2019 - reprofacts · had oligo-amenorrhea or polycystic ovarian reproductive endocrinology...

HIGHLIGHTS OF THE ANNUAL MEETING OF THE

EUROPEAN SOCIETY OF HUMAN REPRODUCTION AND EMBRYOLOGY

2019

23rd-26th June 2019Austria, 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.

Sponsored byAugust 2019 GBPMLR/NONF/0819/0199

INTR

OD

UC

TIO

N T

O R

EPR

OFA

CTS

INTR

OD

UC

TIO

N T

O R

EPR

OFA

CTS

The Annual Meeting of ESHRE is considered by many to be the world’s major and most important event in the field of reproductive science and medicine. The latest Annual Meeting was held in Vienna, from 24 to 26 June 2019, attracting 12,003 delegates from 130 countries. All relevant innovations in reproductive science found a platform for exchange and communication at ESHRE 2019. The main scientific program consisted of 234 peer-reviewed oral communications and 63 invited lectures, with an additional 789 posters in electronic format.

The key themes ranged from the role of luteal phase support, male infertility and the importance of counselling the patient, to debates on the increased incidence of ICSI and freeze-all. The ESHRE 2019 program was truly packed with inspiring content.

However, the wealth and breadth of information can make it challenging for individual delegates to not only understand the general themes but to also single out and focus on the truly relevant news from each subspecialty. For that reason, the REPROFACTS initiative was founded in Germany in 2011.

Eight experts in different subspecialties share among them the whole scientific program of the annual meeting, visiting the lectures, browsing the posters, speaking to the presenters, investigating the background and finally selecting what they think represents the “must-know” content from the conference.

Nine days after the conclusion of the ESHRE meeting, the REPROFACTS meeting was held in Frankfurt, Germany. The REPROFACTS faculty presented their selection of studies to a large audience of practicing clinicians and embryologists, putting study findings in perspective and extracting the practice points. The faculty is totally independent in their choice of studies and their evaluation.

This report contains some of the key highlights from the REPROFACTS meeting 2019.

Prof. Dr. med. Heribert KentenichBerlin. Subspecialities: safety and quality, law and ethics, psychology

Prof. Dr. med. Michael von WolffBern. Subspecialities: fertility preservation, ovarian reserve, early pregnancy

Prof. Dr. med. Kazem NouriVienna. Subspecialities: endometrium, endometriosis, surgery

Dr. rer. nat. Jens HirchenhainDüsseldorf. Subspeciality: clinical embryology

Priv.-Doz. Dr. rer. nat. Verena Nordhoff,Münster. Subspecialities: basic science and reproductive genetics

Prof. Dr. med. Michael ZitzmannMünster. Subspeciality: andrology

Prof. Dr. med. habil. Jürgen M. WeissLucerne. Subspecialities: female infertility and ovarian stimulation

Prof. med. Ludwig WildtInnsbruck. Subspeciality: endocrinology

Faculty members

CO

NTE

NTS

CO

NTE

NTS

Endometriosis and the endometrium

Ovarian stimulation and infertility

Progesterone on the day of embryo transfer

Reproductive endocrinology

Predicting luteal progesterone levels

AMH as a driving force of PCOS

AMH levels in adolescence and the presence of PCOS

Frozen embryo transfer and miscarriage rate

Endometrial scratching after one failed IVF/ICSI cycle

GnRHa therapy before IVF

Linzagolix for endometriosis pain

Comparing biosimilar to originator recombinant follitropin alfa

Long vs classical antagonist protocol

Freeze-all versus fresh embryo transfer

Safety, psychology and counsellingART and risk of congenital heart defects

Fertility preservation

Clinical embryology

Andrology

Oocyte aging

IVF after caesarean section

Outcomes from different ovarian tissue grafting sites

ICSI versus conventional IVF

Impact of the time interval between ovulation triggering and oocyte injection

Blastocyst morphology and NIPGT-A accuracy

Gene editing – past, present and future

Sperm morphology as a marker of nuclear quality and epigenetic status

De novo mutations affecting male infertility

Impact of male factors on ICSI outcomes

The long-term health of IVF-ICSI babies

Ovarian tumour risk after ART

Mobile apps and fertility

Background

Artificial frozen-thawed embryo transfer cycle regimens often exclusively employ vaginal progesterone for secretory transformation of the endometrium and for early pregnancy support.2

In a previous publication, Elena Labarta et al have already suggested that the serum levels of progesterone achieved by vaginal administration may be insufficient for optimal outcomes for a substantial proportion of oocyte donation recipients.3

Study Summary

The present prospective cohort study included 1155 patients undergoing either autologous or heterologous frozen-thawed embryo transfers in artificial anovulatory cycles. All patients had a

REP

RO

DU

CTI

VE

END

OC

RIN

OLO

GY

REP

RO

DU

CTI

VE

END

OC

RIN

OLO

GY

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

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

E. Labarta Demur et alE. Labarta Demur et al

blastocyst transfer after endometrial preparation with 2x400mg vaginal progesterone. On the day of embryo transfer, the serum level of progesterone was measured.1

Results

The mean serum progesterone level was 12.0±5.8 ng/mL. Serum progesterone levels were associated with ongoing pregnancy in univariate analysis. Women with serum P levels <8.8 ng/mL (percentile 30) had a significantly lower ongoing pregnancy rate compared to patients above this threshold.1 (Figure 1)

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

Practice message

0

10

20

30

40

50

60

≥8.8 ng/mL<8.8 ng/mL

Ong

oing

Pre

gnan

cy R

ate

(%)

39.8

58.0

Serum progesterone levels

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

After adjusting for the confounders age, body mass index (BMI), endometrial thickness, serum E2, number of embryos transferred and origin of oocytes, low progesterone levels defined as <8.8 ng/mL remained a significant negative predictor for ongoing pregnancy (OR 0.39, 95% CI:0.28-0.53, p=0.000).1

Key Findings

This study adds to the existing concerns about only using vaginal progesterone for luteal phase support in the context of an anovulatory artificial cycle, where endometrial receptivity and early pregnancy completely rely on the exogenous progesterone source.3-6

Figure 1: Ongoing pregnancy rate at different levels of serum progesterone1

Watch Prof. Ludwig Wildt discuss measuring progesteronein the luteal phase

https://vimeo.com/351369078/abbb147478

#

REP

RO

DU

CTIV

E E

ND

OC

RIN

OLO

GY

Background

The optimal serum progesterone level in the luteal phase of a fresh in vitro fertilization (IVF) cycle after controlled ovarian stimulation, is still under debate. It is assumed that the number of corpora lutea is a strong determinant of the total amount of circulating progesterone.2

As yet, little is known about other determinants of ovarian progesterone production and subsequent serum progesterone levels in the luteal phase of an IVF cycle.

The luteal phase of the fresh IVF cycle is eliciting more and more interest. New compounds for luteal phase support have been tested and introduced to the market, such as subcutaneous progesterone or dydrogesterone.3,4 Also, the corpus luteum function is now considered not only a determinant of success, but also pregnancy course, maternal health and, potentially, fetal health.5,6

Luteal serum progesterone levels cannot be predictedin IVF patients - A prospective study of 432 IVF/ICSI cycles, O-1771

L. Thomsen et al

Two to three days after oocyte retrieval, serum progesterone levels were measured. The following predictors of progesterone levels were assessed by linear regression modelling:1

Age

BMI

Numberoffinalfollicles

Type of ovulation trigger

The day of progesterone assessment

Protocol type

Duration of stimulation

Smoking

Total gonadotropin dose

Type of gonadotropin

Key Findings

It was found that all factors taken together could explain only approximately 50% of the variation in serum levels between patients. In other words, predicting the serum progesterone from patient and treatment characteristics, respectively, cannot reliably be done. The authors therefore speculate that some patients suffer from some form of impairment of corpus luteum function.1

Study Summary

This prospective cohort study assessed 432 patients. Patients underwent:1

• Controlled ovarian stimulation in a long GnRH-agonist or GnRH-antagonist protocol

• hCG or GnRH-agonist triggering of final oocyte maturation

• Fresh embryo transfer

• Identical luteal phase support regimens using vaginal progesterone

REP

RO

DU

CTIV

E E

ND

OC

RIN

OLO

GY

Background

Polycystic ovary syndrome (PCOS) patients often have high serum luteinizing hormone (LH) levels, which may contribute to an excess of androgen via theca cell stimulation.1 There is also high correlation between elevated Anti-Müllerian hormone (AMH) serum levels and follicle numbers in the polycystic ovary.1 The association of AMH with LH levels, hypothetically via central stimulation of gonadotropin-releasing hormone (GnRH) neurons by AMH, has not yet been demonstrated in humans.1

Antimüllerian Hormone as a driving force of PCOS, independently from insulin-resistance, O-0091

G. Robin et al

Study Summary

In this retrospective mono-centric study, 639 PCOS patients (diagnosed according to the Rotterdam criteria) were compared with 137 non-PCOS controls. A discriminant analysis was performed to identify which clinical, hormonal, metabolic and ultrasound variables related to high or low serum AMH levels in PCOS women compared to the controls.1

Practice message

Results

In the control patients, AMH was only associated with age and number of follicles.1

In PCOS patients, higher AMH was related to increases and decreases in many variables.1 (Figure 1)

Figure 1: Variables associated with higher AMH in PCOS patients1

serum FSH

BMI

waist circumference

plasma insulin (I) levels

incidence of obesity

serum levels of LH

serum levels of androgens

follicle numbers

hyperandrogen

oligo-anovulation

Incr

easi

ng

>

Decre

asin

g >

Key Findings

These observations hint at a stimulatory effect of AMH on LH secretion which drives an AMH dependent phenotype of PCOS (e.g. hyperandrogenic anovulation).1

PCOS patients with high AMH appear to show more of an “ovarian phenotype” rather than a “metabolic phenotype”.

