cervical, Caesarean scar and intramural) should be described as partial or complete. Draft document • The term intramural pregnancy should Ectopic pregnancies have traditionally been be used to describe a pregnancy which is labelled as tubal or non-tubal, which is no longer located within the uterus, but it breaches the considered appropriate as pregnancies can endometrial/myometrial junction and invades potentially implant anywhere along the passage myometrium of the uterine corpus above the from the ovary to the cervical canal with some internal os. pregnancies being partially implanted within and partially outside the uterine cavity. • Tubal ectopic pregnancies should be described as either interstitial, isthmic or Selected key recommendations of the draft ampullary. document are as follows:
• A pregnancy which is located within the uterine cavity, should be described as normally- Practice point sited (eutopic) pregnancy, a pregnancy which is located within the uterine cavity, with Ectopic pregnancies are not necessarily embryonic/foetal heart pulsations should be extrauterine pregnancies, but all described as a live normally-sited (eutopic) extra-uterine pregnancies are ectopic pregnancy. pregnancies.
• The term miscarriage should be used to describe a normally-sited (eutopic) pregnancy with abnormal development. The term miscarriage should not be used for an ectopic pregnancy.
17 Updated terminology for early pregnancy assessment, O-046 EARLY PREGNANCY
D. Jurkovic
Early Pregnancy
Normally Sited Ectopic Not identified
Early Pregnancy of Live unknown location Cornual Extra-uterine Uterine Miscarriage (PUL)
Tubal Cervical Interstitial Caesarean scar Isthmic Intramural Ampullary Ovarian Abdominal
Figure 1: Flow diagram illustrating how to classify an early pregnancy.
Location of the Ectopic Pregnancy
Morphology of the Ectopic Pregnancy
Gestational Sac Solid
+/- Yolk Sac +/- Fetal Pole hCG +ve hCG -ve
+/- Cardiac Residual Ectopic Activity Pregnancy
Figure 2: Flow diagram illustrating how to evaluate the morphology of an ectopic pregnancy.
18 Live birth rate and utilization rate of eggs and embryos following fertility preservation (FP) in 879 female cancer patients over 19 years, O-036 REPRODUCTIVE SURGERY
FERTILITY PRESERVATION AND Khalife et al.
Background
Fertility preservation for medical reasons is widely available in industrialized countries. With increasing numbers of cryobanked cases, utilization rate and outcomes are now receiving more and more attention. A recent systematic review reported a rate of use of cryopreserved semen of 8%1 in cancer patients. The utilization rate of cryopreserved oocytes has previously been estimated as ~ 6%2,3, the rate of use of cryopreserved ovarian tissue as ~3%4,5.
Study
In a retrospective evaluation of single center data, Eventually, 61 of 373 cases (16.4%) used their 879 women who underwent fertility preservation cryopreserved material, 44/61 (72.1%) achieved counselling in a hospital in London because of a a live birth per utilization, equaling a 11.8% live cancer diagnosis were identified within the time birth incidence in 373 cases with cryopreservation. frame 2000 to 2019. 373 (43.4%) of women These rates were similar in the total population eventually underwent a fertility preservation and the subpopulation of women with breast procedure, the majority for breast cancer cancer. (63%), the vast majority (99%) underwent cryopreservation of oocytes or/and embryos.
Oocytes and embryos Ovarian cortex cryopreserved cryopreserved 5% 1%
Ovarian cancer 2% Other Brain cancer 15% 2%
Embryos Oocytes Lymphoma cryopreserved cryopreserved Breast cancer 18% 40% 54% 63%
Figures 1 and 2: Distribution of diagnoses and type of fertility preservation performed. 19 Live birth rate and utilization rate of eggs and embryos following fertility preservation (FP) in 879 female cancer patients over 19 years, O-036 REPRODUCTIVE SURGERY
Khalife et al. FERTILITY PRESERVATION AND
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75 72.1 70.3
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0 Utilization Live birth rate Live birth rate Utilization Live birth rate Lve birth rate (thawing) rate per utilization per freezing (thawing) rate per utilization per freezing (thawing) procedure (thawing) procedure
Total Population (n=373) Subpopulation Breast Cancer (n=236)
Figure 3: Rates in the total population and the subpopulation of women with breast cancer.
Comment
This rather large study with a comparatively long follow-up detects utilization rates higher than previously reported. Of note, the majority of patients were breast cancer patients (with a rather good overall survival prognosis) and the vast majority had oocytes or embryos banked. Utilization and success rates are likely to be lower in ovarian tissue cryopreservation programs. A weakness of the study is the incomplete follow- up with lack of information on survival and Watch Prof. Michael von Wolff discuss what we know about utilization of cryopreserved material and longer-term clinical spontaneous pregnancy. outcomes.
Practice point
Fertility preservation programs should have a high utilization rate to be efficacious and thus women with good prognosis and high risk of ovarian failure should be prioritized.
20 LH prevents follicular damage and preserves the meiotic potential of oocytes exposed to chemotherapy at the primordial stage, O-260 REPRODUCTIVE SURGERY
FERTILITY PRESERVATION AND Castillo et al.
