Fertility Flash - Issue 5

F e Flash

HIGHLIGHTS Day 2/Day 3 Cleavage Stage Embryo Transfer Versus Blastocyst Transfer in IVF ICSI Program: A Comparative Study - Dr. Nandita Palshetkar; Dr. Rohan Palshetkar Extended Letrozole Therapy for Ovulation Induction in PCO not Responding to Conventional CC/Letrozole Regimen - Dr Fessy Louis T Untargeted Metabolomics Approach to Identify Obesity Associated Differences in the Human FF Metabolome Being Overweight was a Risk Factor for both Low-Quality Embryos and Miscarriage WHO Recommendations on the Use of Uterotonics for the Prevention of Postpartum Haemorrhage (PPH) Effectivity of Prophylactic Enoxaparin in Avoiding Miscarriages for Women Undergoing IVF Newborn Metabolic ProďŹ le Combined with Clinical Characteristics: Identify Preterm Newborns at Increased Risk for Mortality or Major Neonatal Morbidity

ISSUE

5

Fertility Flash is an academic initiative from Corona Remedies to link medical fraternity with latest updated information in infertility. This will be a bi-Monthly series. Through this scientific information service to the Infertility specialists, we wish to contribute our part in fulfilling the dream of motherhood.

EXPERT INSIGHTS Day 2/Day 3 Cleavage Stage Embryo Transfer Versus Blastocyst Transfer in IVF ICSI Program: A Comparative Study

CASE STUDY Extended Letrozole Therapy for Ovulation Induction in PCO not Responding to Conventional CC/Letrozole Regimen

CONTENTS

PREFACE

Infertility, though not life threatening, can cause intense agony and trauma to the infertile couples. Infertility evaluations and treatments have undergone remarkable and very positive evolutions over the past few decades. Improvements have been made in virtually every way to diagnose and treat patients. Innovations in imaging techniques and endoscopic procedures and markedly improved success rates with in vitro fertilization (IVF) have led to both subtle and dramatic improvements in care for patients.

1 5

EVIDENCE UPDATE Live Birth Rate of IVF Following Brief Incubation versus Standard Incubation of Gametes Untargeted Metabolomics Approach to Identify Obesity Associated Differences in the Human FF Metabolome Elective Frozen Embryo Transfer in IVF/ICSI Cycles possess Positive Effect on Reproductive Outcomes

IMAGE OF THE MONTH DIAGNOSTIC UPDATE Being Overweight was a Risk Factor for both Low-Quality Embryos and Miscarriage

GUIDELINES UPDATE WHO Recommendations on the Use of Uterotonics for the Prevention of Postpartum Haemorrhage (PPH)

7 11 13 15

CONFERENCE UPDATE Effectivity of Prophylactic Enoxaparin in Avoiding Miscarriages for Women Undergoing IVF Newborn Metabolic Profile Combined with Clinical Characteristics: Identify Preterm Newborns at Increased Risk for Mortality or Major Neonatal Morbidity

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TRAZER HUNT

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CONFERENCE CALENDER

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QUIZ

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F e Flash EXPERT INSIGHTS Day 2/Day 3 Cleavage Stage Embryo Transfer Versus Blastocyst Transfer in IVF ICSI Program: A Comparative Study Contributed by:

Dr. Nandita Palshetkar Dr. Nandita Palshetkar (MD FCPS FICOG) is an IVF Consultant for more than 25 years with a special interest in High Risk Obstetrics. Besides this she is also the President of Federation of Obstetric and Gyneacological Societies of India and the Vice President of Association of Maharashtra Obstetrics and Gynaecological Societies. Apart from being the president of FOGSI, she has also had the honour of being the former President of Mumbai Obstetrics and Gynaecological Society and Indian Association of Gynaecological Endoscopists. She has also been the Immediate past chairperson of Maharashtra Chapter of ISAR. She has delivered over 700 talks, contributed more than 100 chapters and papers and delivered more than 30 orations. She is a pioneer in the field of IVF and has been the first to bring many innovative technologies to India. Apart from her professional life, she is also working with all the police families to uplift their health. She is also working with adolescent girls of Mumbai to empower them. She has started the She's Ambassador Program for the underprivileged girls of Mumbai to instill leadership qualities & make them the ambassadors of good healthy in their communities.

Dr. Rohan Palshetkar Dr. Rohan Palshetkar is an ART Specialist and Enodscopic Surgeon. He is an Assistant Professor at D.Y.Patil, School of Medicine, Navi Mumbai and is also the Unit Head of Hiranandani Bloom IVF, Vashi. He is currently a Managing Committee Member of Maharashtra Chapter of Indian Society for Assisted Reproduction. He is also an active member of Youth Council of Mumbai Obstetric and Gynaecological Society (MOGS). He has won multiple awards for posters and paper presentation. He is the recipient of FOGSI Corion Award and has received the MOGS Best Youth Council Member. Besides this he has held a camp for over 1500 adolescent girls in Jamnagar.

Introduction Traditionally, since the beginning of human IVF, embryos transferred into the patient's uterus on day 2 or 3. Day 2/day 3 transfers were considered advantageous because embryos on days 2 and 3 presented distinct morphological features which were convenient for visual evaluation in order to select the best quality embryos for transfer, compared to morulae on day 4, which were difficult to separate from each other in terms of quality.¹ Moreover, it was technologically challenging and expensive to culture embryos successfully in vitro beyond 3 days.

Furthermore, culture media sophisticated enough to support the more complex demands of blastocysts was yet to be developed. However, with the recent development of more advanced blastocyst culture media and development of sequential media, it is feasible to culture embryos upto blastocyst stage.² Growth upto blastocyst stage is an indicator of the most developmentally competent embryos and thus a marker of embryo quality.3 Thus, in a blastocyst culture program, embryos which do survive the extended culture in order to develop to blastocysts are thought to be the best quality embryos. This process of 'self-selection' means that blastocysts are more likely to implant into the endometrium compared to day 3 embryos. However, blastocyst culture is a more expensive procedure and technologically more challenging. Only a sub-set of day 3 embryos will go on to grow to blastocysts. Thus, day 5 embryo transfer strategy is associated with greater cycle cancellation rates due to unavailability of embryos for transfer.4

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F e Flash Aims and Objectives The objectives of this study are to compare day 2/3 embryo transfers versus day 5/6 blastocyst transfers in IVFICSI cycles. Following outcomes were compared Ÿ

Implantation rate

Ÿ

Clinical pregnancy rate- as determined by fetal heartbeat on ultrasound

Ÿ

Incidence of multiple pregnancies

Study Design Prospective and retrospective comparative study Inclusion criteria 1. Normo-ovulatory women with regular ovulatory cycles undergoing IVF-ICSI 2. Aged below 37 years Exclusion Criteria 1. PCOS patients 2. Patients above 37 years age