Background

Diagnostic criteria for polycystic ovary syndrome (PCOS) must not be applied to adolescents as irregular cycles are frequent, clinical signs of hyperandrogenism are difficult to classify and there is lack of normal references for ovarian morphology.2

Study Summary

Between 1990 and 1997, adolescents with menstrual irregularities were included in this Dutch long-term follow-up study. 271 stored adolescent serum samples were available from this cohort.1 Anti-Müllerian hormone (AMH) was now measured and information on current menstrual cycle pattern and presence of PCOS features in the grown up females was collected.1

Results

It was found that AMH levels at adolescence were already significantly higher in girls who had oligo-amenorrhea or polycystic ovarian

REP

RO

DU

CTIV

E E

ND

OC

RIN

OLO

GY

Anti-Müllerian hormone levels in adolescence in relation to long-term follow up for presence of polycystic ovary syndrome, O-0101

M. Caanen et al

morphology (PCOM) compared with regular cycling girls (Figure 1).1

In the follow-up study, 11.9% of females were diagnosed with PCOS. These women had higher AMH in adolescence as compared to women without PCOS (4.7 vs. 3.6 μg/L, p=0.051). (Figure 1) The same phenomenon was observed for adults with oligomenorrhea.1

Serum AMH measured in adolescence was a poor predictor of PCOS in adulthood, especially given the incidence of oligomenorrhea in adolescence.1

In the words of Caanen and colleagues: “Given adolescent oligomenorrhea, using high AMH as factor to predict adult PCOS or adult oligo-amenorrhea was of no value”.1

Key Findings

This unique long-term follow-up project confirmed the association of AMH measured in adolescence with the development of signs of PCOS. However, serum AMH measured in adolescence is not a clinically useful predictor of PCOS in the adult.1

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

0

1

2

3

4

5

6

No ad

ult PC

OS

Adult

PCOS

No PC

OMPC

OM

Normal

cycle

Oligom

enor

rhea

AM

H (

µg/L

)

3.1

5.5

3.1

5.2

4.7

3.6

EN

DO

METR

IOS

IS A

ND

TH

E E

ND

OM

ETR

IUM

Background

The 2013 ESHRE guideline on the management of women with endometriosis states that clinicians can prescribe GnRH-analogues for a period of 3 to 6 months prior to assisted reproduction in order to increase pregnancy rates in infertile women with endometriosis.2

Study Summary

A Cochrane systematic review and meta-analysis summarized seven randomized studies, incorporating 496 women, on the effects of a minimal treatment period of three months with GnRH-agonists prior to IVF/ICSI.1

Results

It was found that:1

Clinical pregnancy rate (RR 1.31, 95% CI 1.05 to 1.64) and mean number of oocytes (MD 1.09, 95% CI 0.32 to 1.86) were increased after GnRH-agonist treatment

Live birth rate was only reported in one small study and thus no robust conclusion is currently possible

Long-term gonadotrophin-releasing hormone agonist (GnRHa) therapy before in vitro fertilisation (IVF) for improving fertility outcomes in women with endometriosis: a Cochrane systematic review and meta-analysis, O-2081

E. Georgiou et al

There was no difference in miscarriage rate, multiple pregnancy rate or number of embryos

There was a lack of data on adverse events such as ectopic pregnancy rate or fetal abnormalities

It was noted that the quality of the evidence was not consistently high and there was heterogeneity in studies and outcomes.1

Key Findings

The available evidence indicates a small benefit for pregnancy rate of GnRH-agonist treatment prior to IVF/ICSI.1

Subfertile patients with endometriosis should be counselled about the available evidence.

Practice message

Background

Incidence of frozen-thawed embryo transfers (FET) is increasing due to the use of freeze all cycles for patients at risk of developing ovarian hyperstimulation syndrome (OHSS) and undergoing preimplantation genetic diagnosis (PGD).2 Frozen-thawed embryos may be transferred in a natural cycle (with or without hCG triggering and luteal phase support), an anovulatory artificial cycle or a stimulated cycle.1 To date, there is no consensus on the optimal protocol for efficacy, maternal safety or fetal safety.

EN

DO

METR

IOS

IS A

ND

TH

E E

ND

OM

ETR

IUM

EN

DO

METR

IOS

IS A

ND

TH

E E

ND

OM

ETR

IUM

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

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

L. Vinsonneau et alL. Vinsonneau et al

Study Summary

This multicentric retrospective study evaluated 14,421 FET cycles, corresponding to 3,844 pregnancies.1 (Table 1)

Results

The artificial cycle was most frequently used overall (56.6% of all cycles) and more often used in women with a history of ovulatory disorder and previous pregnancy.1

The miscarriage rate was highest in the artificial cycle and lowest in the stimulated cycle.1 (Figure 1)

Use of natural or stimulated ovulatory FET cycles may be preferential to an artificial FET cycle.

Practice message

After adjustment for available confounders, including maternal age and previous miscarriage, the artificial cycle was associated with a significantly higher risk of miscarriage.1 (Table 2)

Accordingly, the live birth rate (LBR) was lower in artificial cycles.1

Table 1: The number of pregnancies associated with each protocol1

Protocol Number of women Pregnancies

Artificial cycle 8139 2214

Natural cycle 3126 812

Stimulated cycle 3156 818

Total 14421 3844

0

5

10

15

20

25

30

35

40

Stimulated cycleNatural cycleArtificial cycle

36.50

25.6023.60

Mis

carr

iage

rat

e (%

)

Protocol

Figure 1: The miscarriage rate associated with each endometrial preparation protocol1

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

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

Key Findings

This study adds to the growing body of evidence evidence that the suppression of ovulation and the lack of a corpus luteum in early pregnancy associated with artificial cycles may be associated with decreased efficacy.3

Further data discussed at the ESHRE meeting indicated that the lack of a corpus luteum may also be associated with changes in the maternal cardiovascular system with implications for preeclampsia and long-term fetal health.1,4-6

Background

Sex steroid withdrawal via GnRH-analogue administration is an established therapy for endometriosis-associated pain.1 Low levels of estrogen and progesterone induced by GnRH-analogues can affect bone mineral density and overall quality of life.2,3 Linzagolix is a novel, non-peptide orally active gonadotropin-releasing hormone antagonist that reduces circulating serum sex steroid levels.1

Study Summary

In this phase II study, women with endometriosis-associated pain received oral Linzagolix once daily in doses of 50, 75, 100 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 assessed on a Verbal Rating Scale.1

EN

DO

METR

IOS

IS A

ND

TH

E E

ND

OM

ETR

IUM

EN

DO

METR

IOS

IS A

ND

TH

E E

ND

OM

ETR

IUM

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

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

E. Bestel et alE. Bestel et al

Results

Compared to placebo, doses ≥75 mg resulted in a significant increase in patients reaching the primary endpoint.1 (Figure 1)

A similar pattern of results was seen for dysmenorrhea and non-menstrual pelvic pain. The effects were maintained or increased at 24 weeks.1

Median E2 levels changed from 35 to 47pg/mL with a 75mg dose and from 12.5 to 13 pg/mL with a 200 mg dose.1

Changes in bone mineral density from baseline to week 24 were reported for doses 75-200mg.1 (Table 1)

Linzagolix has been shown to reduce endometriosis related pain however this must be confirmed in larger trials.