Background
Chemotherapy drugs, particularly those in the • LH treatment appeared to be also alkylating category, are detrimental to the associated with less spindle damage in the ovaries. The damage is thought to be inflicted oocytes mostly by DNA alterations leading to apoptosis and follicular depletion in the ovary. Apart from freezing ovarian tissue or oocytes, only GnRH agonist downregulation is effective in protecting the ovaries during chemotherapy, in terms of maintenance and resumption of menstruation, preventing treatment-related premature ovarian failure and resumption of ovulation1,2. Recently, a protective effect of luteinizing hormone (LH) on the primordial follicle pool of prepubertal mice ovaries against cisplatin induced apoptosis has been suggested.3 Watch Prof. Michael Von Wolff discuss whether LH can be used as a protective substance against chemotherapy induced ovarian damage. Study
In an experimental animal study, 24 seven- Comment week old female mice (n=8/group) were treated as follows: Control; chemotherapy (ChT) LH treatment could be a new therapeutic option (intraperitoneally injection of 12mg/Kg-busulfan for ovarian protection from ChT induced damage. and 120mg/kg-cyclo-phosphamide); or ChT+LH However, pre-clinical studies on human tissue (1 IU LH 24hrs before ChT and 1IU together followed by clinical studies in the human must be with ChT). Ovaries from 6 animals/group were undertaken before routine use. collected at 12 and 24 hours, while the remaining mice were maintained for 30 days. Practice point Key findings were: To date, the only clinically accepted • LH treatment increased the expression of method of ovarian protection in young the DNA repair gene Rad51 women facing gonadotoxic chemo- and/or radiotherapy is the use of • LH treatment enhanced cell survival via an gonadotropin-releasing hormone activation of a DNA repair signaling pathway agonists for downregulation of the (increase in Bcl2/cleaved caspase-3 protein hypothalamus-pituitary- ovarian axis. ratio)
• In the LH treated mice, apoptosis and DNA damage were reduced in oocytes and granulosa cells
21 Septum resection versus expectant management in women with a septate uterus: a randomised controlled trial (NTR 1676), O-057 REPRODUCTIVE SURGERY
Rikken et al. FERTILITY PRESERVATION AND
Background Study
A septate uterus is a common anomaly in the In a multi-national, randomized clinical trial led human. Definitions of septate uterus vary and by researchers from Amsterdam, 80 women with accordingly so do estimated incidences1. While it is a (predominantly partial) septate uterus and a acknowledged that septate uterus are associated history of subfertility, pregnancy loss or preterm with a higher risk of infertility, miscarriage and birth were randomized to hysteroscopic septum pre-term birth2, little robust evidence is available resection (n=40) or expectant management on which to build consensus regarding the optimal (n=40). The primary outcome was live birth within management strategies. 12 months after randomization. No benefit of the septum resection for any of the reproductive outcomes was found, including fetal presentation and mode of delivery. One uterine perforation occurred in the resection group.
Septum resection Expectant management Relative Risk and 95% (n=39) (n=40) confidence interval
Clinical pregnancy rate, n (%) 22 (56%) 19 (48%) 1.2 (0.77-1.9)
Miscarriage rate, n (%) 11 (28%) 5 (13%) 1.8 (0.83-3.8)
Live birth rate, n (%) 12 (31%) 14 (35%) 0.91 (0.58-1.41)
Table 1: Reproductive outcomes after septum resection vs. expectant management.
Comment
This RCT adds high-quality evidence to a recently published, large retrospective analysis also led by the group from Amsterdam3. In this multi-centric evaluation of a large sample size (n=257 women, 81% with a partial septum), live birth occurred in 80/151 women following septum resection (53.0%) compared to 76/106 women following expectant management (71.7%) (HR 0.71 95% CI 0.49-1.02). ASRM, NICE and ESHRE guidelines have so far been inconsistent in their management recommendations. Foreseeably, expectant management will soon receive an upgrade on the recommendation list of professional organizations on how to manage septate uterus.
22 Septum resection versus expectant management in women
with a septate uterus: a randomised controlled trial (NTR EMBRYOLOGY 1676), O-057 REPRODUCTIVE SURGERY
FERTILITY PRESERVATION AND Rikken et al.
Watch Prof. Michael von Wolff discuss the potential use of uterine septum resection in fertility management.
Practice point
Routine resection of a partial uterine septum in subfertile women or women with previous miscarriage should be discouraged. Data regarding a full septum are still too limited to draw a conclusion.
23 New evidence on mosaic developmental potential: multicentric
EMBRYOLOGY study of 822 mosaic embryos diagnosed by preimplantation EMBRYOLOGY genetic testing with trophectoderm biopsy, O-081
F. Spinella et al.
Background
Mosaicism, a phenomenon where within one embryo two or more cytogenetically distinct cell lines exist, occurs frequently in human preimplantation embryos with estimated incidences of 15-90% in cleavage stage embryos1 and up to 30% in blastocysts2. The origin of mosaicism is mitotic, and therefore mosaicism occurs independently of maternal age3. It is already known that mosaic blastocysts have a lower chance of implantation and a higher risk of miscarriage. Nevertheless, it is also acknowledged that mosaic embryos can establish a viable and healthy pregnancy, though the Watch Prof. Verena Nordhoff discuss the latest insights on the management and relevance of mosaic findings. extent of mosaicism and the type of chromosomal abnormality involved may play a role4.
Study 80.0 mosaic embryos (all) 2,685 PGT-A cycles with 12,187 blastocysts euploid embryos analyzed by next-generation sequencing were 60.0 included in a multi-centric, prospective study 52.3 (March 2016 to January 2020). Trophectoderm biopsies were classified as mosaic if they had 37.0 20%-80% abnormal cells. In total, 2,282 % 40.0 (18.7%) mosaic embryos were detected, of which approximately 50% had numerical and 50% 20.4 segmental aneuploidies. 1,000 mosaic embryos 20.0 were eventually transferred to 923 women (467 8.6 of which had no euploid embryo available for transfer). A comparison group consisted of 5,561 0.0 transferred euploid embryos. Overall, outcome Ongoing Miscarriage rate was better in the euploid embryo transfer group. pregnancy rate
Figure 1: Ongoing pregnancy and miscarriage rate in mosaic embryos versus euploid embryos.
24 New evidence on mosaic developmental potential: multicentric
EMBRYOLOGY study of 822 mosaic embryos diagnosed by preimplantation genetic testing with trophectoderm biopsy, O-081
F. Spinella et al.
A statistically insignificant negative association of the extent of mosaicism and pregnancy rate was found for whole-chromosome mosaics, but not for segmental mosaics.
60.0 <0.05 n.s. 43.9 45.0 41.5 36.1
% 30.0 19.3 15.0
0.0 <50% ≥50% <50% ≥50% Whole chromosome mosaic Segmental mosaic
Figure 2: Ongoing pregnancy rate in whole chromosome versus segmental mosaic.