Materials and Methods The study was carried out at a urban tertiary care centre IVF clinic in Nerul, Navi Mumbai, Maharashtra between January 2014 to Jan 2018. Institutional ethics committee clearance was obtained for the study. All patients underwent COH using the antagonist protocol. IVF or ICSI was done as per standard protocol and patient indication. Decision of whether to transfer Day 2/3 or Day 5 was taken depending upon parameters such as number of oocytes and number of embryos available and patient age and history. A maximum of 3 cleavage stage embryos or 2 blastocysts were transferred per patient. A total of 280 patients were finally included in the study for data analysis, 216 in the day 3 ET group (A) and 64 in the blastocyst group (B). Serial serum beta HCG estimation was carried out on day 14 & 16 following embryo transfer to check for pregnancy. For the purpose of the study, clinical pregnancy was documented by USG demonstration of gestational sac and fetal cardiac activity. Similarly, retrospective data analysis was done for patients who met the inclusion criteria.

Results Patient demographic parameters Ovarian reserve was similar between the 2 groups AMH (2.45 vs 2.61, p=0.7).

Table 1. Mean AMH values in the two study groups Variables

Group

N

Mean

SD

A

216

2.45

2.35

B

64

2.61

0.96

AMH

P-Value

0.714

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F e Flash Cycle parameters Data analysis revealed that significantly more number of follicles (8.91±3.51 vs 6±3.71; p<0.05) and oocytes (7.28±3.17 vs 5.31±3.39, p<0.05) Group(B) than Group A Table 2. No. of follicles, oocytes and embryos obtained in the two study groups Variables

Group

N

Mean

SD

No. of Follicles Aspirated

A

216

6.00

3.71

B

64

8.91

3.51

No. of Oocytes

A

216

5.31

3.39

B

64

7.28

3.17

A

216

3.90

2.27

B

64

4.03

2.31

No. of Embryos

P-Value

<0.01

<0.01

<0.01

Table 3. No. of Embryos at ET between the two groups Variables No of Embryos Transferred

Group

N

Mean

SD

A

216

2.41

0.67

B

64

1.38

0.49

P-Value

<0.01

Table 4. Implantation Rate between the two groups Variables

N

Implantation Rate

Group A

216

21.1%

Group B

64

32.8%

Table 5. Pregnancy Rates achieved in the two groups Pregnancy Outcome

Group

Total

Table 6. Incidence of multiple pregnancies in the two groups Multiple Pregnancy

A

B

116

40

156

53.7%

62.5%

55.7%

100

24

124

46.3%

37.5%

44.3%

Group

Tatal

A

B

No

212

64

276

Yes

4

0

55.7%

216

64

280

Negative

Positive Total

Outcome measures Upon analysis, it was seen that implantation rate in blastocyst group (32.8%) was higher than the implantation rate in day 3 embryo group (21.1%), bordering on statistical significance (p=0.06).

However, we could demonstrate no clinically significant difference in pregnancy rates between the two study groups (46.3% in group A vs 37.5% in group B, p=0.4), although the gross pregnancy rate was higher in the day 3 cleavage stage embryo transfer group.

There were 4 twin gestations (no higher order multiple births) in the Day 3 group while none in the day 5 group The difference was not statistically significant.

Discussion The number of follicles and oocytes was higher in the blastocyst group (p<0.05). This was expected because patients were not randomised. Rather the decision for D5 transfers was taken after oocyte retrieval and once embryos were generated. This was done to maximise the possibility of all patients going upto ET and therefore much should not be read into these results. Number of embryos transferred was significantly higher in the day 3 ET group, as expected. Since, blastocysts are developmentally more advanced and differentiated structures than 3

F e Flash D3 embryos, they are expected to have a higher implantation rate in IVF cycles as seen in our study. However it was not statistically significant. Rather, the clinical pregnancy rate was higher in the day 3 ET group, but again it was not statistically insignificant. Thus, in contrast with Cochrane meta-analysis.5 But there have been studies in the past which have had results similar to ours.6 There were 4 twin gestations in the Day 3 ET group as compared to none in the blastocyst group. This was not statistically significant. There were no high order multiple births Bec of the fact that nearly 50% of D3 transfers were either 1 or 2 embryos while single embryo transfers were done in over 65% of the blastocyst transfers.

Blastocyst culture is more expensive and technically challenging. Therefore in a country such as ours where there is no law yet to make single embryo transfers compulsory, 2-3 Day 3 embryos maybe a more effective intervention strategy to provide our patients with the best chance at IVF without incurring higher costs to the patient.

CONCLUSIONS It can be seen that D5 transfers have a marginal edge over D2/D3 transfers in terms of implantation but this gets neutralised when assessing the overall pregnancy rates. However out data indicates that this does cause any significant health and welfare challenges in terms of multiple gestation. Therefore, it is reasonable to wonder whether it is justified to incur the higher costs of D5 transfers when D3 transfers appear to give similar pregnancy rates at a lower cost. This could be relevant when considering poorer patients where any increased cost could result in a greater financial burden on them.

Recommendations 1. Based on our findings, we propose that double embryo transfer of day 3 embryos could be adopted as a viable and practical solution in our practice setting in order to offer patients the maximum chance of having a successful pregnancy, while at the same time limiting costs and the incidence of multiple births.

2. We believe that given a strong and robust IVF laboratory with skilled embryologists and good quality control, this would emerge as a very viable and successful intervention in most patients.

3. We further propose that the maximum number of embryos transferred into any patient should not exceed 3, in order to reduce the twinning rate and minimize the chance of higher order multiple births.

References: 1. Stylianou, C., Critchlow, D., Brison, D. R., & Roberts, S. A. (2012). Embryo morphology as a predictor of IVF success: An evaluation of the proposed UK ACE grading scheme for cleavage stage embryos. Human Fertility, 15(1), 11–17.; 2. Germond, M., Wirthner, D., Senn, A., Calhaz-Jorge, C., Castilla, J. A., Cohen, J., Yunakova, M. (2008). Core data for assisted reproductive technology registers: Results of a consensus meeting. Reprod BioMedicine Online, 17(6), 834–840.; 3. George, K., Mangalraj, A., Muthukumar, K., Aleyamma, T., & Kamath, M. (2009). Blastocyst stage transfer vs cleavage stage embryo transfer. Journal of Human Reproductive Sciences, 2(1), 23.; 4. Dessolle, L., Fréour, T., Barrire, P., Daraï, E., Ravel, C., Jean, M., & Coutant, C. (2010). A cycle-based model to predict blastocyst transfer cancellation. Human Reproduction, 25(3), 598–604.; 5. Glujovsky, D., Farquhar, C., Quinteiro Retamar, A. M., Alvarez Sedo, C. R., & Blake, D. (2016). Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database of Systematic Reviews.; 6. H r e i n s s o n , J . , Rosenlund, B., Fridström, M., Ek, I., Levkov, L., Sjöblom, P., & Hovatta, O. (2004). Embryo transfer is equally effective at cleavage stage and blastocyst stage: A randomized prospective study. European Journal of Obstetrics Gynecology and Reproductive Biology, 117(2), 194–200.