Practice message

Key Findings

Linzagolix is the third orally active GnRH-antagonist tested for endometriosis therapy following the large trial on Elagolix in 2017 and ASP1707.2,4 Orally active GnRH-antagonists may form the treatment standard of the future. A 75mg dose of oral Linzagolix will be tested in a larger phase III trial. Also, the impact of estrogen/progestogen add-back to Linzagolix treatment still needs to be established.1

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

Dose Mean percent (95% CI) BMD change P-value

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

Figure 1: Proportion of patients reporting a ≥30% reduction in pelvic pain over 28 days1

0

10

20

30

40

50

60

70

80

% P

atie

nts

39.8

49.5(p=0.155)

Placebo 50 75 100 200

Dose (mg)

61.5(p=0.003) 56.4

(p=0.039)56.3

(p=0.034)

EN

DO

METR

IOS

IS A

ND

TH

E E

ND

OM

ETR

IUM

EN

DO

METR

IOS

IS A

ND

TH

E E

ND

OM

ETR

IUM

Endometrial scratching in women after one failed IVF/ICSI cycle: results of a randomized controlled trial (SCRaTCH trial), O-0231

Endometrial scratching in women after one failed IVF/ICSI cycle: results of a randomized controlled trial (SCRaTCH trial), O-0231

N.E. van Hoogenhuijze et al N.E. van Hoogenhuijze et al

Background

Data from past randomized controlled trials (RCTs) have been conflicting as to whether endometrial scratching improves live birth rate in patients undergoing in vitro fertilization (IVF).2 The PIP trial involved 1,364 participants and was presented at the 2018 ESHRE annual meeting.3 The PIP trial suggested that endometrial scratching had no significant effect on live birth rate (LBR).3 However, the PIP trial was criticized for a lack of standardization of the scratching procedure and insufficient homogeneity of the population.2

Study Summary

In the multicenter, non-blinded SCRaTCH trial, 942 participants with one failed intracytoplasmic

sperm injection (ICSI)/IVF cycle were recruited. Participants underwent endometrial scratching using an endometrial biopsy catheter in the mid-luteal phase, prior to ovarian stimulation.1

Results

The LBR was increased following endometrial scratching in the fresh IVF cycle but this effect was not present when the cumulative LBR per cycle was analyzed. (Figures 1 and 2)1

Key Findings

Despite a small non-significant increase in LBR with endometrial scratching in the SCRaTCH trial, the available evidence is not consistently in favor of scratching.1,2

Scratching may not improve pregnancy outcomes for women with failed IVF cycles.

Practice message

Figure 1: LBR outcomes from the SCRaTCH trial4

Figure 2: Cumulative LBR outcomes from the SCRaTCH trial4

0

5

10

15

20

No scratchScratch

LBR (

%)

18.9

14.0

RR 1.35, 95% CI: 1.01-1.81, p=0.043LBR = live birth rate per first embryo transfer

0

5

10

15

20

25

No scratchScratch

Cum

ulat

ive

LBR (

%)

23.6

20.8

RR 1.14, 95% CI: 0.9O-1.46, p=0.271cumulative LBR = live birth rate per first embryo transfer and

subsequent frozen-thawed cycles

OV

AR

IAN

STIM

ULA

TIO

N

AN

D I

NFE

RTIL

ITY

OV

AR

IAN

STIM

ULA

TIO

N

AN

D I

NFE

RTIL

ITY

Background

Follicle stimulating hormone (FSH) is a complex glycoprotein expressed in Chinese hamster ovary cells for pharmaceutical use.2

After one of the originator compounds, follitropin alfa, lost its patent protection, biosimilars to follitropin alfa have entered the market based on an abbreviated approval procedure with surrogate primary outcomes for pregnancy and live birth.3,4

Study Summary

A systematic review and meta-analysis reviewed three randomized controlled trials. The biosimilar preparations were Bemfola and Afolia in two studies respectively, and Ovaleap in the third study.1

A systematic review and meta-analysis comparing Biosimilar versus Originator Recombinant Follitropin Alfa in women undergoing IVF/ICSI, O-2381

S. Longobardi et al

Results

Compared with the originator preparation, the live birth rate and clinical pregnancy rate was significantly lower when using biosimilars. No difference in ovarian hyperstimulation syndrome (OHSS) was observed.1 (Table 1) The trials were statistically and clinically homogenous.1

Key Findings

After meta-analyzing these small sized individual studies on biosimilars to follitropin alfa, the authors indicated a statistically significant difference for live birth rate, the primary efficacy outcome. This finding warrants further investigations.1

Table 1: Clinical outcomes using biosimilars compared with the originator preparation1

Clinical outcome RR (95% CI)

Live birth rate 0.82 (0.70-0.97)

Clinical pregnancy rate 0.83 (0.71-0.96)

OHSS (moderate to severe) 1.30 (0.83-2.70)

Background

The GnRH-antagonist multiple dose protocol with daily 0.25mg antagonist administration from cycle day 5 or 6 has become a widely used stimulation regimen in women undergoing in vitro fertilization (IVF), because of its patient friendliness and safety.2,3

A major drawback of the GnRH-antagonist protocol is that the initiation of stimulation relies on the occurrence of spontaneous menstruation or withdrawal bleeding after sex steroid pre-treatment.3 This is one reason why many centers may still use the long luteal GnRH-agonist protocol.

Long-Antagonist protocol versus Classical-day-6 Antagonist. Single luteal use of long-acting GnRH-antagonist Degarelix can efficiently downregulate LH during ovarian stimulation for IVF achieving comparable pregnancy outcome, O-2371

E. Papanikolaou et al

Study Summary

In a small, randomized proof-of-concept study, 113 women received either:1

• 0.5ml of the long-acting GnRH-antagonist Degarelix in the luteal phase preceding the stimulation cycle, or

• a multi-dose, 0.25mg GnRH-antagonist regimen with first administration on day 6 of the stimulation cycle

Results

The duration of stimulation was slightly longer in the long luteal antagonist protocol, while no difference was observed for oocyte and blastocyst numbers, respectively, and pregnancy rates.1

Key Findings

A long luteal GnRH-antagonist protocol may help in cycle scheduling but a number of issues, including side-effects, need to be addressed in future studies.1

This years’ ESHRE meeting saw another trial report from Najdecki et al which evaluated the use of a single dose of 0.1ml Degarelix on cycle day 6 instead of daily 0.25 mg GnRH-antagonist.1 Remarkably, GnRH-agonist triggering was successfully performed in all patients after Degarelix administration.1

Background

A number of large randomized controlled trials (RCTs) comparing fresh vs. frozen embryo transfer have been published in the last four years.2-5

A recent systematic review and meta-analysis of the available RCTs reported a significantly higher probability of live birth in high, but not normal responders, after the first frozen embryo transfer (ET) in a freeze-only cycle strategy when compared to a fresh ET.6

Study Summary

In a multicenter, randomized trial conducted in Denmark, Sweden and Spain, 460 women were allocated 1:1 to either undertake:1

OV

AR

IAN

STIM

ULA

TIO

N

AN

D I

NFE

RTIL

ITY

OV

AR

IAN

STIM

ULA

TIO

N

AN

D I

NFE

RTIL

ITY

Freeze-all versus fresh embryo transfer in ART: A multicentre randomised controlled trial in normo-ovulatory women, O-0691

Freeze-all versus fresh embryo transfer in ART: A multicentre randomised controlled trial in normo-ovulatory women, O-0691

S. Stormlund et alS. Stormlund et al

• GnRH agonist trigger and single vitrified-warmed blastocyst transfer in a subsequent natural cycle, or

• hCG trigger and single blastocyst transfer in the fresh cycle

All participants were normo-ovulatory.1

Results

The ongoing pregnancy rate (OPR) per randomized patient after the first potential blastocyst transfer was comparable in the freeze-all group and the fresh transfer group.1 (Figure 1)

OPR per embryo transfer (only including patients who had a transfer) was also comparable in the freeze-all group compared with the fresh embryo transfer group.1 (Figure 2)

Normoresponder patients should not routinely defer fresh embryo transfer.