No difference in ongoing pregnancy rate was seen for whole-chromosome mosaics with monosomy vs. trisomy. Segmental mosaic embryos had a higher chance of a positive outcome as compared to embryos with two or more whole chromosome aneuploidies, as well as complex mosaics.
Comment Practice point
This study adds that mosaic embryos with low or Embryos with different patterns of high level of segmental anomalies have a better chromosomal mosaicism have different chance of viability than any other mosaic embryo likelihoods of positive outcomes. A group. Furthermore, the study corroborated that recently published scoring system for mosaic monosomies implant and establish a viable prioritizing mosaic aneuploid embryos pregnancy with a similar incidence as do mosaic for transfer5 may help in genetic trisomies. counselling and clinical decision making.
25 Complex mosaic embryos after preimplantation genetic testing: EMBRYOLOGY go for a second biopsy? O-281
Z. Shuang et al.
Background
Embryonic mosaicism is frequently encountered in the context of PGD-Aneuploidy Screening when performed with methods of high sensitivity such as high-resolution next-generation sequencing. Non- complex, low level mosaic embryos can be considered for transfer, especially if there is no euploid embryo available1. A complex mosaicism is defined as three or more affected chromosomes or chromosome segments. Clinicians are currently cautioned against transfer of complex, high level mosaic embryos1.
Study Comment
Within a large PGD-Aneuploidy Screening program A significant false-positive rate of PGD-A is a in a Chinese IVF center, the overall incidence of serious concern, as is the potential harm of biopsy mosaic embryos was 2.4% (per total embryo and vitrification to the embryo and the financial number n= 13,451), with similar incidences cost of PGD-AS.2 It is reassuring, that the incidence in different age groups. No association was of complex mosaicism was confirmed to be low in found between blastocyst morphology and the the present study. However, the diagnosis could occurrence of complex mosaicism. 85 patients not be re-iterated in more than 70% of cases with at least one complex mosaic embryo frozen with re-biopsy hinting at inherent methodological chose to undergo embryo warming, re-biopsy, re- shortcomings of PGD-AS. analysis by NGS and re-vitrification for a potential later transfer. Re-biopsy and re-analysis were successful in 86/89 cases (97%).
Key findings were: Practice point • Approximately 60% of the re-biopsied samples were classified as euploid. In case of a complex mosaic embryo, • Of the 38% (33/86) cases that were found re-biopsy and re-diagnosis is a clinical not to be euploid in re-analysis, only 33% of option. the second diagnosis were concordant with the first diagnosis.
• 100% of 18 euploid blastocysts (by second diagnosis) that were warmed, survived double vitrification and double biopsy.
• Pregnancy rate was 39% (7/18), four healthy babies born to date.
26 EMBRYOLOGY Novel Technologies for Single-Sperm Vitrification with Cryotop and Cell Sleeper: A Follow-Up Study, O-226
Endo et al.
Background Study
Open system oocyte vitrification using, for In a retrospective study (January 2010 to example, the “CryoTop” carrier system (Kitazato December 2018), 12/1825 (0.7%) of patients Biopharma, Japan) is now widely performed. with severe male factor infertility required single Single spermatozoa in case of cryptozoospermia sperm cryopreservation. 475 spermatozoa were or TESE have also been vitrified with this system, cryopreserved in 55 “CryoTops” and 171 sperm however, samples are in direct contact with the in 18 “Cell Sleeper” devices (approx. 8-9 sperm liquid nitrogen and therefore specific devices (such per container). A higher rate of recovery of sperm as “Cell Sleeper”, “Cryo Piece” or “Sperm VD”), was observed with the “cell sleeper” container which are closed types of cell-cryopreservation system, however, a better fertilization rate was container, have been developed1. observed with “CryoTop” system. Pregnancy rate was similar in the two groups. In total, four babies were born.
Warmed Warmed Collected spermatozoa straws spermatozoa Total Motile
n n n n
Cell Sleeper 16 148 135 (91%) 20 (15%)
Cryotop 30 264 218 (83%) 75 (34%)
Table 1: Recovery rates of single sperm in two different vitrification systems.
27 Novel Technologies for Single-Sperm Vitrification with Cryotop EMBRYOLOGY and Cell Sleeper: A Follow-Up Study, O-226
Endo et al.
Cycles ICSI AOA 2PN fertilisation Cleavage
n n n n
Cell Sleeper 14 74 24 (32%) 23 (96%)
Cryotop 16 87 42 (48%) 37 (88%)
Table 2: Outcome of ICSI (AOA = artificial oocyte activation).
Comment
Single sperm cryopreservation and use for later ICSI is at the outermost boundary of treating severe male factor infertility. Single sperm vitrification may save time on the day of oocyte retrieval for searching for sperm in depleted ejaculate or tissue samples. This study, together with further evidence2,3, demonstrates the feasibility of this approach. However, the optimal procedure and carrier still need to be determined.
Practice point
Single sperm cryopreservation can be an option for cases of cryptozoospermia or TESE.
28 Intracytoplasmic sperm injection versus conventional in
EMBRYOLOGY vitro fertilisation in couples with non-male factor infertility: a randomised controlled trial, O-167
Dang et al.
Background Study
On a global scale, ICSI instead of IVF is increasingly In a bi-centric, open-label RCT conducted in being used to inseminate oocytes, even in cases of Vietnam, 1064 couples were randomized 1:1 to non-male factor infertility. One of the reasons for ICSI or IVF if the male partner had normal sperm the increasing preferential use of ICSI is that ICSI count and motility (by WHO 2010 definition) and putatively provides a better chance of fertilization, had under-gone ≤2 previous IVF/ICSI attempts. which would be especially pertinent in the case Key exclusion criteria were frozen semen, poor of low ovarian response (e.g. only few oocytes fertilization rate in a previous cycle, or in-vitro available). A Cochrane review1 identified a single maturation of oocytes. The study was designed RCT2 comparing IVF vs. ICSI for the treatment as a superiority trial (e.g. an increase of 10% live of non-male factor infertility showing no benefit birth rate with ICSI above a control arm estimated of ICSI in the case of normal sperm parameters. live birth rate of 31.5% was hypothesized5). Recently, retrospective studies reported no Patients underwent day 3 embryo transfer with advantage of ICSI over IVF in non-male factor ≤2 embryos, approximately 55-60 had ‘freeze-all’ infertility, either in terms of blastulation rate3 or and the primary outcome was live birth rate after in terms of clinical outcome stratified by ovarian first ET. response4.