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F e Flash CASE STUDY Extended Letrozole Therapy for Ovulation Induction in PCO not Responding to Conventional CC/Letrozole Regimen Contributed by:

Dr Fessy Louis T Senior Consultant and Asst. Professor, Department of Reproductive Medicine & Surgery, AMRITA Fertility Centre, AIMS-AMRITA Institute of Medical Sciences, MG Road, Kochi.

Secretary | KFOG (Kerala Federation of O & G): 2012-18 Secretary | Kerala Chapter, ISAR Executive Member | Kerala Chapter–IFS FOGSI | International Academic Exchange Committee Chairperson: 2013–15 SAFOG | Executive Member: 2013–2016 Member FIGO | Reproductive Medicine Core Committee 2013–2014

Case Presentation A 27 yrs old Mrs X, married since 4 years with primary infertility referred to our centre with h/o PCOS with clomiphene resistance (3 cycles of ovulation induction with CC 100mg – no response) for further management.

On Evaluation Patient with h/o irregular menstrual cycles, only withdrawal bleeding with hormones, BMI: 31, mild hirsutism+, USG showing PCO. Husband semen analysis – normal (54million, 52% progressive motility, 8% normal forms)

Management We planned for withdrawal bleeding followed by tubal testing (SSG)–Normal cavity with B/L patent tubes. Next cycle O/I with Letrozole 5 mg for 5 days from D2~D6. Follicular study on D10–no response seen. Option of adding Gonadotropins given to the patient. Patient was not willing.

Extended Letrozole Regimen Next cycle after withdrawal bleeding, planned for extended Letrozole regimen of 2.5 mg daily for 10 days (D3–D12) –scan on D12 showed three follicles of 12–14 mm and D14 scan showed one follicle >17 mm. Trigger with HCG 5000 IU given, ovulation documented, advised timed intercourse. Patient conceived and TVS at 6 weeks showed singleton live IUP.

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F e Flash Discussion Polycystic ovary syndrome (PCOS) is a common endocrine disorder in young women which manifests itself in a variety of clinical ways. Although clomiphene citrate (CC) is still the traditional therapy used for inducing ovulation in this condition, clomiphene resistance, which refers to persistence of an ovulation after standard CC therapy, occurs in 15%–20% of patients.

Aromatase inhibitors (AIs), such as Letrozole or anastrozole, have been introduced for treatment of PCOS women with CC-resistant anovulation.1,2 There have been several mechanisms proposed for AI success. It was put forward that it would be possible to block estrogenic negative feedback, without depletion of estrogen receptors by administration of an AI in the early part of the menstrual cycle. Inhibition of aromatization would block estrogen production from all sources and would release the hypothalamic-pituitary axis from estrogenic negative feedback. The resultant increase in gonadotropin secretion would stimulate growth of ovarian follicles. Withdrawal of estrogen centrally also increases activins, which are produced by a wide variety of tissues, including the pituitary gland, and stimulate synthesis of FSH. In contrast to clomiphene citrate, Letrozole is rapidly eliminated from the body and does not deplete estrogen receptors and therefore has no antiestrogenic effects on endometrium or endocervical mucosa.

Several studies revealed that Letrozole can be used as an alternative to clomiphene citrate for superovulation in patients with unexplained infertility Because AIs do not deplete estrogen receptors, normal central feedback mechanisms remain intact. As the dominant follicle grows and estrogen levels rise, normal negative feedback occurs centrally, resulting in suppression of FSH and atresia of the smaller growing follicles. A single dominant follicle, and mono-ovulation, should occur in most cases. This might be of advantage in cases of PCOS, thereby avoiding the risk of OHSS. A novel protocol of extended Letrozole therapy to keep the in vivo production of FSH continuous for a longer duration was tried in this patient.3 Decremented follicular-phase FSH levels (referred to as the FSH window) appear to be crucial for selection of a single dominant follicle from the recruited cohort. As FSH levels fall, all but the dominant follicle (with its increased sensitivity to FSH) lose the stimulus to further development and become atretic. The concept of extending the FSH window by administering exogenous FSH or extending the duration of Letrozole therapy in the mid follicular phase would maintain FSH levels above the threshold, allowing multifollicular development to occur. Extended Letrozole regimen has no increased cost, no increased risk of multiple pregnancy or OHSS than usual risk.

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

References: 1. Mitwally M, Casper R. Use of aromatase inhibitor for ovulation induction in patients with an inadequate response to clomiphene citrate. Fertil Steril. 2001;75: 305–309.; 2. Usama M Fouda and Ahmed M Sayed. Extended letrozole regimen versus clomiphene citrate for superovulation in patients with unexplained infertility undergoing intrauterine insemination: A randomized controlled trial. Reproductive Biology and Endocrinology 2011; 9:84.; 3. Bafawy A, Mosbah A, Tharwat A, et al. Extended letrozole therapy for ovulation induction in clomiphene-resistant women with polycystic ovary syndrome: A novel protocol. Fertil Steril. 2009;92(1):263–239.

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F e Flash EVIDENCE UPDATE Live Birth Rate of IVF Following Brief Incubation versus Standard Incubation of Gametes cycles undergoing IVF between September 2015 and October 2016 were enrolled in the study and were randomized into the brief incubation group (n=160) or the standard incubation group (n=160) according to a computer-generated randomization list.