Practice message

In the fresh embryo transfer group, 25 participants were converted to freeze-all due to risk of ovarian hyperstimulation syndrome (OHSS). One case of OHSS with hospital admission occurred in the fresh transfer group.1

Key Findings

The findings of this RCT do not support general utilization of a freeze-all approach in normo-ovulatory women but rather a freeze-all for distinct patients, such as hyper-responders or those where an impairment of endometrial receptivity is suspected.1

Figure 1: Ongoing pregnancy rate (OPR) per patient1

0

5

10

15

20

25

30

35

40

FrozenFresh

Ong

oing

Pre

gnan

cy R

ate

(%)

28.826.1

Embryo transfer

OR 0.88, 95% CI 0.58-1.34; p=0.54

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

0

5

10

15

20

25

30

35

40

FrozenFresh

Ong

oing

Pre

gnan

cy R

ate

(%)

36.8 36.1

Embryo transfer

OR 0.97, 95% CI 0.62-1.52; p=0.89

Watch Prof. Jurgen Weiss discuss whether freeze-all is appropriate for all

Background

Assisted reproductive techniques are associated with an increased risk of birth defects.2 In births from assisted reproductive technology (ART), congenital heart defects are more common than natural births, with an estimated incidence of 0.8% after natural conception and 1.6% after ART.1

Study Summary

In this registry-based cohort study, all deliveries (n=302,811) and terminations of pregnancy in South Australia from January 1986 to December 2002 were linked to all cycles of ART (6,163 births) for the same period.1

The registry included information on births and terminations of pregnancy. These were linked to all cycles of ART and to all congenital anomalies (defined using ICD-9 British Paediatric Association codes) notified up to the 5th birthday. Logistic regression was used to investigate associations between parental factors, treatment modality and the presence of congenital heart defects.1

Results

Multiple comparisons including drug administration and culture media revealed:1 (Table 1)

• Increased risk for Patent Ductus Arteriosus was associated with fresh in vitro fertilization (IVF) cycles and frozen intracytoplasmic sperm injection (ICSI) cycles

• Clomiphene citrate treatment for ovulation 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

SA

FETY

, P

SY

CH

OLO

GY

A

ND

CO

UN

SELL

ING

SA

FETY

, P

SY

CH

OLO

GY

A

ND

CO

UN

SELL

ING

Treatment factors and the risk of specific congenital heart defects, O-0631

Treatment factors and the risk of specific congenital heart defects, O-0631

M. Davies et alM. Davies et al

All associations were identified as positive in direction, meaning that the authors only observed increases in risk. The distribution of multiple increased risks with ART is unlikely to be random.1

Key Findings

Techniques of ART, including ovarian stimulation, are associated with an increased risk of serious cardiac defects.1

The subgroup findings on distinct medications and culture media from this study need corroboration from further epidemiological research.

Of note, a history of infertility without ART is also associated with an increased risk for organ malformations, as has been shown in previous studies.3,4 Mechanistic studies are now also needed for a better understanding of the underlying pathways and for finding ways to decrease exposure by treatment.

Counselling patients on the risks associated with ART must include counselling specifically on the risk increase of congenital heart defects.

Practice message

Table 1: Estimated risks for congenital heart defects1

Defect (subgroup) aOR 95% CI

Any cardiac defect (IVF & ICSI combined) 1.42 1.13-1.80

Congenital Aorta Valve Stenosis (IVF & ICSI combined) 3.20 1.26-8.11

Patent Ductus Arteriosus (IVF & ICSI combined) 1.88 1.18-3.00

Patent Ductus Arteriosus (only fresh IVF) 2.69 1.32-5.48

Patent Ductus Arteriosus (only frozen ICSI) 4.59 1.84-11.44

Coarctation Of Aorta (only if ovulation induction with clomiphene) 5.90 1.05-33.11

Patent Ductus Arteriosus (Culture medium X, IVF) 5.56 1.31-23.53

Endocardial Cushion Defects (spontaneous conception after ART) 4.06 1.43-11.50

Cardiac Septal Closure Anomalies (history of “infertility” but no IVF) 1.90 1.12-3.23

Atrial Septal Defect (history of “infertility” but no IVF) 3.65 1.88-7.12

Patent Ductus Arteriosus (history of “infertility” but no IVF) 3.09 1.26-7.56

aOR= adjusted odds ratio; 95% CI = 95% confidence interval

SA

FETY

, P

SY

CH

OLO

GY

A

ND

CO

UN

SELL

ING

SA

FETY

, P

SY

CH

OLO

GY

A

ND

CO

UN

SELL

ING

Alarming findings when using administrative databases and national registries, O-0911

C. Bergh

Watch Prof. Heribert Kentenich discuss research on the long-term health effects of ART

Background

Manipulation of pituitary function, ovarian stimulation and oocyte retrieval alter normal ovarian physiology.2 So far, no alarming risk increases for ovarian tumors have been associated with assisted reproductive technology (ART) in follow-up studies, but results are not fully consistent, especially for invasive ovarian cancers.3

Study Summary

The OMEGA study was based on a nationwide historical cohort with prospective follow-up in the Netherlands.4

This cohort included 30,636 women who received ovarian stimulation for ART (ART group) between 1983 and 2001 in one of the 12 Dutch IVF centers and 9,969 women who underwent subfertility treatments other than ART (non-ART group) between 1980 and 2001.1

National Cancer Registry data was linked with:1

• The initial medical records on ART treatment

• Updated information on reproductive performance and lifestyle factors

Long-term risk of ovarian tumours after assisted reproductive technology, O-1831

M. Spaan et al

Associations with ovarian cancer risk were explored by multi-variable time-dependent Cox regression analysis.1

Results

After a median follow-up of 22 years, no increased risk of invasive ovarian cancers was found, with an estimated incidence of 36/10,000 vs. 35/10,000 in ART and non-ART subjects respectively (HR 1.03, 95% CI: 0.70-1.52).1

The risk was also not increased with higher numbers of cycles or when long-term follow-up data (>25 years) was examined.1

Key Findings

The OMEGA study provides robust and externally valid data not only because of the large sample size and the prospective follow-up, but also because of the use of an internal control group of subfertile subjects not undergoing ART.1

Patients undergoing ovarian stimulation and oocyte pick-up may be worried about developing ovarian cancer later on. Patients should be counselled that this recent large epidemiological study found no increased risk for invasive cancers after ART.

Practice message

Background

Many women trying to conceive use fertility and cycle tracking apps to track their cycle.1 Between 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

Less than 10% of applications cited published 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

FER

TIL

ITY

PR

ES

ER

VA

TIO

N

SA

FETY

, P

SY

CH

OLO

GY

A

ND

CO

UN

SELL

ING

A systematic review and meta-synthesis of mobile device fertility applications: More than a glitch in the matrix!, O-1011 S. Costa and A. Yazdani

Patients should be advised to exercise caution when using fertility apps.

Practice message

Watch Prof. Kazem Nouri discuss the role of mobileapplications in fertility

Key Findings

Fertility and cycle applications are often unreliable.1

Oocyte quality during reproductive aging: Are the chromosomal abnormalities the only problem?, O-0531

S. Ledda and D. Bebbere

Watch Prof. Verena Nordhoff discuss oocyte aging and the role of chromosomal abnormalities

https://vimeo.com/351368659/bd8037f705

#

Background

Caesarean section (CS) is the most common surgery performed around the world.2 The rates of delivery by CS are rising on a global scale with ART associated with greater odds of CS compared with fertile women.3,4

Sequelae of CS include niches (scar defects), bleeding disorders and obstetrical complications.2 It has previously been reported that non-IVF patients who underwent a CS had a 9% lower subsequent pregnancy rate [RR 0.91, 95% CI (0.87, 0.95)] and 11% lower birth rate [RR 0.89, 95% CI (0.87, 0.92)] compared with patients who had delivered vaginally.5

However, the available study results are not completely consistent.6 It has been suggested that a woman’s clinical and social circumstances play larger roles for future fertility than the surgical procedure itself.6

FER

TIL

ITY

PR

ES

ER

VA

TIO

N

FER

TIL

ITY

PR

ES

ER

VA

TIO

N

Adverse/ reproductive outcomes of reduced pregnancy and live birth rates after In Vitro Fertilization in women with previous caesarean section: a retrospective cohort study, O-3011

Adverse/ reproductive outcomes of reduced pregnancy and live birth rates after In Vitro Fertilization in women with previous caesarean section: a retrospective cohort study, O-3011

J. Vissers et alJ. Vissers et al

Study Summary

This retrospective cohort study included all women who underwent an in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle at a single academic center in the Netherlands between 2006 and 2016 with one previous delivery (1317 women total, 334 women with a previous caesarean section, 983 women with a previous vaginal delivery).1

Only the first fresh embryo transfer was considered for the analyses.1

Multivariable logistic regression analyses were performed with adjustment for possible confounders (age, BMI, smoking, indication for IVF/ICSI, uterine pathology, endometrioses, duration of infertility) to study the association of a previous CS on the outcome of the subsequent IVF cycle.1

Elective caesarean sections should be discouraged if a woman intends to have further children via IVF.

Practice message

Results

It was found that live birth rates were significantly lower in women after a CS. (Table 1) The rate of difficult transfers was higher in the CS group (9.3% vs. 1.0%).1

Key Findings

As the quality and number of embryos transferred was similar between the groups, this study suggests that a CS scar may have an impact specifically on implantation, since in an IVF population confounding from alterations of sperm transport or tubal function cannot play a major role.1

Watch as Prof. Michael von Wolff shares key insights on caesarean section and future fertility

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

Previous CSn=334

Previous VDn=983 aOR (95% CI)

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

Background

Approximately 120 live births from autologous re-transplantation of cryopreserved ovarian tissue have been reported to date.1 The optimal site for grafting is still under debate.

