Fertility Flash - Issue 8

ISSUE

F e Flash HIGHLIGHTS Rare Case of Adenomyotic Uterine Horn Rectified Laparoscopically Increasing Risk of Miscarriage in Intracytoplasmic Sperm Injection Treatments Over In Vitro Fertilization Treatment Combination of Follicle Stimulating Hormone and Human Chorionic Gonadotropin Effective in Improving Pregnancy Rate Induction of Acrosome Reaction in Human Spermatozoa by GlcNAc-Neoglycoproteins Enhances Fertilizing Ability Bio-Molecular Components in Follicular-Fluid Influence Embryo Development and Pregnancy Outcomes in IVF Cycles Reducing Follicle-Stimulating Hormone Concentration Could Diminish its Detrimental Effect on Oocytes during Human In Vitro Maturation The Faculty of Sexual and Reproductive Healthcare (FSRH) Guidelines on Overweight, Obesity and Contraception

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expansion in world population. Attempts to control population growth have focused on reducing fertility with some apparent effect. Up to 30 % of infertile couples remain childless devoid of identifiable causes—leading to a diagnosis of unexplained infertility, even after extensive evaluation of both partners.

Fertility Flash is an academic initiative from Corona Remedies to link medical fraternity with latest updated information in infertility. This is 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.

CASE REPORT Rare Case of Adenomyotic Uterine Horn Rectified Laparoscopically

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EVIDENCE UPDATES Increasing Risk of Miscarriage in Intracytoplasmic Sperm Injection Treatments Over In Vitro Fertilization Treatment

CONTENTS

PREFACE

Fertility and its determinants have been urgent topics for research in recent decades with rapid

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Combination of Follicle Stimulating Hormone and Human Chorionic Gonadotropin Effective in Improving Pregnancy Rate

DIAGNOSTIC UPDATE Induction of Acrosome Reaction in Human Spermatozoa

by GlcNAc-Neoglycoproteins Enhances Fertilizing Ability

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ESHRE 2019 ABSTRACTS Bio-Molecular Components in Follicular-Fluid Influence Embryo Development and Pregnancy Outcomes in IVF Cycles Reducing Follicle-Stimulating Hormone Concentration Could Diminish its Detrimental Effect on Oocytes during Human In Vitro Maturation

IMAGE OF THE MONTH

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GUIDELINES The Faculty of Sexual and Reproductive Healthcare (FSRH) Guidelines on Overweight, Obesity and Contraception

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TRAZER HUNT

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CONFERENCE CALENDER

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QUIZ

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F e Flash CASE REPORT Rare Case of Adenomyotic Uterine Horn Rectified Laparoscopically

Contributed by:

Dr. Sunita Tandulwadkar M.D (Obstetrics and Gynaecology), FICS (Gynae Endoscopy) FICOG Diploma in Endoscopy (Germany) Head of the Department (OBGY), Ruby Hall Clinic, Advisor, IVF & Endoscopy Department, D.Y. Patil Medical College Chief, Ruby Hall IVF & Endoscopy Centre, Founder & Medical Advisor, SOLO STEMCELLS - A Stem Cell Research & Application Center, Director, Solo Clinic, Centre of Excellence Infertility & Endoscopy, Pune President, Indian Association of Gynaeocological Endoscopists 2019-2020, Chairperson, Maharashtra State Chapter of ISAR, Joint Secretary, Indian Society of Assisted Reproduction (ISAR), Founder Secretary, Maharashtra Chapter ISAR, Advisor & Reviewer, Journal of Human Reproductive Sciences.

Mullerian anomalies are rare complications that are asymptomatic and may result in primary infertility. Patients presenting with a unicornuate uterus with rudimentary horn are at an increased risk of gynecologic complications with symptoms like dysmenorrhea, chronic pelvic pain and adenomyosis. The condition is usually treatable and requires surgical interventions for its management. Here we present a rare case of adenomyotic uterine horn causing severe pelvic pain that required hysteroscopic rectification.

Current Complaint and History of Present Illness: A 31-years old female, married for 6 years, with primary infertility and complaints of severe dysmenorrhea for the last 14 years and menorrhagia since last 2 years presented to infertility clinic.

Past Medical History Ÿ

She had undergone laparotomy 12 years back for removal of tubo-ovarian mass (chocolate cyst).

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Undergone laparoscopy for re-evaluation and intra operative findings were suggestive of grade I endometriosis.

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The patient was taking oral contraceptive pills, dienogest and ormeloxifene on and off to relieve dysmenorrhea symptoms.