The aim of this randomized triple blind study is to compare the live birth rate (LBR) of in vitro fertilization (IVF) following brief incubation versus standard incubation of gametes. The hypothesis is that brief incubation improves the LBR of IVF. A total of 320 infertile women for their first or repeated

43.4 41.1

50.9 49.1

13.2 11.3 Miscarriage rate

Implantation rate

25.0 25.0

30.0 27.3

27.3 27.3

36.4 36.4

20

Miscarriage rate

Implantation rate

0

Live birth rate

10

Clinical pregnancy rate

Rate (%)

12.3 12.5 Normal sperm (n=250)

Brief incubation

Live birth rate

Clinical pregnancy rate

Miscarriage rate

Implantation rate 31.2 33.2

Miscarriage rate

Miscarriage rate

0

33.7 32.7

Rate (%)

11.1

21.4

21.6 26.6

28.6 30.6

20

0

Implantation rate

30

30

10 Live birth rate

32.1 38.9

40

10

Repeated cycle (n=56)

First cycle (n=216)

Implantation rate

22.0 13.3

Rate (%)

50

31.1

20

20

40 42.4 42.1

39.4 21.4

30

Clinical pregnancy rate

Rate (%)

40

30

Age(years) ³35 (n=64)

60

30.4

50

39.1 45.5

Age(years) <35 (n=208)

40

0 Clinical pregnancy rate

Miscarriage rate

Implantation rate

Live birth rate

Clinical pregnancy rate

0

50

10

Live birth rate

10

49.2 49.6

20

60

Live birth rate

13.5 9.3

30

45 40 35 30 25 20 15 10 5 0

Clinical pregnancy rate

40

Rate (%)

33.7 34.1

Rate (%)

50

45.0 46.3

60

53.0 51.9

Figure 1: Subgroup analysis of the effect of brief incubation versus standard incubation.

The women were grouped as <35/³35 years, in a first/repeated cycle, and with normal/abnormal semen parameters.

No statistically significant differences between the groups were demonstrated using chi-square test (P>0.05).

Abnormal semen parameters (n=22)

Standard incubation

7

F e Flash In the brief incubation group, oocytes were incubated with spermatozoa (0.3-1.2 million motile sperm/ml) for 3-4 h, while in standard incubation group; oocytes were incubated with spermatozoa at similar concentration for 20 h. The primary outcome measure was the LBR in fresh cycles, and the secondary outcome measures included clinical pregnancy, ongoing pregnancy, miscarriage, multiple pregnancy, fertilization, polyspermy and implantation rates in fresh cycles. In addition to the fresh cycle results, the outcome of the consecutive vitrification–warming cycles was analysed.

Results from the study reported to no significant difference in the LBR between the brief and standard incubation groups based on both intention-to-treat [33.0% (53/160) versus 36.8% (59/160), relative risk (RR) 0.898 (95% CI=0.666–1.212), P=0.482] and per protocol [41.4%(53/128) versus 41.0% (59/144), RR1.011 (95% CI=0.760–1.343), P=0.942] analyses.

The live birth, clinical pregnancy, miscarriage and implantation rates in fresh cycles were also comparable between the two groups (see Fig. 1). The sub group analysis also demonstrated similar results

with advanced maternal age, abnormal semen analysis and repeated IVF cycles. No differences were observed in cumulative LBR between two groups.

The use of brief incubation of gametes requires more manpower as two teams of embryologists are generally needed to implement the practice of brief insemination. It is likely that brief incubation of oocytes and spermatozoa is not necessary, and this can save the already tight manpower common in many laboratories.

In con clusio brief n, incub ation of oo (3–4 h cyte ) low c s and with oncen a tratio of spe n rmat (0.3–1 .2 mil ozoa l sperm ion motile per m does not im l) prove the LB R in I VF.

Source: Chen ZQ, Wang Y, Ng EHY, et al. A randomized triple blind controlled trial comparing the live birth rate of IVF following brief incubation versus standard incubation of gametes. Hum Reprod. 2019 Jan 1;34(1):100–108.

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F e Flash Elective Frozen Embryo Transfer in IVF/ICSI Cycles possess Positive Effect on Reproductive Outcomes The present systematic review and meta-analysis was based on RCTs, aiming to provide an update on the impact of eFET on the reproductive outcomes in IVF/ICSI cycles. Besides, the effectiveness of eFET in comparison to fresh embryo transfer in different subgroups of patients undergoing IVF/ICSI cycles was also assessed. A systematic literature search using PubMed/MEDLINE and EMBASE was performed to identify all relevant RCTs on the eFET strategy until March 2018. The participants included infertile couples undergoing IVF/ICSI with or without preimplantation genetic testing for aneuploidy (PGT-A).

Elective frozen embryo transfer (eFET), has recently increased significantly with the introduction of the GnRH agonist trigger protocol and improvements in cryotechniques. The present article discusses about the use of eFET to overall IVF population or only limited to set of patients. Several randomized controlled trials (RCT) and meta-analyses have supported the use of eFET with several benefits such as reduces ovarian hyperstimulation syndrome (OHSS and also improves reproductive outcomes.

However, the data is limited, and recent RCTs challenge the use of eFET for the general IVF population.

Figure 1: Forest-plots comparing live birth rates after fresh and elective frozen embryo transfer.

Intention-to-treat analysis for (a) live birth rates and (b) cumulative live birth rates after 12 months.

Study or subgroup

A

Ferraretti 1999 Shapiro 2011b Shapiro 2011a Chen 2016 Aghahosseini 2017 Coates 2017 Vuong 2018 Aflatoonian 2018 Shi 2018

Frozen ET

Fresh ET

Events Total

Events Total

23 37 37 368 15 56 132 33 525

Total (95% CI) Total events

58 60 70 746 43 91 391 140 1077

26 33 27 320 15 35 123 32 542

2676 1226

Weight (%)

Risk ratio M–H, Random, 95% CI

Year

Risk ratio M–H, Random, 95% CI

67 62 67 762 46 88 391 140 1080

4.9 8.5 6.5 23.1 2.9 8.6 14.5 5.1 25.8

1.02 (0.66, 1.58) 1.16 (0.85, 1.57) 1.31 (0.91, 1.89) 1.17 (1.05, 1.31) 1.07 (0.60, 1.92) 1.55 (1.14, 2.10) 1.07 (0.88, 1.31) 1.03 (0.67, 1.58) 0.97 (0.89, 1.06)

1999 2011 2011 2016 2017 2017 2018 2018 2018

2703

100.0

1.12 (1.01, 1.24)

1153

Heterogeneity: Tau2=0.01, Chi2=14.84, df=8 (P=0.06); I2=46% Test for overall effect: Z=2.10 (P=0.04)

B

Chen 2016 Ferraretti 1999 Shapiro 2011a Shapiro 2011b Vuong 2018

465 23 37 37 191

Total (95% CI) Total events

753

746 58 70 60 391

455 26 35 39 185

762 67 67 62 391

67.1 2.3 4.3 5.7 20.6

1.04 (0.96, 1.13) 1.02 (0.66, 1.58) 1.01 (0.74, 1.39) 0.98 (0.74, 1.29) 1.03 (0.89, 1.19)

— — — — —

1325

1

349

100.0

1.04 (0.97, 1.11)