ICSI IVF Difference or RR P-value n 32 n 32 CI
Fertilisation rate per oocyte inseminated 70.1 % 64.4 % 5.7 (2.5 - .0) 0.001
Fertilisation rate per oocyte retrieved 55.6 % 52.7 % 2. (-0.1 - 5.8) 0.06
Fertilisation failure, n (%) 2 (5.5) 34 (6.4) -0. (-4.0 - 2.1) 0.60
No embryo available on day3, n (%) 8 (1.5) 23 (3. ) -2.4 (-4.6 - -0.3) 0.02
GQ day 3 embryos 4.5 ± 3.4 4.4 ± 3. 0.04 (-0.4 - 0.5) 0.87
Clinical pregnancy rate 42.7 % 3 .8 % RR 1.07 (0. 3-1.24) 0.38
Ongoing pregnancy rate 35.7 % 32.7 % RR 1.0 (0. 2-1.2 ) 0.33
Live birth rate per first ET 34.6 % 31.2 % RR 1.11 (0. 3-1.32) 0.27
Cumulative ongoing pregnancy 12 months 44.0% 42. % RR 1.03 (0.8 -1.28) 0.75 after randomization
Table 1: Key findings from the ICSI vs. IVF trial
29 Intracytoplasmic sperm injection versus conventional in vitro fertilisation in couples with non-male factor infertility: a EMBRYOLOGY randomised controlled trial, O-167
Dang et al.
Comment
Key findings were: This is by far the strongest evidence to date that routine ICSI use in case of normal sperm count and • The fertilization rate was not significantly motility does not bring relevant benefit. However, increased in ICSI cases per mature oocyte it is also re-assuring that the invasiveness of retrieved ICSI is not associated with a negative effect on live birth rate, as reported at the ESHRE meeting • Approx. 2.5% more patients had at least in 20196 and reported by a systematic review of one embryo available for transfer on day 3 in mostly retrospective cohort studies this year7. The the ICSI group reasons for the global increase in ICSI utilization over the years is multi-fold and factors are “erring • The live birth rate per ITT per first ET was on the safe side”, the extension of embryo biopsy statistically not significantly increased in the in the context of PGT-AS, the availability of the ICSI group (absolute difference: 3.4% [95% technology on a global scale and financial aspects. CI: 0.93-1.32], p=0.24)
• Maternal and fetal safety parameters were highly similar
Practice point
Use of ICSI in the case of non-male factor infertility is associated with only small and insignificant benefits, and therefore IVF should be routinely used for non-male factor infertility.
30 EMBRYOLOGY Embryos excluding multinucleated cells during blastocyst formation increase their reproductive potential, O-231
Munuera Puigvert
Background
Fragmentation, blastomere asymmetry, reverse cleavage, direct cleavage, blastocyst collapse and multinucleation are considered prognostically negative morphometric criteria of the developing preimplantation embryo. A blastomere containing more than a single interphase nucleus is defined as being multinucleated. The presence of multinucleation is considered abnormal, the incidence of multinucleation in human embryos has been estimated as 15-70%, the chance of implantation appears to be decreased with an increasing proportion of multinucleated cells within the embryo1-3. However, the underlying mechanism leading to multinucleation are not fully understood and live births from transfer of multinucleated embryos have been reported suggesting that correction mechanisms may exist4.
Study
A retrospective study from Brazil included time-lapse observational data of 20,779 embryos from 5,621 cycles performed between 2014 and 2019. Embryos with at least one multi-nucleated blastomere (n=3,879) were compared with embryos without multinucleation (n=16,897). The blastulation rate was significantly lower in multinucleated embryos.
Day 2/3 Embryos Blastulation rate Blastocysts transferred
n n n
Embryos without multinucleation 16,897 9,793 (57.9%) 4210
Embryos with at least one 3,879 (18.7%) 776 (20.0%)* 307 (261 analysed) multinucleated blastomere
Table 1: Development of embryos with and without at least one multinucleated blastomere. (* p <0.05)
Embryos transferred belonging to MNC Group No difference in blastocyst formation rate and (n=307) were subdivided according to the quality was detected between the groups. multinucleated cell location after blastulation: Embryos from group MNC-3, e.g. embryos that were able to exclude multi-nucleated cells, had • MNC-1 (N=142), no cells excluded a higher chance of live birth than embryo from groups MNC-1 and -2. • MNC-2 (N=73), mononucleated cells excluded
• MNC-3 (n=46), multinucleated cells excluded
31 Embryos excluding multinucleated cells during blastocyst EMBRYOLOGY formation increase their reproductive potential, O-231
Munuera Puigvert
Blasotcyst <3CB Blasotcyst ≥3CB Comment 100 This study corroborates previous findings that 75 have suggested auto-correction mechanisms take place in cleaving embryos. It has also been 88% 71.2% 87% % 50 shown, that a large percentage (approx. 60%) of 25 2-cell multinucleated embryos develop into good- quality blastocysts and that half of those embryos 4 0 were euploid . MNC-1 MNC-2 MNC-3
Figure 1: Blastocyst quality by type of multinucleation process.
56.5
50.6 50
41.5
32. 34.4 %
24.8 22.2 16.2 11.3 .6 6.5
MNC-1 MNC-2 MNC-3 control MNC-1 MNC-2 MNC-3 control MNC-1 MNC-2 MNC-3 control
Clinical pregnancy rate Miscarriage rate Live birth rate
Figure 2: Clinical outcome by type of multinucleation process and control blastocysts.