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Last visited the facility with similar complaints of severe dysmenorrhea relieved only with parenteral NSAIDs.

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She had no bowel or bladder complaints.

Physical Examination Her vitals, general physical and systemic examination were normal. Abdominal examination was normal; non tender, no organomegaly and on speculum examination single cervix was seen with normal vagina.

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Sonographic/ Laparoscopic Evaluation A pelvic ultrasound and diagnostic laparoscopy revealed Ÿ

A duplication anomaly of uterus with normal sized right uterus having non communicating adenomyotic left horn of size 6.1 X 2.6 X 5.9 cm with adhesions all around left uterus.

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Left kidney was absent.

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Right kidney was scarred and echogenic with poor cortico-medullary differentiation.

Hematologic Parameters Blood urea and creatinine values were deranged.

Diagnosis Based on the investigations the patient was diagnosed to have a unicornuate right hemiuterus with a noncommunicating adenomyotic left horn along with renal agenesis.

Treatment Ÿ

The patient was referred to a nephrologist to correct renal dysfunction.

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The patient was operated for 3D laparoscopic removal of adenomyotic of uterus.

Recovery and follow-up The patient showed good recovery post-surgery and was eventually relieved of her long-lasting severe dysmenorrhea symptoms.

Discussion The overall incidence of Mullerian duct anomalies has been reported to be 3.2% in women with normal reproductive outcomes and is higher in women with recurrent first-trimester (5% to 10%) or late first- and early second-trimester miscarriages (>25%). As per the American Society of Reproductive Medicine, Müllerian Anomalies can be classified into 7 classes of which unicornuate uterus constitutes approximately 20% of all cases (Table 1).1 Patients presenting with a unicornuate uterus often encounter repeated second trimester spontaneous abortions, preterm deliveries normal presentations; rarely as ectopic pregnancy. Gynecological conditions such as dysmenorrhea (estimated in 70% of cases), hematometra (in 50%), and endometriosis (in 20%–40% of cases) have

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been reported but adenomyosis is extremely rare.2,3 Additionally, renal anomalies are seen to occur in 29% of Mullerian duct anomalies, more commonly seen in unicornuate uteri than with other anomalies. It has been estimated that roughly 40% of unicornuate patients have renal anomalies and are ipsilateral to the rudimentary horn. Renal agenesis is the most commonly repor ted anomaly, occurring in 67% of cases.4

Table 1: American Society of Reproductive Medicine Classification of

Müllerian Anomalies Class I II III IV V VI VII

Anomaly Uterovaginal hypoplasia and agenesis Unicornuate uterus Uterus didelphys Bicornuate uterus Septate uterus Arcuate uterus Uterine anomalies related to diethylstilbestrol exposure

It is critical that proper identification and diagnosis of Mullerian anomaly is made in order to assess the right surgical approach for its management because the procedure is greatly influenced by the specific subtype and by anatomical characteristics of the uterus, such as the extent of the connection between the rudimentary horn and the unicornuate uterus. However, the relative rarity of this kind of congenital malformation makes its diagnosis and management a challenge for the gynecologist.3 Also, the scanning radiologists should be familiar with the imaging features of the seven classes of anomalies as the appropriate course of treatment relies upon the correct diagnosis and categorization of each anomaly.4,5 With the advent of modern minimally invasive surgical techniques which offer advantages of shorter hospital stay, small incisions and less post-operative pain, laparoscopy has become the first choice in such complicated surgical procedures.5 The present case was a classic example of a unicornuate uterus with rudimentary horn and renal agenesis which remained undiagnosed at the early age only to be identified later due to extreme pelvic pain. It is noteworthy here that in managing such challenging cases of anomaly surgeon skill and decision are extremely critical. In the case, surgical resection resulted in pain relief and hence better quality of life.

References 1. Khati NJ, Frazier AA, Brindle KA. The unicornuate uterus and its variants: clinical presentation, imaging findings, and associated complications. J Ultrasound Med. 2012;31(2):319-31.; 2. Pawde A, Khadkikar R, Mayadeo NM, Chauhan AR. Adenomyosis In Non-Communicating Uterine Horn. JPGO. 2014. 1 (12):1-5.; 3. M o r e l l i M , Venturella R, Mocciaro R, et al. An unusual extremely distant noncommunicating uterine horn with myoma and adenomyosis treated with laparoscopic hemihysterectomy. Case Rep Obstet Gynecol. 2013;2013:160291.; 4. Chandler TM, Machan LS, Cooperberg PL, et al. Mullerian duct anomalies: from diagnosis to intervention. Br J Radiol. 2009;82(984):1034–1042.; 5. Tekani H, Karthik G. Unicornuate Uterus with a Functional Non-communicating Horn in a Parous Woman. J Obstet Gynaecol India. 2016;66(Suppl 2):604–606.