—

740

Heterogeneity: Tau2=0.00; Chi2=0.21, df=4 (P=0.99); I2=0% Test for overall effect: Z=1.05 (P=0.30)

0.01

0.1 1 10 100 Favours Favours fresh ET fronzen ET

ET=Embryo transfer

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F e Flash in PGT-A cycles (RR=1.55; 95% CI: 1.14–2.10). There was no significant difference between the eFET and fresh ET groups (RR = 1.04; 95% CI: 0.97–1.11; Fig. 2B) in cumulative LBR based on the number of women randomized. No differences were observed in the implantation rates between the eFET group and the fresh ET group (RR=1.16; 95% CI: 0.98–1.36; I 2 =80%; Fig. 2A); however, heterogeneity was substantial. Similarly, no difference was noted in the miscarriage rates between eFET and fresh ET cycles among the biochemical pregnancies (RR=1.08; 95% CI: 0.72–1.61; I2=62%; Fig. 2b), but heterogeneity was substantial. No statistical differences were noted in the remaining secondary outcomes.

The primary outcome measure was the live birth rate (LBR), per woman randomized. The secondary outcome measures were the cumulative LBR (per women randomized) and the rates of implantation, miscarriage, OHSS, ectopic pregnancy, preterm birth, pregnancy-induced hypertension, pre-eclampsia, birth weight and congenital anomalies.

Nine studies reported LBR including 2676 patients randomized in the eFET group and 2703 patients in the fresh ET group. The overall RR for LBR was 1.12 (95% CI: 1.01–1.24; I2=46%; P=0.04; Fig. 1A), favoring the eFET group. Subgroup analyses indicated higher LBRs by eFET than by fresh embryo transfer in hyper-responders (RR=1.16; 95% CI: 1.05–1.28) and

Figure 2: Forest-plots comparing outcomes after fresh and elective frozen embryo transfer. (a) Overall implantation rate, (b) miscarriage rate and (c) moderate/severe ovarian hyperstimulation syndrome.

Study or subgroup

A

Shapiro 2011b Shapiro 2011a Coates 2017 Vuong 2018 Shi 2018

Frozen ET

Fresh ET

Events Total

Events Total

63 63 79 224 809

Total (95% CI) Total events

93 89 104 780 1966

60 37 58 210 857

3032 1238

Weight (%)

Risk ratio M–H, Random, 95% CI

Year

103 95 86 778 2027

18.3 14.8 20.1 21.3 25.5

1.16 (0.94, 1.44) 1.82 (1.37, 2.42) 1.13 (0.94, 1.35) 1.06 (0.91, 1.25) 0.97 (0.90, 1.05)

2011 2011 2017 2018 2018

3089

100.0

1.16 (0.98, 1.36)

1222

Heterogeneity: Tau2=0.03; Chi2=19.83, df=4 (P=0.0005); I2=80% Test for overall effect: Z=1.75 (P=0.08)

B

Ferraretti 1999 Shapiro 2011a Shapiro 2011b Chen 2016 Aghahosseini 2017 Vuong 2018 Shi 2018 Aflatoonian 2018

5 6 4 108 0 25 67 13

Total (95% CI) Total events

58 70 60 746 36 391 1077 140

3 7 5 161 2 15 69 2

2578 228

Risk ratio M–H, Random, 95% CI

0.01

0.1

1

10

100

Favours fresh ET Favours fronzen ET

67 67 62 762 36 391 1080 140

6.6 10.0 7.6 26.6 1.7 17.1 24.4 6.0

1.93 (0.48, 7.71) 0.82 (0.29, 2.32) 0.83 (0.23, 2.93) 0.69 (0.55, 0.86) 0.20 (0.01, 4.03) 1.67 (0.89, 3.11) 0.97 (0.70, 1.35) 6.50 (1.49, 28.27)

2605

100.0

1.08 (0.72, 1.61)

1999 2011 2011 2016 2017 2018 2018 2018

264

Heterogeneity: Tau2=0.15; Chi2=18.52, df=7 (P=0.010); I2=62% Test for overall effect: Z=0.36 (P=0.72)

0.01

0.1

1

10

100

Favours fronzen ET Favours fresh ET

10

F e Flash Figure 2: Forest-plots comparing outcomes after fresh and elective frozen embryo transfer. (a) Overall implantation rate, (b) miscarriage rate and (c) moderate/severe ovarian hyperstimulation syndrome.

Study or subgroup

C

Ferraretti 1999 Shapiro 2011b Shapiro 2011a Chen 2016 Aflatoonian 2018 Vuong 2018 Shi 2018

Frozen ET

Fresh ET

Events Total

Events Total

0 0 1 10 43 3 7

Total (95% CI) Total events

58 60 70 746 140 391 1077

4 0 1 54 51 4 22

2542 64

Weight (%)

Risk ratio M–H, Random, 95% CI

Year

Risk ratio M–H, Random, 95% CI

67 62 67 762 140 391 1080

6.2 — 6.7 23.8 27.0 14.6 21.7

0.13 (0.01, 2.33) Not estimable 0.96 (0.06, 14.99) 0.19 (0.10, 0.37) 0.84 (0.61, 1.17) 0.75 (0.17, 3.33) 0.32 (0.14, 0.74)

1999 2011 2011 2016 2018 2018 2018

2569

100.0

0.42 (0.19, 0.96)

136

Heterogeneity: Tau2=0.62; Chi2=21.01, df=5 (P=0.0008); I2=76% Test for overall effect: Z=2.06 (P=0.04)

Use of eFET has significantly increased LBR in hyperresponders and in patients undergoing PGT-A and its use is significantly increased in the recent years.

Besides, eFET significantly decreases the risk of moderate and severe OHSS, albeit at the expense of

0.01

0.1

Favours fronzen ET

1

10

100

Favours fresh ET

an increased risk of pre-eclampsia. Taken together, the present data suggest that the eFET policy should be individualized in line with modern patient handling approaches.

Source: Roque M, Haahr T, Geber S, et al. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: A systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update. 2019;25(1):2–14.

Image of the month The images obtained using color Doppler FINE allowed a precise diagnosis of fetal hypoplastic left heart and coarctation of the aorta at 26 weeks of gestation. More details about the case and color Doppler FINE can be found in an accompanying article in this issue of UOG3 Prenatal diagnosis of hypoplastic left heart and coarctation of the aorta with color Doppler FINE Source: Ultrasound Obstet Gynecol. 2017;50:543–544.