Study Summary

In this retrospective cohort study, 18 women with previously cryopreserved ovarian tissue, had autografts into a pelvic peritoneal pocket close to the ovary or an abdominal pocket.1

After resumption of cycling, these women received ovarian stimulation and transvaginal or transabdominal oocyte retrieval.1

CLI

NIC

AL

EM

BR

YO

LOG

Y

FER

TIL

ITY

PR

ES

ER

VA

TIO

N

Outcomes from heterotopic and orthotopic grafting of human cryopreserved ovarian tissue, O-1351

D. Gook et al

Results

Similar outcomes were observed with both graft sites including:1 (Table 1)

• Number of oocytes recovered

• Number of mature oocytes

• Proportion of fertilized oocytes which cleaved on day 2

Overall, the number and quality of oocytes from the abdominal site were similar to the oocytes from the pelvic sites.1

Key Findings

This study suggests that the previous notion of a benefit of the ‘ovarian niche’ for the autografted tissue may be incorrect.2

Gene editing – past, present and future, O-0021

B. Davies

Watch Prof. Verena Nordhoff explain the role of gene editing and what we can expect in future

Table 1: Outcomes from ovarian grafting1

Oocyte retrieval failure (%)

Mature oocytes retrieved (%)

Embryos developed on day 2 (%)

Abdominal site 29.8 66.7 88.9

Pelvic site 33.3 63.5 86.5

https://vimeo.com/351368659/bd8037f705

#

Background

On a global scale, intracytoplasmic sperm injection (ICSI) is increasingly being used to inseminate oocytes instead of in vitro fertilization (IVF).1 The underlying assumption for the preferential use of ICSI is that it provides a better chance of fertilization, which would be especially appropriate in case of low ovarian response where only a few oocytes are available.1

A Cochrane review identified a single randomised controlled trial (RCT) comparing IVF vs. ICSI for the treatment of non-male factor infertility.2 The RCT showed no benefit of ICSI in case of normal sperm parameters.3 However, the effect of using ICSI in different ovarian response categories has not been sufficiently evaluated.

Study Summary

This study was a retrospective analysis of data collected in 15 centres between 2009 and 2014.1

CLI

NIC

AL

EM

BR

YO

LOG

Y

CLI

NIC

AL

EM

BR

YO

LOG

Y

ICSI does not offer any benefit over conventional IVF across different ovarian response categories: a European multicenter analysis, O-2281

ICSI does not offer any benefit over conventional IVF across different ovarian response categories: a European multicenter analysis, O-2281

P. Drakopoulos et alP. Drakopoulos et al

Only one cycle, the first per patient, was included in case of GnRH-antagonist stimulation and in case of a normal sperm analysis (as per 5th edition of the WHO manual).5

Patients were divided into 4 groups based on their ovarian response:

• Group 1: poor responders (1-3 oocytes)

• Group 2: suboptimal responders (4-9 oocytes)

• Group 3: normal responders (10-15 oocytes)

• Group 4: high responders (>15 oocytes)1

Results

4891 patients were analyzed, of whom 4227 underwent ICSI and 664 underwent IVF. The ratio of ICSI:IVF was similar across the response categories.1

The mean fertilization rate was not different between the ICSI and IVF group (overall

Patients with low response do not appear to benefit from the use of ICSI instead of IVF, where there are normal sperm parameters.

Practice message

fertilization rate 61 ± 23% vs. 60 ± 27% p=0.90) and this was the case for all ovarian response subgroups.1

The total number of transferred and cryopreserved embryos per number of fertilized oocytes was also similar between groups, irrespective of the ovarian response category.1 (Figure 1) The type of insemination was also not a predictor of live birth or cumulative live birth in a multi-variable regression analysis.1

Key Findings

The outcome of this study indicated that ICSI does not yield higher fertilization or pregnancy rates than in vitro fertilization in case of non-male infertility. This suggests that ICSI may function only as a normalizer of fertilization in case of sperm impairment. Limits of the study relate to the retrospective, non-randomized design and the rather low number of IVF cases when split by ovarian response.1

Another retrospective study presented at the ESHRE annual meeting on the same topic by Lattes Altamirano et al claimed that ICSI in non-male factor cases performs worse than IVF in terms of pregnancy and live birth rate, even in poor responders.1

Watch Prof. Jens Hirchenhain share key insights into whether ICSI should be used in place of conventional IVF

Figure 1: Fertilization rate* in non-male factor ICSI and IVF cases by ovarian response category4

0

10

20

30

40

50

60

70

80

IVF

ICSI

High responseNormalSuboptimalPoor responseTotal

Fert

iliza

tion

rate

(%

)

61.0 61.0

66.6 66.662.5

66.6

60.063.6

55.753.3

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

Background

The time interval between human chorionic gonadotropin (hCG) injection for inducing final oocyte maturation and oocyte injection by intracytoplasmic sperm injection (ICSI) can be split into:1

• The time from hCG injection to oocyte pick-up (35-36 hours)

• The post pick-up waiting period before denudation and injection (1-3 hours)

Little is known if variation in these time spans are associated with outcome.1

Study Summary

This retrospective cohort study analyzed 8,889 ICSI cycles performed between 2010 and 2015 in a single center. Seven time interval categories were defined: <36h, 36h, 37h, 38h, 39h, 40h and ≥41h.1

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. Otherwise, the center routine was to perform OPU after 36h and the variation observed originated predominantly from the post-pick up period.1

CLI

NIC

AL

EM

BR

YO

LOG

Y

CLI

NIC

AL

EM

BR

YO

LOG

Y

Time interval between ovulation triggering and oocyte injection: does it affect the clinical outcome?, O-2331

Time interval between ovulation triggering and oocyte injection: does it affect the clinical outcome?, O-2331

L. Vandenberghe et alL. Vandenberghe et al

Results

It was found that the time interval was not associated with clinical pregnancy rates (range 21.9%-36.5%; p=0.286) or live birth rates (range 15.6%-27.9%; p=0.263), after adjusting for potential confounders.1

There was a tendency towards lower live birth rate in the <36h cases as compared to 38h after OPU. A period of ≥41h post-injection was not associated with a difference in outcome compared to injection at 38h.1 (Figure 1)

Key Findings

The optimal time window for ICSI is less stringent than previously thought, which may be reassuring to busy centers.1

When oocyte retrieval is performed 36h after hCG, there is leeway of several hours for the laboratory to perform ICSI.

Practice message

Figure 1: Clinical pregnancy rate (CPR) and live birth rate (LBR) stratified by time interval between hCG injection and ICSI2

0

5

10

15

20

25

30

35

40

LBRCPR

>41h40h39h38h37h36h<36h

%

21.9

15.6

34.0 34.7

26.6

34.2 34.6

26.1

33.8

36.5

25.3 26.124.7

27.9

*

* 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

Background

Cell-free DNA has been found in blastocoelic fluid and embryo culture medium.2,3 These fluids have been used for non-invasive genetic testing.1

The cell-free DNA is likely to be nuclear by origin, stemming from apoptotic or necrotic cellular events. However, it may also include extra-chromosomal mitochondrial DNA.3

It has been postulated that cell-free DNA present in the blastocoel cavity of human embryos positively correlates with embryonic morphology.4 Therefore, lower quality blastocysts may have a higher rate of apoptosis and as result, a higher quantity of cell-free DNA.

Study Summary

In this prospective study, 21 patients underwent preimplantation genetic testing for aneuploidies (PGT-A) with trophectoderm biopsy of fresh blastocysts.1

From these blastocysts, the following non-invasive preimplantation genetic testing for aneuploidies (NIPGT-A) samples were collected:1

• Culture medium

• Blastocoelic fluid (after pulse-laser collapse)

35 good quality blastocysts and 36 moderate/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

CLI

NIC

AL

EM

BR

YO

LOG

Y

CLI

NIC

AL

EM

BR

YO

LOG

Y

Assessment of the impact of blastocyst morphology on the accuracy of non-invasive preimplantation genetic testing (NIPGT-A) utilizing culture-conditioned embryo culture medium combined with blastocoel fluid, O-2011

Assessment of the impact of blastocyst morphology on the accuracy of non-invasive preimplantation genetic testing (NIPGT-A) utilizing culture-conditioned embryo culture medium combined with blastocoel fluid, O-2011

S. Madjunkova et alS. Madjunkova et al

Results

It was found that WGA-DNA was detected in all 71 NIPGT-A and 71 TE samples.1

The difference in DNA amount was lower for good quality blastocysts as compared to moderate/low quality blastocyts, but the difference was small and statistically not significant.1 (Figure 1)

In addition, no difference in DNA fragment length was found.1

63/71 (88.7%) NIPGT-A samples and 70/71 (98.6%) of the TE samples were informative, while concordance for ploidy was 100%.1

Key Findings

This study did not provide evidence that cell-free DNA from culture medium and blastocoelic fluid can serve as a proxy for embryo quality. Culture medium combined with blastocoelic fluid has the potential for use with NIPGT-A.1

As a side observation, the authors found it unlikely that cell apoptosis would be the only mechanism leading to cell-free DNA given the large size of the DNA fragments observed (apoptotic fragments are typically only ~180bp).6

Therefore, non-apoptosis related active or passive forms of DNA release are likely to play a role.