Practice point
Embryos with multinucleated blastomeres that can exclude these cells during development up to the blastocyst stage have the same reproductive potential as embryos without multinucleation.
32 What is the optimal gonadotropin releasing hormone (GnRH) antagonist protocol during ovarian stimulation for assisted reproductive technologies (ART)? A pairwise and network meta-
OVARIAN STIMULATION analysis, O-119
C. Venetis
Background
GnRH-antagonists are commonly used for ovarian stimulation and GnRH-antagonist protocols are recommended for predicted normal and high responder patients undergoing IVF1. A number of modifications to the so-called fixed start, multiple-dose GnRH-antagonist protocol have been published and there is wide variety of protocols used in secular practice.
Study
A systematic literature review identified 72 RCTS comparing different GnRH-antagonist protocols with one another (direct data) and 69 RCTs comparing GnRH-antagonist protocols with GnRH-agonist protocols (indirect data). The following protocol aspects were evaluated: the type of GnRH antagonist (cetrorelix or ganirelix), the type of protocol (fixed day 5/6 or flexible protocol) and the type of pre- treatment (no pre-treatment or pre-treatment with OCPs, estrogens, progestins).
Key findings of the direct comparison meta- These findings were, in essence, corroborated by analysis were: the network meta-analysis.
• A lower ongoing pregnancy rate (OPR) was Comment observed after a flexible protocol compared with the fixed day 5/6 protocol (RR: 0.74, A network meta-analysis combines direct (within 95% CI: 0.58 to 0.96, I2=0%; 5 RCTs; 703 trial) and indirect (between trial) comparisons of participants; moderate quality evidence) interventions based on a common comparator. This systematic review thus comprehensively • A lower OPR was observed after oral collates all the currently available evidence on contraceptive pill pre-treatment compared with the efficacy of commonly used GnRH-antagonist no pre-treatment (RR: 0.79, 95% CI: 0.64 to protocols, however, data were too limited to arrive 0.97; I2=0%; 4 RCTs, n=1,244 participants; at conclusions on some protocol modifications moderate quality evidence) such as pre-treatment with progesterone or estrogen. The main findings of the meta-analysis • There was no difference in clinical corroborate an expert recommendation from pregnancy rates when comparing cetrorelix 20092. However, the flexible protocols used in the with ganirelix (RR: 0.99, 95% CI: 0.74 to included studies have been very heterogeneous 1.33; I2=0%; 2 RCTs; 258 participants; low- and it is not clear to which extend standardization quality evidence) of flexible protocols might improve outcomes.
Practice point
In normo-ovulatory patients, pretreatment with a combined oral contraceptive pill is not recommended. A fixed GnRH antagonist protocol appears to result in better outcomes than a flexible GnRH-antagonist protocol, possibly related to lack of standardization and heterogeneity of flexible protocols. No outcome differences between cetrorelix and ganirelix have been demonstrated.
33 Comparison of different progestin regimens for pituitary suppression during ovarian stimulation for assisted reproductive
technology, a systematic review, O-121 OVARIAN STIMULATION
B. Ata
Background
Oral progestins are effective in blocking the LH surge and may serve as an alternative to GnRH- antagonists for prevention of premature LH rises during ovarian stimulation. Medroxyprogesterone- acetate (MPA), dydrogesterone (DYD) and bioidentical progesterone (P), administered concomitantly with gonadotropins, have been used for this purpose. The term “progestin primed ovarian stimulation (PPOS)” has been established for this procedure.
Study
A systematic literature review identified five randomized clinical trials and cohort studies (n= 2,404 women) in which two different progestins or two different doses of the same progestin were compared. The most often used dosages of the progestins were daily 10mg for MPA, daily 20mg for DYD and daily 100-200 mg for P.
Author Design Intervention Comparator
Huang 2019 RC MPA 10 mg n=315 DYG 20 mg N=105
Yu 2018 RCT MPA 10 mg n=256 DYG 20 mg N=260
Zhu 2017(a) RCT DYG 20 mg n=125 MP 100 mg n=125
Guo 2019 RC MPA 10 mg n=1002 MP 200 mg n=186
Zhu 2017(b) PC MP 100 mg n=75 MP 200 mg n=75
Donh 2017 RCT MPA 10 mg n=150 MPA 4 mg n=150
Table 1: Studies included in the systematic review on progestin primed ovarian stimulation (RC = retrospective cohort; PC = prospective cohort).
Outcomes of interest were live birth rate and pregnancy rate (including ectopic and multiple pregnancy rate), as well as stimulation characteristics (duration of stimulation, gonadotropins consumed, number of oocytes and number of MII oocytes).
34 Comparison of different progestin regimens for pituitary suppression during ovarian stimulation for assisted reproductive
OVARIAN STIMULATION technology, a systematic review, O-121
B. Ata
Key findings were:
No (statistically significant) differences were found for any of the outcomes when comparing:
• MPA 10mg vs. DYD 20mg
• DYD 20mg vs. 100mg P
• MPA 10mg vs. 200mg P
A RCT on 300 women1 confirmed similar pregnancy outcomes in progestin primed ovarian stimulation with a daily dose of 4 or 10 mg MPA.
In the studies measuring endocrine levels, all progestins were associated with a similar extent of endogenous LH suppression.
Comment
The sample sizes in subgroups are insufficient to reliably detect clinically relevant outcome differences and the methodological quality of some of the evidence is not sufficiently high for definitive answers. For testing the true efficacy of progestins for preventing LH surges, a placebo-controlled trial would be warranted.
Practice point
Until contrary evidence arises, MPA 10mg, DYD 20mg or P 100-200mg appear equally suitable for preventing premature LH surges during ovarian stimulation in ‘freeze-all’ cycles.