11

F e Flash Untargeted Metabolomics Approach to Identify Obesity Associated Differences in the Human FF Metabolome Obesity is associated with menstrual irregularities, impaired oocyte quality, low rates of implantation and delayed embryo development. Several studies have reported that obese women undergoing in vitro fertilization have reduced quantity and quality of oocytes when compared to normal weight (NW) women. Imbalances in nutritional status and hormonal levels may transform the ovarian environment to induce intracellular stress in the oocyte, which could influence oocyte development and quality. Within a broad range of tissues, obesity negatively influences the metabolic homeostasis of cells; however its impact on oocyte metabolism is not clear till date.

To address this research gap, researchers designed a clinical study of women undergoing fertility treatments to: 1) examine the impact of obesity on the metabolome of human FF using untargeted metabolomics for primary metabolism and lipidomics and 2) to establish if serum metabolites are reflective of FF profiles in OW compared to NW women. An exploratory assessment of the follicular fluid (FF) metabolome in 8 overweight/obese (OW) and 9 normal weight (NW) women undergoing in vitro fertilization was conducted. FF and serum were collected and analyzed by untargeted metabolomics using GC-QTOF-MS and CSH-ESI QTOF MS/MS. Untargeted metabolomics identified obesity-associated changes in FF metabolites related to oxidative stress/antioxidant capacity, xenometabolism/amino acid biosynthesis, and lipid metabolism.

Results from the study reported that obese weight (OW) women had higher serum leptin levels and elevated serum inflammatory markers (CRP and CCL2) compared to NW women. Besides, OW women demonstrated decrease in serum HDL and increase in serum TG levels. FF leptin, TG and CRP levels were significantly increased in OW compared to NW women. Partial least squares-discriminant analysis (PLS-DA) showed good model performance and 230 discrimination of samples and metabolites. Discriminant FF metabolites included elevated uric acid, isothreonic acid, 1 unknown primary Resea metabolite, and 6 unknown complex lipids in OW compared to NW rcher s of th opine women. es d

tu that o impo besity dy rtant has con the fo On the other hand, 2-dimethylacetal-ketoglucose, aminomalonate, llicula sequences on r envi durin 2 unknown primary metabolites, and 2 unknown complex lipids ronm g the e pre nt perio were decreased in FF of OW relative to NW women. In both FF d, a w -concepti o indow n that m and serum of OW women, indole-3-propionic acid (IPA), a of tim ay be e im lifesty bacterial derived metabolite, was also decreased (p<0.05). The le inte portant fo a m r r vent important association between antioxidant IPA in serum and FF eliora ions t te ob o esi (R= 0.95, p<0.0001), suggests a potential serum biomarker of risk fa ty-associat ed ctors.

FF antioxidant status or reflection of the gut metabolism

interaction with the follicle.

Source: Ruebel ML, Piccolo BD, Mercer KE, et al. Obesity Leads to Distinct Metabolomic Signatures in the Follicular Fluid of Women Undergoing in vitro Fertilization. Am J Physiol Endocrinol Metab. 2019 Jan 2. doi: 10.1152/ajpendo.00401.2018.

12

F e Flash DIAGNOSTIC UPDATE Being Overweight was a Risk Factor for both Low-Quality Embryos and Miscarriage Gn consumption per day, was significantly lower in the non-overweight groups. The number of available embryos was higher in non-overweight-HA group than in overweight-non-HA group. The level of progesterone (P4) and the endometrial thickness on the day of hCG administration were not different among the four groups.

The retrospective study was designed to assessed whether the effect of BMI on IVF outcomes vary with the level of androgen in PCOS with a GnRH-antagonist protocol. A total of 583 infertile women with PCOS who underwent IVF using the conventional GnRHantagonist protocol were enrolled in the study. This cohort study included four groups of patients with PCOS: BMI ³25 kg/m2 with HA (overweight-HA group,

Figure 1: Receiver operating characteristic (ROC) curves analysis of body mass index (BMI) and androstenedione (AND) on prediction of miscarriage rate.

ROC curves

1.0

with normal androgen

(overweight-non-HA group, n=117), BMI <25 kg/m2 with HA (non-overweight-HA group, n=152), and BMI <25 kg/m 2 with normal androgen (nonoverweight-non-HA group, n=218). Primary outcome measures were rate of clinical pregnancy, miscarriage rate, and rate of live birth. Secondary outcome measures were Gn dosage, number of oocytes collected, and number of available embryos.

Results from the study reported that the number of oocytes retrieved and the estradiol levels on the day of hCG administration were significantly higher in the non-overweight groups than in the overweight groups, although the total Gn consumption, as well as

0.8

Sensitivity

n=96), BMI ³25 kg/m

2

Clinical pregnancy rate was of no significant difference among four groups. When compared to nonoverweight-non-HA group, live-birth rates in the overweight groups were significantly lower (28.4%, 42.5% and 23.9%). Similarly the miscarriage rate in overweight-HA group was significantly higher than that in non-overweight-non-HA group (45.2% vs.

14.5%, P<0.05). Both BMI and basal androstenedione

0.6

0.4 BMI AND Line of reference

0.2

0 0

0.2

0.4 0.6 1-specificity

0.8

1.0

13

F e Flash (AND) both acted as significantly influent factors on miscarriage rate, as revealed by multivariate logistic regression analysis. The area under the curve (AUC) in receiver operating characteristic (ROC) analysis for BMI Resea rcher and basal AND on miscarriage rate s opin r is k f ed th actor were 0.607 (P=0.029) and 0.657 at b for b m is ca oth lo eing over rriage (P=0.001), respectively, and weigh w-qu proto . In IVF cy ality t was the cut-off values of BMI and e c c mbr y les w a ol, ec non-o 2 i o o t s and h GnR nomi basal AND were 25.335 kg/m ver w c H bene eight Gn co fits w -antagon and 10.95 nmol/L, respectively patie st an ist e r nts w e see ith PC n in HA w d more re (see Fig. 1). trie as OS

a pos , ved o good itivel ocyte with less -qual y s infl . How ity em m is ca eve br yos uential fac rriage tor fo r, but a . Mul analy r tivari risk f ses sh ate lo actor ow th both g f o istic r at BM s egres r I and misca ignificant s b i on as ly infl rriage uenti al AND we abilit r a t e al fac , with y. T tors o re mode misca he predic n r ate p tiv rriage redic was s e value of tive lightl basal y stro AND nger on than BMI.

Source: Yang W, Yang R, Lin M, et al. Body mass index and basal androstenedione are independent risk factors for miscarriage in polycystic ovary syndrome. Reprod Biol Endocrinol. 2018 Nov 19;16(1):119.