Table 1: Cell-free DNA amount and fragment size from blastocoel and embryo culture medium5

WGA positiveWGA-DNAng/μl

(range)

WGA-DNAng/μl

(mean± SD)

DNA fragment size

(mean± SD)

NIPGT-AGood quality blastocyst 35/35 5.1 – 30.0 13.9 ± 0.9 747 ± 43 bp

NIPGT-A Low/moderate quality blastocyst 36/36 6.3 – 36.0 15.7 ± 1.0 737 ± 27 bp

TE biopsy 71/71 25.0 – 46.0 31.3 ± 1.2 --

WGA= whole genome amplification; NIPGT-A = Non-invasive preimplantation genetic testing- aneuploidy; TE = trophectoderm

AN

DR

OLO

GY

AN

DR

OLO

GY

De novo mutations affecting male infertility, O-1611

J. Veltman

Watch Prof. Michael Zitzmann discuss the role of de novo mutations in male infertility

Background

Analyzing the isolated impact of male factors and sperm parameters on the outcome of assisted reproductive technology (ART) is difficult, due to confounding factors from the female side. For example, sperm from older men often meet oocytes from older women.2 The oocyte donation model can reduce some of the confounding, such as advanced maternal age or oocyte numbers available for in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).2

Study Summary

In this retrospective study from a private IVF center, 268 vitrified oocyte donor ICSI cycles and 321 oocyte recipients undergoing 427 oocyte recipient ICSI cycles, participating in an egg-sharing donation program between January 2015 and May 2017, were analyzed.1

Using a general mixed model, the impact of paternal age, ejaculatory abstinence and semen quality on recipients’ ICSI outcomes was assessed.1

Impact of paternal age, ejaculatory abstinence length and semen quality on the outcomes of intracytoplasmic sperm injection (ICSI) in an egg-sharing donation program, O-0171

A. Setti et al

Results

It was found that paternal age had a statistically significant negative association with:1

• fertilization rate

• cleavage rate

• blastocyst development rate

• high quality blastocyst development

• odds of pregnancy

Positive confounders for embryological parameters (fertilization rate, embryo development) were sperm count and total motile sperm count. Ejaculatory abstinence was also associated with negative laboratory parameters (especially normal embryonic development).1

Key Findings

This study used an elegant model to find an association between paternal age and immediate outcomes of ICSI. This was also reported in another study on couples with idiopathic infertility undergoing IVF/ICSI presented at ESHRE 2019 by Horta et al.1 Morris et al estimated that clinical pregnancy rate was reduced to approximately 30% in an overall IVF/ICSI population, when the male partner age was >51 years.1

Frequent ejaculation is potentially associated with better outcomes. Patients should be discouraged to ‘accumulate sperm’ by ejaculatory abstinence before undergoing ART treatment.

Practice message

AN

DR

OLO

GY

AN

DR

OLO

GY

Human sperm morphology as a marker of its nuclear quality and epigenetic status: implications for oocyte injection, O-1811

M. Bendayan et al

Background

Intracytoplasmic sperm injection (ICSI) is the most frequent method for in vitro insemination of oocytes where identifying the most competent spermatozoon is needed.2

Various techniques have been tested in trials and are clinically used for that purpose, including:2

• intracytoplasmic morphologically selected sperm injection

• hyaluronic binding

• polarized light microscopy

• annexin V agent identification

Decades after the introduction of sperm organelle morphology examination, several questions have not been clarified relating to the prevalence, origin, location, and clinical consequences of sperm vacuoles.3

In alive human sperm, vacuoles have been associated with low chromatin condensation levels.1 Histones are replaced by protamines during spermatogenesis to allow chromatin condensation.4 It was postulated that the nuclear integrity of sperm might differ by presence or absence of vacuoles.1

Study Summary

Sperm samples from 20 infertile patients with differing sperm profiles were studied. From those, 200 alive normal spermatozoa from each sperm sample were selected under high-magnification:1

• 100 without vacuole

• 100 with a vacuole (occupying >15% of head-area)

Epigenetic marks, known to be present on human spermatozoa and as potentially implied in embryo development, were assessed by immunostaining at the one-cell scale:1

H3K4me1

H3K4me2

H3K4me3

H3K9me1

H3K9me2

H3K9me3

H3K27me3

H4k20me2

Next, the epigenetic profiles of 4000 alive spermatozoa were studied by three-dimensional deconvolution microscopy.1

Human sperm morphology as a marker of its nuclear quality and epigenetic status: implications for oocyte injection, O-1811

M. Bendayan et al

Results

It was found that:1

• spermatozoa with vacuoles were significantly more prone to retaining histone H3 and H3K4me3 than spermatozoa with no vacuole

• spermatozoa with no vacuole presented higher degrees of protamination and H3K27me3 than vacuolated spermatozoa

These epigenetic profiles suggest that vacuolated spermatozoa have an immature chromatin closest to spermatids, which may negatively affect embryo development.1

3D visualization of vacuolated spermatozoa showed that protamine was located at the basement of vacuoles while H3, H3K4me3 and H3K9me1 (all related to DNA decondensation) filled these areas, described until now as DNA – free spaces. Accordingly, vacuoles appear to have an epigenetic signature.1

Key Findings

This study was the first to demonstrate that a morphological characteristic of alive spermatozoa is linked to epigenetic marks.1

The biological and clinical relevance of this finding still needs to be defined.

REF

EREN

CES

REF

EREN

CES

1. Abstracts of the 35th Annual Meeting of the European Society of Human Reproduction and Embryology. Hum Reprod. 2019;34(Supplement_1):i1-i543. doi: https://doi.org/10.1093/humrep/34.Supplement_1.1

2. Mackens S, Santos-Ribeiro S, van de Vijver A, et al. Frozen embryo transfer: a review on the optimal endometrial preparation and timing. Hum Reprod. 2017;32(11):2234-2242. doi: https://doi.org/10.1093/humrep/dex285

3. Labarta E, Mariani G, Holtmann N, Celada P, Remohí J, Bosch E. Low serum progesterone on the day of embryo transfer is associated with a diminished ongoing pregnancy rate in oocyte donation cycles after artificial endometrial preparation: a prospective study. Hum Reprod. 2017;32(12):2437-2442. doi: https://doi.org/10.1093/humrep/dex316

4. Alsbjerg B, Thomsen L, Elbaek HO, et al. Progesterone levels on pregnancy test day after hormone replacement therapy-cryopreserved embryo transfer cycles and related reproductive outcomes. Reprod Biomed Online. 2018;37(5):641-647. doi: https://doi.org/10.1016/j.rbmo.2018.08.022

5. Cédrin-Durnerin I, Isnard T, Mahdjoub S, et al. Serum progesterone concentration and live birth rate in frozen-thawed embryo transfers with hormonally prepared endometrium. Reprod Biomed Online. 2019;38(3):472-480. doi: https://doi.org/10.1016/j.rbmo.2018.11.026

6. Järvelä IY, Pelkonen S, Uimari O, et al. Controlled ovarian hyperstimulation leads to high progesterone and estradiol levels during early pregnancy. Hum Reprod. 2014;29(11):2393-2401. doi: https://doi.org/10.1093/humrep/deu223

Progesterone on the day of embryo transfer

Reproductive endocrinology


2. Järvelä IY, Pelkonen S, Uimari O, et al. Controlled ovarian hyperstimulation leads to high progesterone and estradiol levels during early pregnancy. Hum Reprod. 2014;29(11):2393-2401. doi: https://doi.org/10.1093/humrep/deu223

3. Griesinger G, Blockeel C, Sukhikh GT, et al. Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial. Hum Reprod. 2018;33(12):2212-2221. doi: https://doi.org/10.1093/humrep/dey306

4. Doblinger J, Cometti B, Trevisan S, Griesinger G. Subcutaneous Progesterone Is Effective and Safe for Luteal Phase Support in IVF: An Individual Patient Data Meta-Analysis of the Phase III Trials. PLoS One. 2016;11(3):e0151388. https://doi.org/10.1371/journal.pone.0151388