35 Can Medroxiprogesterone acetate (MPA) serve as a pituitary suppressor instead of GnRH antagonist during ovarian stimulation (OS) in oocyte donation (OD) cycles trigger with
GnRH agonist? O-010 OVARIAN STIMULATION
Giles et al.
Background Comment
A daily dose of oral MPA 10mg has been suggested This RCT adds further evidence to the existing to be as effective as oral dydrogesterone 20mg clinical studies (reported herein by Ata et al., O-121) in blocking LH surges in women undergoing on the feasibility of progestin administration during ovarian stimulation1. MPA has been suggested as ovarian stimulation for oocyte donors and freeze- an alternative to GnRH-antagonists for ovarian all cycle. Another retrospective analysis presented stimulation of oocytes donors. at the ESHRE meeting2 reported the outcome of 1090 oocyte donor cycles, in which 200mg bioidentical progesterone were orally administered Study to prevent LH surges. When compared to a matched cohort receiving GnRH-antagonists, the A RCT conducted in a university-affiliated infertility number of oocytes and MII oocytes were highly clinic in Spain included 318 oocyte donors, 161 of similar, as were other stimulation characteristics which received 10 mg daily administered oral MPA and clinical outcomes. and 156 received daily 0.25mg GnRH-antagonist (started once the leading follicle reached 13 mm). Primary outcome was the number of oocytes Practice point retrieved. For oocyte donors or freeze-all No differences were identified for: patients (for example in the context of PGD-M), oral progestins used in the • Number of oocytes retrieved (21.4±11.7 follicular phase to prevent LH-surge vs. 21.3±9.3 in the two groups) appear to be comparable to GnRH antagonists with respect to number of • Total dose of rFSH oocytes, duration of stimulation and reproductive outcomes. GnRH-agonist • Duration of stimulation triggering of final oocyte maturation is possible in progestin primed cycles3. • Endocrine profile in follicular fluid An overall health economic and patient experience comparison of oral • Pregnancy rate & pregnancy loss rate progestins with GnRH-antagonists, using validated state of the art methodologies, is needed taking into Oral MPA was found to be superior in terms of: account all cycle-specific costs, as some studies have indicated a higher • Total number of injections per ovarian consumption of gonadotropins when stimulation cycle oral progestins are used.
• Ease of administration
36 Pituitary supression is not necessary for blocking LH surge
OVARIAN STIMULATION during luteal-phase stimulation, O-156
Palomino et al.
Background
Ovarian stimulation initiated in the luteal phase results in a similar number of oocytes of similar development competence as compared to oocytes originating from ovarian stimulation initiated in the early follicular phase1,2. Furthermore, after conventional ovarian stimulation started in the follicular phase, triggering of final oocyte maturation and oocyte pick-up, ovarian stimulation may be re-initiated in the ensuing luteal phase for a second oocyte pick, a concept termed “DuoStim”3.
Study
In a prospective randomized trial, oocytes donors underwent follicular phase ovarian stimulation with 225 IU daily rFSH, 10mg MPA and GnRH-agonist trigger and, after oocyte pick-up, reinitiated ovarian stimulation with 225 rFSH with (n=10) or without (n=10) MPA as a LH suppressant. The endocrine profile was similar as was the oocyte number in patients with and without MPA suppression of endogenous LH in the luteal phase.
Follicular phase Luteal phase Luteal phase P-value comparing Stimulation Stimulation Stimulation Luteal phase MPA MPA - MPA stimulation MPA
Stim. duration 11 13 12.1 0.31
LH basal 6.11±1.6 IU 1.6±1.3 IU 1.7±0.6 IU 0.335
LH on trigger day 3.1±1.8 IU 0.5±0.4 IU 1.5±0.6 IU 0.300
P4 on trigger day 1.4±0.3 ng/ml 0.6±0.1 ng/ml 0.4±0.1 ng/ml 0.3 8
COCs 16.7±3.0 14.5±1.6 12.8±2.1 0.575
MII 14.2±3.5 11.7±1.0 10.4±2.3 0.60
Table 1: Main findings from the DuoStim study with and without LH suppression by MPA in the luteal phase ovarian stimulation.
Comment
The authors conclude from their study that LH suppression is not necessary in ovarian stimulation cycles initiated in the luteal due to the LH suppression from the endogenous progesterone from multiple follicles.
Practice point
Further studies on larger samples are needed to corroborate these findings. If replicated, DuoStim could be further simplified. 37 Natural cycle frozen-thawed embryo transfer (FET): A comparison of outcomes following blastocyst transfer on day six versus day seven after urinary luteinising hormone (LH) surge,
O-168 OVARIAN STIMULATION
M. Noble
Background
The optimal time for transferring a blastocyst in a natural cycle after occurrence of the endogenous LH surge has not been properly studied as of yet.
Study
In a private IVF center in the UK, the protocol for transferring frozen-thawed blastocysts was changed in May 2018. Before that time-point, blastocyst transfers were performed on day seven after urinary LH surge (LH+7), after May 2018, transfers were done on day six after urinary LH surge (LH+6). In a retrospective analysis, the clinical outcomes of 378 treatment cycles “LH+7“ were compared against 180 treatment cycles “LH+6”. Only vitrified, unbiopsied blastocyst transfers were analyzed. Asan internal control, artificial hormone replacement cycles from the same time period were evaluated. It was found that the (adjusted) likelihood of live birth was approximately 2-fold higher in “LH+6” patients. In the artificial cycles, ongoing pregnancy rate was approximately 39-42%.
Comment
This is an interesting study suggesting an impressive effect of transferring a blastocyst into a “younger” endometrium. However, because of the retrospective nature of the analysis, risk of bias is high.
LH+6 LH+7 (n=180) (N=378)
Ongoing aOR: 2.06 pregnancy 45.0% 29.1% 95% CI: 1.42-3.01 rate p< 0.0001
Clinical aOR 2.30 pregnancy 52.2% 32.8% 95% CI 1.58 – 3.33 rate p<0.0001
aOR 0.79 Miscarriage 27.0% 30.8% 95% CI 0.45- 1.36 rate p=0.317
Table 1: Main findings from the natural cycle blastocyst transfer study.