Answers for TRAZER HUNT: Across: (1) Hatching (3) Capacitation (4) Blastocyst (6) Polyspermy (7) Adhesion (9) Amniocentesis Down: (2) Insemination (3) Cumulus (5) Micromanipulation (8) Hysteroscope

14

F e Flash GUIDELINES UPDATE WHO Recommendations on the Use of Uterotonics for the Prevention of Postpartum Haemorrhage (PPH) Introduction Postpartum Haemorrhage (PPH) is commonly deďŹ ned as a blood loss of 500 ml or more within 24 hours after birth. Globally, PPH is the primary cause of nearly one quarter of all maternal deaths, and the leading cause of maternal mortality in low-income countries. The majority of the deaths due to PPH occur within 24 hours of birth, which can be avoided through the use of prophylactic utero - tonics during the third stage of labour and by timely and appropriate management. EďŹ&#x20AC;orts to prevent and reduce morbidity and mortality due to PPH can help address the profound inequities in maternal and perinatal health globally. The World Health Organization (WHO) maternal and perinatal health recommendations prioritized the updating of the existing WHO recommendations on the use of uterotonics for PPH prevention, in response to the availability of new evidence.

Figure 1: Forest-plots comparing live birth rates after fresh and elective frozen embryo transfer.

Intention-to-treat analysis for (a) live birth rates and (b) cumulative live birth rates after 12 months.

Context

Recommendation

Category of recommendation

The use of an effective uterotonic for the prevention of PPH during the third stage of labour is Efficacy and recommended for all births. safety of uterotonics for To effectively prevent PPH, only one of the following uterotonics should be used: PPH prevention ! ! ! ! !

Choice of uterotonics for PPH prevention

oxytocin (Recommendation 1.1) carbetocin (Recommendation 1.2) misoprostol (Recommendation 1.3) ergometrine/methylergometrine (Recommendation 1.4) oxytocin and ergometrine fixed-dose combination (Recommendation 1.5).

1.1

The use of oxytocin (10 IU, IM/IV) is recommended for the prevention of PPH for all births.

1.2

The use of carbetocin (100 mg, IM/IV) is recommended for the prevention of PPH for all births in contexts where its cost is comparable to other effective uterotonics.

Context-specific recommendation

1.3

The use of misoprostol (either 400 mg or 600 mg, PO) is recommended for the prevention of PPH for all births.

Recommended

1.4

The use of ergometrine/methylergometrine (200 mg, IM/IV) is recommended for the prevention of PPH in contexts where hypertensive disorders can be safely excluded prior to its use.

Context-specific recommendation

1.5

The use of a fixed-dose combination of oxytocin and ergometrine (5 IU/500 mg, IM) is recommended for the prevention of PPH in contexts where hypertensive disorders can be safely excluded prior to its use

Context-specific recommendation

1.6

Injectable prostaglandins (carboprost or sulprostone) are not recommended for the prevention of PPH.

2.

In settings where multiple uterotonic options are available, oxytocin (10 IU, IM/IV) is the recommended uterotonic agent for the prevention of PPH for all births

Recommended

3.

In settings where oxytocin is unavailable (or its quality cannot be guaranteed), the use of other injectable uterotonics (carbetocin, or if appropriate rgometrine/ methylergometrine, or oxytocin and ergometrine fixed-dose combination) or oral misoprostol is recommended for the prevention of PPH

Recommended

4.

In settings where skilled health personnel are not present to administer injectable uterotonics, the administration of misoprostol (400 mg or 600 mg, PO) by community health workers and lay health workers is recommended for the prevention of PPH.

Recommended

Recommended

Not recommended

Source: Accessed from https://apps.who.int/iris/bitstream/handle/10665/277276/9789241550420-eng.pdf?ua=1&ua=1. Accessed on 27th Jan 2019.

15

F e Flash FIGO CONFERENCE 2018 Effectivity of Prophylactic Enoxaparin in Avoiding Miscarriages for Women Undergoing IVF Women presenting with inherited thrombophilia, at high risk of recurrent miscarriage and is major cause of in vitro fertilization (IVF) failure over the last few years. However, studies still give conflicting results. The retrospective cohort study assessed the clinical outcomes of women presenting altered thrombophilia profile and undergoing IVF treatment who received prophylactic enoxaparin. Women receiving enoxaparin were compared with those who not received enoxaparin and normal thrombophilia profile ones (control group).

A total of 95 women undergoing IVF treatment who had thrombophilia profile were enrolled in the study and were randomized into 3 groups: ! Control (n=24)–women who presented normal thrombophilia profile and received IVF treatment and embryos transfer as routine. ! Thrombophilia (n=24)–women who presented any alteration in the thrombophilia profile and received IVF treatment and embryos transfer as routine. ! Thrombophilia+Enoxaparin (n=46)–women who presented any alteration in the thrombophilia profile and received IVF treatment and prophylactic enoxaparin (40 mg/day) since the embryos transfer.

Results from the study reported that all three groups were homogeneous regards age (37.9±5.8; 35.2±3.7; 35.7±6.2;

Figure 1: Enoxaparin effective in reducing clinical pregnancy and live births.

p=0.147), basal FSH (8.8±5.3; 6.8±2.8; 9.0±9.0; p=0.463), number of MII oocytes (7.1±3.6; 5.9±4.2; 7.6±3.9; p=0.257)

80

and embryos transferred (2.2±0.7; 2.3±0.6; 2.3±0.6; p=0.743),

70 Clinical efficacy (%)

respectively. When compared to Thrombophilia+Enoxaparin and control groups, the clinical pregnancy and live birth rates were lower in the thrombophilia (see Fig. 1). The miscarriage rate was significantly higher in the thrombophilia (45.5%) than Thrombophilia+Enoxaparin (9.4%) and Control (14.0%; p=0.041) groups.

69.6

60

60.9

50 40

60.9 52.2

45.8

30 20

25.0

Researchers of the study opined that the miscarriage 10 rates are higher leading to worst clinical outcomes of 0 I V F ( l i ve b i r t h r a te s ) i n wo m e n w i t h a l te re d EnoxaThromboControl parin philia+ thrombophilia profile. On the other hand, if they receive Enoxaparin prophylactic enoxaparin, the clinical outcomes are similar to those of control women without Live births Clinical pregnancy thrombophilia profile alteration. Researchers suggested that enoxaparin should be administered since the embryo transfer for all women with any thrombophilia profile alteration.

Source: Roberto LJ, Lambert L, Ueno J, et al. EP0662 | Effectivity of Prophylactic Enoxaparin in Avoiding Miscarriages for Women Undergoing IVF THEME. Int J Gynecol Obstet. 2018; 143 (Suppl 3):158–542.