5. Frauke von V-H, Purnima N, Seda STE, et al. Absent or Excessive Corpus Luteum Number Is Associated With Altered Maternal Vascular Health in Early Pregnancy. Hypertension. 2019;73(3):680-690. doi: https://doi.org/10.1161/HYPERTENSIONAHA.118.12046

6. Baker VL, Brown MB, Luke B, Conrad KP. Association of number of retrieved oocytes with live birth rate and birth weight: an analysis of 231,815 cycles of in vitro fertilization. Fertil Steril. 2015;103(4):931-938.e2. doi: https://doi.org/10.1016/j.fertnstert.2014.12.120

Predicting luteal progesterone levels


AMH as a driving force of PCOS


2. Rosenfield RL. The Diagnosis of Polycystic Ovary Syndrome in Adolescents. Pediatrics. 2015;136(6):1154 LP-1165. doi: https://doi.org/10.1542/peds.2015-1430

AMH levels in adolescence and the presence of PCOS


2. Coutifaris C. Freeze-only in vitro fertilization cycles for all? Fertil Steril. 2017;108(2):233-234. doi: https://doi.org/10.1016/j.fertnstert.2017.06.028

3. Mackens S, Santos-Ribeiro S, van de Vijver A, et al. Frozen embryo transfer: a review on the optimal endometrial preparation and timing. Hum Reprod. 2017;32(11):2234-2242. doi: https://doi.org/10.1093/humrep/dex285

4. Baker VL, Brown MB, Luke B, Conrad KP. Association of number of retrieved oocytes with live birth rate and birth weight: an analysis of 231,815 cycles of in vitro fertilization. Fertil Steril. 2015;103(4):931-938.e2. doi: https://doi.org/10.1016/j.fertnstert.2014.12.120

5. Frauke von V-H, Purnima N, Seda STE, et al. Absent or Excessive Corpus Luteum Number Is Associated With Altered Maternal Vascular Health in Early Pregnancy. Hypertension. 2019;73(3):680-690. doi: https://doi.org/10.1161/HYPERTENSIONAHA.118.12046

6. Ishihara O, Araki R, Kuwahara A, Itakura A, Saito H, Adamson GD. Impact of frozen-thawed single-blastocyst transfer on maternal and neonatal outcome: an analysis of 277,042 single-embryo transfer cycles from 2008 to 2010 in Japan. Fertil Steril. 2014;101(1):128-133. doi: https://doi.org/10.1016/j.fertnstert.2013.09.025

Frozen embryo transfer and miscarriage rate

Endometriosis and the endometrium


Endometrial scratching after one failed IVF/ICSI cycle


2. Taylor HS, Giudice LC, Lessey BA, et al. Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist. N Engl J Med. 2017;377(1):28-40. doi: https://doi.org/10.1056/NEJMoa1700089

3. Laganà AS, La Rosa VL, Rapisarda AMC, et al. Anxiety and depression in patients with endometriosis: impact and management challenges. Int J Womens Health. 2017;9:323-330. doi: https://doi.org/10.2147/IJWH.S119729

4. D’Hooghe T, Fukaya T, Osuga Y, et al. Efficacy and safety of ASP1707 for endometriosis-associated pelvic pain: the phase II randomized controlled TERRA study. Hum Reprod. 2019;34(5):813-823. doi: https://doi.org/10.1093/humrep/dez028

Linzagolix for endometriosis pain


2. Dunselman GAJ, Vermeulen N, Becker C, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29(3):400-412. doi: https://doi.org/10.1093/humrep/det457

GnRHa therapy before IVF

https://doi.org/ 10.1093/humrep/34.Supplement_1.1

https://doi.org/10.1093/humrep/dex285


https://doi.org/10.1016/j.rbmo.2018.08.022



https://doi.org/10.1093/humrep/deu223

https://doi.org/10.1093/humrep/34.Supplement_1.1


https://doi.org/10.1093/humrep/dey306


https://doi.org/10.1371/journal.pone.0151388


https://doi.org/10.1161/HYPERTENSIONAHA.118.12046


https://doi.org/10.1016/j.fertnstert.2014.12.120





https://doi.org/10.1542/peds.2015-1430











https://doi.org/10.1056/NEJMoa1700089

https://doi.org/10.2147/IJWH.S119729

https://doi.org/10.1093/humrep/dez028


https://doi.org/10.1093/humrep/det457

REF

EREN

CES

REF

EREN

CES


2. Orlova NA, Kovnir S V, Khodak YA, et al. High-level expression of biologically active human follicle stimulating hormone in the Chinese hamster ovary cell line by a pair of tricistronic and monocistronic vectors. PLoS One. 2019;14(7):e0219434. https://doi.org/10.1371/journal.pone.0219434.

3. de Mora F, Fauser BCJM. Biosimilars to recombinant human FSH medicines: comparable efficacy and safety to the original biologic. Reprod Biomed Online. 2017;35(1):81-86. doi: https://doi.org/10.1016/j.rbmo.2017.03.020

4. Markus R, Liu J, Ramchandani M, Landa D, Born T, Kaur P. Developing the Totality of Evidence for Biosimilars: Regulatory Considerations and Building Confidence for the Healthcare Community. BioDrugs. 2017;31(3):175-187. doi: https://doi.org/10.1007/s40259-017-0218-5

Comparing biosimilar to originator recombinant follitropin alfa

Ovarian stimulation and infertility


2. Zhang D, Xia L, Xu H, et al. Flexible Low-Dose GnRH Antagonist Protocol Is Effective in Patients With Sufficient Ovarian Reserve in IVF. Front Endocrinol (Lausanne). 2018;9:767. doi: https://doi.org/10.3389/fendo.2018.00767

3. Lambalk CB, Banga FR, Huirne JA, et al. GnRH antagonist versus long agonist protocols in IVF: a systematic review and meta-analysis accounting for patient type. Hum Reprod Update. 2017;23(5):560-579. doi: https://doi.org/10.1093/humupd/dmx017

Long vs classical antagonist protocol


2. Chen Z-J, Shi Y, Sun Y, et al. Fresh versus Frozen Embryos for Infertility in the Polycystic Ovary Syndrome. N Engl J Med. 2016;375(6):523-533. doi: https://doi.org/10.1056/NEJMoa1513873

3. Shi Y, Sun Y, Hao C, et al. Transfer of Fresh versus Frozen Embryos in Ovulatory Women. N Engl J Med. 2018;378(2):126-136. doi: https://doi.org/10.1056/NEJMoa1705334

4. Vuong LN, Dang VQ, Ho TM, et al. IVF Transfer of Fresh or Frozen Embryos in Women without Polycystic Ovaries. N Engl J Med. 2018;378(2):137-147. doi: https://doi.org/10.1056/NEJMoa1703768

5. Wei D, Liu J-Y, Sun Y, et al. Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial. Lancet. 2019;393(10178):1310-1318. doi: https://doi.org/10.1016/S0140-6736(18)32843-5

6. Bosdou JK, Venetis CA, Tarlatzis BC, Grimbizis GF, Kolibianakis EM. Higher probability of live-birth in high, but not normal, responders after first frozen-embryo transfer in a freeze-only cycle strategy compared to fresh-embryo transfer: a meta-analysis. Hum Reprod. 2019;34(3):491-505. doi: https://doi.org/10.1093/humrep/dey388

Freeze-all versus fresh embryo transfer


2. Liberman RF, Getz KD, Heinke D, et al. Assisted Reproductive Technology and Birth Defects: Effects of Subfertility and Multiple Births. Birth Defects Res. 2017;109(14):1144-1153. doi: https://doi.org/10.1002/bdr2.1055

3. Zhu JL, Basso O, Obel C, Bille C, Olsen J. Infertility, infertility treatment, and congenital malformations: Danish national birth cohort. BMJ. 2006;333(7570):679. doi: https://doi.org/10.1136/bmj.38919.495718.AE

4. Rimm AA, Katayama AC, Katayama KP. A meta-analysis of the impact of IVF and ICSI on major malformations after adjusting for the effect of subfertility. J Assist Reprod Genet. 2011;28(8):699-705. doi: https://doi.org/10.1007/s10815-011-9583-z

ART and risk of congenital heart defects

Safety, psychology and counselling


The long-term health of IVF-ICSI babies


2. Macklon NS, Stouffer RL, Giudice LC, Fauser BCJM. The Science behind 25 Years of Ovarian Stimulation for in Vitro Fertilization. Endocr Rev. 2006;27(2):170-207. doi: https://doi.org/10.1210/er.2005-0015

3. Kroener L, Dumesic D, Al-Safi Z. Use of fertility medications and cancer risk: a review and update. Curr Opin Obstet Gynecol. 2017;29(4):195-201. doi: https://doi.org/10.1097/GCO.0000000000000370