Practice point
The optimal protocol in terms of pregnancy rate for transferring frozen- thawed embryos has not been determined. For now, the choice of protocol will vary between settings based on individual efficacy beliefs, financial aspects and the practicability of a protocol within a center working routine.
38 Maternal and treatment contributions to perinatal outcomes after transfer of fresh and cryopreserved embryos in assisted SAFETY & OUTCOME reproduction: A Nordic sibling study, O-029
Westvik-Johari et al.
Background
Outcome differences of children conceived by natural conception or by IVF with frozen or fresh embryo transfers have been well documented. The contribution of parental vs. treatment factors to phenomena such as altered fetal growth or pre-term birth are not yet fully elucidated1. In a sibling study design (same mother), maternal factors can be controlled. Comparing siblings after different types of conception therefore allows distinguishing the contribution of treatment factors from maternal factors to perinatal outcomes.
Study
In a large registry cohort study (CoNARTaS project) combining data from Denmark (1994-2014), Norway (1988-2015) and Sweden (1988-2015), birthweight and the incidences of SGA, LGA, preterm birth (<37 weeks) and very preterm birth (VPTB, <32 weeks) were compared at the population levels and in nine sibling pair groups from 27,041 maternal sibling with at least two different conception modes from a total population of 2.6 million babies.
Sibling First baby born Second baby n groups after born after
1 1,353,526 NC NC
2 7,080 NC Fresh
3 1,712 NC Frozen
4 16,674 Fresh NC
5 3,066 Frozen NC
6 8,010 Fresh Fresh only ART
7 5,354 Fresh Frozen only ART
8 1,256 Frozen Fresh only ART
9 1,302 Frozen Frozen only ART
Table 1: Sequence of births in women with two singleton babies resulting in nine different comparison groups in the sibling study (abbr.: NC = natural conception; Fresh = birth after IVF with fresh embryo transfer; Frozen = birth after IVF with frozen-thawed embryo transfer).
The main study findings from the sibling comparisons were that: • Babies after frozen-thawed ET had higher birthweights and increased risk of LGA when compared to spontaneously conceived babies • Babies after fresh ET had lower birthweights and increased risk of SGA as compared to spontaneously conceived babies • Preterm birth risk was modestly increased with a similar effect size for fresh ET and frozen ET 39 These results were similar in the sibling comparisons and the population level. Maternal and treatment contributions to perinatal outcomes after transfer of fresh and cryopreserved embryos in assisted reproduction: A Nordic sibling study, O-029 SAFETY & OUTCOME
Westvik-Johari et al.
Comment
This study is the largest and most robust comparison of ART offspring outcome differences measured on observational data to date. The Sibling Study showed that fetal growth is more strongly influenced by treatment, whereas risk of preterm birth is more strongly influenced by maternal factors.
Watch Prof. Heribert Kentenich discuss the key learnings from the Nordic sibling study.
Birth weight (grams)
Mean Adjusted mean 95% CI difference*
NC 3,528 Population level Fresh-ET 3,401 -85 (-90 to -81) Frozen-ET 3,578 +56 (47 to 64)
NC 3,540 Sibling Comparison Fresh-ET 3,424 -56 (-63 to -48) Frozen-ET 3,623 +72 (58 to 87)
Preterm birth (< 37 gestational weeks)
Prevalence Adjusted odds 95% CI ratio
NC 4.6 Population level Fresh-ET 7.6 1.66 (1.59 to 1.73) Frozen-ET 6.3 1.44 (1.32 to 1.57)
NC 4.7 Sibling Comparison Fresh-ET 6.7 1.27 (1.13 to 1.41) Frozen-ET 5.2 1.22 (1.02 to 1.46)
* adjusted for age, parity, country, year of birth, smoking, height, BMI
Table 2: Main findings from the Nordic Sibling study.
Practice point
The ART treatment itself is likely to impact on fetal growth. As a principal rule, the treatment chosen should be effect but with the least possible alteration of natural conditions. 40 Imprinting disorders in children born after assisted reproductive technology (ART): a Nordic study from the CoNARTaS group, SAFETY & OUTCOME O-139
O. Lidegaard et al.
Background
Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed in a parent-of- origin-specific manner, e.g. the expression of genes of one of the two alleles inherited from mother and father is silenced. During gametogenesis, the principal imprinting of genes determined by the parental origin takes place, while modifications of the established imprinting patterns occur in early embryogenesis, mostly likely induced by environmental factors. An increased risk of imprinting defects and somatic epigenetic changes in ART conceived children has been reported1, but the data are not consistent as yet.
Study
In a bi-national registry study (Denmark and In the total population of 2.7 million naturally Finland), 74,637 children after ART were compared conceived babies, 371 imprinting disorders were with the background population of babies born found. In the ART population, 16 imprinting during the same time period (1990-2014), follow- disorders in 74,631 babies were found. up period of the children was 9-12 years. The imprinting disorders of interest were Prader-Willi- Syndrome, Silver-Russel-Syndrome, Beckwith- Wiedemann-Syndrome and Angelman-Syndrome.
Incident of impriming disorders per 10 000 babies
ART
Natural conception
0.0 0.5 1 1.5 2 2.5
Figure 1: Incidence rates of four imprinting disorders per 10,000 babies in the CoNARTaS registry.
41 Imprinting disorders in children born after assisted reproductive technology (ART): a Nordic study from the CoNARTaS group, O-139 SAFETY & OUTCOME
O. Lidegaard et al.
Comment
Overall, the risk increase for any imprinting To date, the studies have not been consistent on disorder was not statistically significant (OR 1.35, the magnitude of risk increase of distinct imprinting 95%CI: 0.80-2.29). Eight ART children, however, disorders in children after ART. This study, by were diagnosed with Beckwith-Wiedemann now fully published in Human Reproduction2, syndrome, implying a significant risk increase shows that the risk of imprinting disorders in ART (adj. OR 2.84, 95%CI 1.34-6.01). No risk increase children is overall very small and maybe restricted was detected for Prader-Willi-Syndrome, Silver- to Beckwith-Wiedemann Syndrome. Russel-Syndrome and Angelman-Syndrome.