16

F e Flash Newborn Metabolic Profile Combined with Clinical Characteristics: Identify Preterm Newborns at Increased Risk for Mortality or Major Neonatal Morbidity A study was conducted in preterm infants to assess whether metabolic profile at birth can be used to create global measure of risk for risk for neonatal mortality and major morbidity. To assess the association between newborn characteristics, metabolic profile, and neonatal mortality (<30 days) or major morbidity (respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), NEC, IVH, or periventricular leukomalacia (PVL)), multivariate backward stepwise regression was used.

Resea rcher s of th opine e stud d t y hat n metab e w born olic p rofile with c comb linica ined l char can re acteri stics liably ident prete ify rm ne wbor increa ns at sed ri sk for morta lit neona y or major tal m orbid ity.

Results from the study reported that six infant characteristics (birth weight, gestational weeks at birth, sex, race/ethnicity, days at blood collection, total parenteral nutrition ) and 28 metabolites (16 acylcarnitines, 9 amino acids, 17-hydroxyprogesterone, galactose-1- phosphate uridyl transferase, and thyroid stimulating hormone) were included in the final multivariate model for neonatal mortality or major morbidity (all at p<0.05).

Source: Jelliffe-Pawlowsk L, Rogers E, Oltman S, et al. FCS267 | A newborn metabolic profile as a predictor of mortality and major morbidity in preterm neonates theme: AB02 clinical obstetrics/sub-theme: AB 2.6 neonatal care. Int J Gynecol Obstet. 2018; 143 (Suppl 3):158–542.

TRAZER HUNT Across 1

1.

The process by which an embryo at the blastocyst stage separates from the zona pellucida

3.

A process the sperm must undergo that enables fertilization

4.

An embryo, 5 or 6 days after fertilization, with an inner cell mass, outer layer of trophectoderm, and a fluid-filled blastocele cavity

6.

Abnormal condition where the oocyte is fertilized by more than one sperm

7.

Scar tissue attaching abnormally connecting, covering or distorting organs

9.

Sampling a small quantity of the fluid that surrounds the fetus that permits detection of certain abnormalities

2 3

4 5 6

7

8

Down

9

2.

Transfer of semen or sperm for the purpose of establishing a pregnancy

3.

The cloud-like collection of supportive follicle cells that surround the oocyte

5.

A method of assisted reproduction when the process is manually performed under the guidance of the microscope

8.

A telescopic device, much like the laparoscope, that enables examination of the uterine cavity Answers for TRAZER HUNT on page 14

17

F e Flash CONFERENCE CALENDER FOGSI – Wellness of Women (WOW) TOT Date: 15-17 Feb 2019 Place: Delhi, India 24th Annual congress of Indian Society for Assisted Reproduction Date: 1-3 Mar 2019 Place: Mumbai, India ISAR 2019 Date: 1-3 Mar 2019

Place: Mumbai, India

High Risk Obstetrics 26th Annual Spring Conference 2019 Date: 6–9 Mar 2019 Place: Tulum, Mexico AGES Annual Scientific Meeting 2019 Date: 7-9 Mar 2019 Place: Perth, Australia Society For Reproductive Investigation 66th Annual Meeting 2019 Date: 12–16 Mar 2019 Place: Paris, France 2019 SRI 66th Annual Scientific Meeting Date: 13-16 Mar 2019 Place: Paris, FRANCE 2019 Best of ESHRE and ASRM Date: 14-16 Mar 2019 Place: New York City, New York, USA Society of Obstetricians & Gynaecologists of Canada 2019 Date: 14-16 Mar 2019 Place: Alberta, Canada 4th European Congress on Intrapartum Care: Making Birth Safer 2019 Date: 14-16 Mar 2019 Place: Turin, Italy 4th European Congress on Intrapartum Care: Making Birth Safer 2019 Date: 14-16 Mar 2019 Place: Torino, Italy Obstetrics And Gynecology 56th Annual Update 2019 Date: 17-22 Mar 2019 Place: Boston, Ma, United States 56th Annual Update Obstetrics And Gynecology 2019 Date: 17-22 Mar 2019 Place: Boston , Ma, United States 15th ISUOG (International Society of Ultrasound in Obstetrics and Gynecology) International Symposium Date: 12-14 Apr 2019 Place: Sao Paulo, BRAZIL International Society For Gynecologic Endoscopy And European Society Gynecological Endoscopy South African Conference 2019 Date: 13-17 Apr 2019 Place: Cape Town , South Africa 5th World Congress on Polycystic Ovarian Syndrome Date: 23-24 Apr 2019 Place: Berlin, Germany AACE 28th Annual Scientific & Clinical Congress Date: 24-28 Apr 2019 Place: Los Angeles, California, USA

18

F e Flash 9th Congress of the Asia PaciďŹ c Initiative on Reproduction 2019 (ASPIRE) Date: 2-5 May 2019 Place: Hong Kong, China ACOG 67th Annual Clinical Meeting 2019 Date: 3-6 May 2019 Place: Nashville, United States Expert Fetal Medicine 2019 Date: 8-11 May 2019 Place: London, United Kingdom Society Of Endometriosis And Uterine Disorders 5th Congress 2019 Date: 16-18 May 2019 Place: Montreal, Canada British Society For Gynecological Endoscopy 29th Meeting 2019 Date: 21-23 May 2019 Place: Newport , United Kingdom Annual Conference of the Indian Association of Gynecological Endoscopists 2019 Date: 7-9 Jun 2019 Place: Ahmedabad, India RCOG World Congress 2019 Date: 17-19 Jun 2019 Place: London, United Kingdom ESHRE 2019 Date: 23-26 Jun 2019

Place: Vienna, AUSTRIA

18th World Congress In Fetal Medicine 2019 Date: 25-29 Jun 2019 Place: Alicante, Spain ESAG 4th World Congress Date: 27-28 Jun 2019 Place: Edinburgh, Scotland ISSCR 2019 Date: 26-29 Jun 2019

Place: Los Angeles, CA

2nd World Congress on Gynecology & Obstetrics (WCGO-2019) Date: 19-20 Sep 2019 Place: Miami, USA 12th Annual Congress Of The European Urogynaecological Association 2019 Date: 16-18 Oct 2019 Place: Tel Aviv, Israel IVF and Embryology 2019 Date: 25-26 Oct 2019 Place: Paris, France International Meeting of the European Society of Gynaecological Oncology Date: 2-5 Nov 2019 Place: Athens, Greece 48th AAGL Global Congress on MIGS Date: 9-13 Nov 2019 Place: Vancouver, BC Canada 27th World Congress on Controversies in Obstetrics, Gynecology & Infertility (COGI) Date: 21-23 Nov 2019 Place: Paris, France

19

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