4. Klip H, group for the O, Burger CW, et al. Risk of cancer in the offspring of women who underwent ovarian stimulation for IVF. Hum Reprod. 2001;16(11):2451-2458. doi: https://doi.org/10.1093/humrep/16.11.2451

Ovarian tumour risk after ART


Mobile apps and fertility

2. van Hoogenhuijze NE, Kasius JC, Broekmans FJM, Bosteels J, Torrance HL. Endometrial scratching prior to IVF; does it help and for whom? A systematic review and meta-analysis. Hum Reprod Open. 2019;2019(1). doi: https://doi.org/10.1093/hropen/hoy025

3. Abstracts of the 34rd Annual Meeting of the European Society of Human Reproduction and Embryology. Hum Reprod. 2018;33(suppl_1):i1-i541. doi: https://doi.org/10.1093/humrep/33.Supplement_1.1

4. van Hoogenhuijze NE. Endometrial scratching in women with one failed IVF/ICSI cycle: results of a randomized controlled trial (SCRaTCH trial), O-023 presented at ESHRE 2019, Vienna




https://doi.org/10.1007/s40259-017-0218-5

https://doi.org/10.1007/s40259-017-0218-5


https://doi.org/10.3389/fendo.2018.00767

https://doi.org/10.1093/humupd/dmx017

https://doi.org/10.1093/humupd/dmx017





https://doi.org/10.1016/S0140-6736(18)32843-5



https://doi.org/10.1002/bdr2.1055

https://doi.org/10.1136/bmj.38919.495718.AE

https://doi.org/10.1007/s10815-011-9583-z

https://doi.org/10.1007/s10815-011-9583-z



https://doi.org/10.1210/er.2005-0015

https://doi.org/10.1097/GCO.0000000000000370

https://doi.org/10.1093/humrep/16.11.2451


https://doi.org/10.1093/hropen/hoy025

https://doi.org/10.1093/hropen/hoy025


REF

EREN

CES

REF

EREN

CES

Fertility preservation


2. Sholapurkar SL. Etiology of Cesarean Uterine Scar Defect (Niche): Detailed Critical Analysis of Hypotheses and Prevention Strategies and Peritoneal Closure Debate. J Clin Med Res. 2018;10(3):166-173. doi: https://doi.org/10.14740/jocmr3271w

3. Vogel JP, Betrán AP, Vindevoghel N, et al. Use of the Robson classification to assess caesarean section trends in 21 countries: a secondary analysis of two WHO multicountry surveys. Lancet Glob Heal. 2015;3(5):e260-e270. doi: https://doi.org/10.1016/S2214-109X(15)70094-X

4. Stern JE, Liu C-L, Cabral HJ, et al. Factors associated with increased odds of cesarean delivery in ART pregnancies. Fertil Steril. 2018;110(3):429-436. doi: https://doi.org/10.1016/j.fertnstert.2018.04.032

5. Gurol-Urganci I, Bou-Antoun S, Lim CP, et al. Impact of Caesarean section on subsequent fertility: a systematic review and meta-analysis. Hum Reprod. 2013;28(7):1943-1952. doi: https://doi.org/10.1093/humrep/det130

6. Gurol-Urganci I, Cromwell DA, Mahmood TA, van der Meulen JH, Templeton A. A population-based cohort study of the effect of Caesarean section on subsequent fertility. Hum Reprod. 2014;29(6):1320-1326. doi: https://doi.org/10.1093/humrep/deu057

7. Vissers J. Adverse/ reproductive outcomes of reduced pregnancy and live birth rates after In Vitro Fertilization in women with previous caesarean section: a retrospective cohort study, O-301 presented at ESHRE 2019, Vienna

IVF after Cesarean section


2. Kolp LA, Hubayter Z. Autotransplantation of cryopreserved ovarian tissue: a procedure with promise, risks, and a need for a registry. Fertil Steril. 2011;95(6):1879-1886. doi: https://doi.org/10.1016/j.fertnstert.2011.02.049

Outcomes from different ovarian tissue grafting sites


Oocyte aging

Clinical embryology


2. van Rumste MME, Evers JLH, Farquhar C. Intra-cytoplasmic sperm injection versus conventional techniques for oocyte insemination during in vitro fertilisation in couples with non-male subfertility. Cochrane Database Syst Rev. 2003;(2). doi: https://doi.org/10.1002/14651858.CD001301

3. Bhattacharya S, Hamilton MPR, Shaaban M, et al. Conventional in-vitro fertilisation versus intracytoplasmic sperm injection for the treatment of non-male-factor infertility: a randomised controlled trial. Lancet. 2001;357(9274):2075-2079. doi: https://doi.org/10.1016/S0140-6736(00)05179-5

4. Drakopoulos P. ICSI does not offer any benefit over conventional IVF across different ovarian response categories: a European multicenter analysis., O-228 presented at ESHRE 2019, Vienna

5. World Health Organisation. WHO laboratory manual for the examination and processing of human semen, 5th ed. World Health Organisation; 2010. https://apps.who.int/iris/handle/10665/44261

ICSI versus conventional IVF


2. Vandenberghe L. Time interval between ovulation triggering and oocyte injection: does it affect the clinical outcome?, O-233 presented at ESHRE 2019, Vienna

Impact of the time interval between ovulation triggering and oocyte injection


2. Palini S, Galluzzi L, De Stefani S, et al. Genomic DNA in human blastocoele fluid. Reprod Biomed Online. 2013;26(6):603-610. doi: https://doi.org/10.1016/j.rbmo.2013.02.012

3. Hammond ER, Shelling AN, Cree LM. Nuclear and mitochondrial DNA in blastocoele fluid and embryo culture medium: evidence and potential clinical use. Hum Reprod. 2016;31(8):1653-1661. doi: https://doi.org/10.1093/humrep/dew132

4. Rule K, Chosed RJ, Arthur Chang T, David Wininger J, Roudebush WE. Relationship between blastocoel cell-free DNA and day-5 blastocyst morphology. J Assist Reprod Genet. 2018;35(8):1497-1501. doi: https://doi.org/10.1007/s10815-018-1223-4

5. Madjunkova S. Assessment of the impact of blastocyst morphology on the accuracy of non-invasive preimplantation genetic testing (NIPGT-A) utilizing culture-conditioned embryo culture medium combined with blastocoel fluid., O-201 presented at ESHRE 2019, Vienna

6. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495-516. doi: https://doi.org/10.1080/01926230701320337

Blastocyst morphology and NIPGT-A accuracy


Gene editing – past, present and future


https://doi.org/10.14740/jocmr3271w

https://doi.org/10.1016/S2214-109X(15)70094-X

https://doi.org/10.1016/S2214-109X(15)70094-X


https://doi.org/10.1093/humrep/det130







https://doi.org/10.1002/14651858.CD001301

https://doi.org/10.1016/S0140-6736(00)05179-5

https://apps.who.int/iris/handle/10665/44261




https://doi.org/10.1093/humrep/dew132

https://doi.org/10.1007/s10815-018-1223-4

https://doi.org/10.1007/s10815-018-1223-4

https://doi.org/10.1080/01926230701320337

https://doi.org/10.1080/01926230701320337



De novo mutations affecting male infertility


2. Gu L, Zhang H, Yin L, Bu Z, Zhu G. Effect of male age on the outcome of in vitro fertilization: oocyte donation as a model. J Assist Reprod Genet. 2012;29(4):331-334. doi: https://doi.org/10.1007/s10815-012-9719-9

Impact of male factors on ICSI outcomes

REF

EREN

CES


2. Simopoulou M, Gkoles L, Bakas P, et al. Improving ICSI: A review from the spermatozoon perspective. Syst Biol Reprod Med. 2016;62(6):359-371. doi: https://doi.org/10.1080/19396368.2016.1229365

3. Perdrix A, Rives N. Motile sperm organelle morphology examination (MSOME) and sperm head vacuoles: state of the art in 2013. Hum Reprod Update. 2013;19(5):527-541. doi: https://doi.org/10.1093/humupd/dmt021

4. Bao J, Bedford MT. Epigenetic regulation of the histone-to-protamine transition during spermiogenesis. Reproduction. 2016;151(5):R55-R70. doi: https://doi.org/10.1530/REP-15-0562

Sperm morphology as a marker of nuclear quality and epigenetic status

Andrology



https://doi.org/10.1007/s10815-012-9719-9




https://doi.org/10.1080/19396368.2016.1229365

https://doi.org/10.1093/humupd/dmt021

https://doi.org/10.1530/REP-15-0562

#

#

2019 - reprofacts · had oligo-amenorrhea or polycystic ovarian reproductive endocrinology...

Documents