Practice point
Patients may be reassured that the absolute risk of having a baby with an imprinting disorder is small and that the relative risk increase observed in ART babies is likewise very small.
42 The risk of major congenital malformations in children SAFETY & OUTCOME conceived after ICSI: a Nordic cohort study, O-141
A.K. Henningsen et al.
Background
The use of ICSI is more prevalent than IVF in most western countries, and ICSI is increasingly often used for non-male factor infertility1. The (unadjusted) prevalence of any birth defect has previously been estimated as 7.1%, 9.9%, and 5.7% after IVF, ICSI, and natural conception, respectively2. However, the specific risk increases with ICSI as compared to IVF are still under debate.
Study
Within the CoNARTaS registry project covering included. Only major malformations (according Denmark, Norway and Sweden, singletons born to EUROCAT) were analyzed. A multivariable after ICSI (n=39,684), IVF (n=58,342) and analysis accounting for maternal age, parity, year natural conception (n=4,804,844) between of birth, child’s sex, body mass index, smoking 1992 and 2015 were identified. Birth after and country was conducted to estimate the risk of fresh or frozen-thawed embryo transfers were birth defects.
Comparison Risk p-value
ICSI vs. IVF aOR 1.06; 95% CI: 0.99-1.13 n.s.
ICSI vs. NC aOR 1.30; 95% CI 1.24-1.36 p<0.0001
ICSI fresh vs. ICSI frozen aOR 1.11; 95% CI: 0.98-1.26 n.s.
ICSI frozen vs. IVF frozen aOR 1.04; 95% CI: 0.9-1.21 n.s.
Table 1: Main findings from the CoNARTaS registry study on malformation risk in IVF and ICSI offspring (NC = natural conception; aOR = adjusted odds ratio; CI = confidence interval).
No risk increase with the use of ICSI vs. IVF was found and only a small risk increase was detected when comparing ICSI with natural conception. Likewise, no risk increase with ICSI was observed in sub-analyses by organ system (ICSI vs. IVF).
Comment
ICSI was initially developed and used for severe male factor infertility and safety concerns alluded to use of such impaired sperm but also to the invasiveness of the technique itself. With the expansion of ICSI and the more liberal use in non-severe male factor infertility, it appears as if registry data now allow ruling out a relevant risk of the ICSI technique itself.
Practice point
ICSI does not pose an independent risk for major malformations in ART offspring based on 39,684 Nordic ICSI children analyzed in the CoNARTaS registry project. 43 O-242: Artificially prepared frozen embryo transfer cycles are associated with an increased risk of preeclampsia SAFETY & OUTCOME
C. Roelens et al. (Brussels)
Background Study
Multiple studies have shown that pregnancies In a retrospective, single-center cohort study, 536 after ART have an increased risk for developing patients were identified who delivered after an hypertensive diseases, e.g. gestational autologous frozen-thawed embryo transfer: 325 hypertension and preeclampsia1. In a large RCT patients after embryo transfer in a natural cycle comparing a deferred frozen embryo transfer with (e.g. with a corpus luteum) and 211 patients in an a fresh transfer policy, it was found that frozen artificial hormone replacement cycle (e.g. with the single blastocyst transfer was associated with a corpus luteum absent). The primary outcome was higher risk of pre-eclampsia (RR 3·13, 95% CI the development of hypertension after 20 weeks of 1·06-9·30, p=0·029)2. Furthermore, it has been gestation associated with one or more new-onset suggested that the risk increase in frozen-thawed conditions: proteinuria, maternal or uteroplacental cycles may originate from ‘artificial’ hormone dysfunctions. Multivariable regression analysis replacement cycles (HRT) in which the corpus was performed to account for confounding factors luteum is suppressed, which then perturbs the knowing to affect the occurrence of PE, including: maternal circulation in early pregnancy and NC versus HRT, body mass index, ethnicity, thereby increases the incidence of preeclampsia3. previous history of hypertension during pregnancy and mean arterial pressure at the first prenatal consultation.
20
NC HRT 15.2 15
11.8 11.4
.5
% 10
5 3.7 2.8
0 Pre-eclampsia Gestational hypertension Early haemorhage (p<0.001) (p<0.001) (p 0.048)
Figure: Incidences of adverse events in pregnancies of patients undergoing a natural cycle or hormone replacement cycle FET. 44 O-242: Artificially prepared frozen embryo transfer cycles are SAFETY & OUTCOME associated with an increased risk of preeclampsia
C. Roelens et al. (Brussels)
The multi-variable analysis showed an increased risk for pre-eclampsia (adjusted OR 2.9; 95% CI: 1.4- 6.0; p=0.005) in HRT patients. The mean arterial pressure at the first prenatal consultation was higher by approximately 5mm meanHg in the HRT group.
Comment
This study adds to the growing concern that HRT cycles for a frozen-thawed embryo transfer cycle may be associated with increased maternal and fetal risks4 . However, both efficacy and safety of the two protocols should be precisely determined via a large sized RCT given the wide-spread use of FET cycles and the multiple ramifications of the protocol choice not only efficacy and safety but also convenience, cost, reliability and treatment calculability.
Watch Prof. Heribert Kentenich discuss the rise of frozen-thawed embryos.
Practice point
Several RCTs are currently being planned or already ongoing that will soon allow a better judgement on outcome and safety differences between natural and HRT cycle FETs.
45 Additional Video Highlights
Watch Prof. Verena Nordhoff discuss modelling blastocyst formation from stem cells.
Watch Prof. Heribert Kentenich discuss the current status of elective single embryo transfer in Germany and how this differs from the rest of the world.
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Major congenital malformations risk in children conceived after ICSI
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