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F e Flash EVIDENCE UPDATES Increasing Risk of Miscarriage in Intracytoplasmic Sperm Injection Treatments Over In Vitro Fertilization Treatment World Health Organization (WHO) describes infertility as a disease that affects 15% to 20% of all couples trying to conceive. In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are the most efficient assisted reproduction techniques (ART) for treating infertile couples. The high DNA stain ability (HDS) is a parameter that expresses the fraction of sperm with higher level of green fluorescence. The current study determines whether HDS, as assessed by the sperm chromatin structure assay (SCSA), predicts the risk of early miscarriage after IVF with ICSI. A retrospective cohort study of consecutive pregnancies after IVF and ICSI treatment was conducted at Reproductive Medicine Center, Skane University Hospital in Malmo, Sweden, between August 2007 and September 2017 with a total of 1,602 pregnancy patients after 832 IVF and 770 ICSI treatments. SCSA was applied to measure HDS interventions. The SCSA was performed on frozen/thawed semen that was diluted with Tris-NACL-EDT (TNE) buffer to a final concentration of 6×106 sperm/mL. Two types of protocol were used to achieve controlled ovarian stimulation; gonadotropin-releasing hormone (GnRH) antagonist short protocol or GnRH agonist long protocol.

For IVF, sperm cells with a concentration of 150,000/mL were added to the oocytes. They were placed in an incubator with a gas phase of 6% CO2, 5%O2, and 89% N2, in which fertilization took place during 90 minutes of coincubation. The HDS represents the proportion of immature spermatozoa lacking the normal exchange of histone for protamine-complexed DNA. The major outcome measure of this study is early miscarriage (≤12 weeks). The odds ratios for early miscarriage with HDS ≤7% as reference are shown in Table 1, and with HDS ≤15% as the reference in Table 2. For HDS >15% compared with HDS ≤7%, a statistically significant increase in OR was seen (OR 1.45; 95% CI, 1.05–2.00; P=.022).

The miscarriage rate of HDS ≤7% was 147 (29%) of 501 whereas it was 129 (34%) of 382 with HDS >15%. In comparison with HDS ≤7%, no statistically significant difference in OR was noticed for 7< HDS <10% or 10< HDS

Table 1: Impact of HDS on early miscarriage in IVF and ICSI combined.

AORa (95% CI)

n

Early miscarriage

OR (95% CI)

p value

HDS <7%

501

147 (29%)

Ref

-

Ref

-

7< HDS <10%

362

106 (29%)

1.00 (0.74-1.34)

0.99

1.06 (0.77-1.47)

0.72

10< HDS <15%

357

108 (30%)

1.05 (0.78-1.41)

0.77

1.04 (0.75-1.44)

0.82

HDS >15%

382

129 (34%)

1.23 (0.92-1.64)

0.16

1.45 (1.05-2.00)

0.022

HDS

p value

Note: AOR = adjusted odds ratio; CI = confidence interval; HDS = high DNA stainability; ICSI = intracytoplasmic sperm injection; IVF = in vitro fertilization; OR = odds ratio; Ref = reference value. a

The AOR was obtained using female age, body mass index, and DNA fragmentation index as covariates. P<0.05 was considered statistically significant.

Jerre. Sperm SCSA HDS and miscarriage risk. Fertil Steril 2019.

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Table 2: Impact of HDS on early miscarriage.

n

Early miscarriage

OR (95% CI)

p value

HDS <15%

1220

361 (30%)

-

HDS >15%

382

129 (34%)

Ref 1.21 (0.95-1.55)

723 109

200 (28%) 29 (27%)

Ref 0.95 (0.60-1.49)

497 273

161 (32%) 100 (37%)

Ref 1.21 (0.89-1.64)

HDS

AOR (95% CI)a

p value

Total ART 0.12

Ref 1.41 (1.07-1.85)

0.014

IVF HDS <15% HDS >15%

0.82

Ref 1.15 (0.70-1.90)

0.58

ICSI HDS <15% HDS >15%

0.24

Ref 1.44 (1.01-2.04)

0.043

Note: AOR = adjusted odds ratio; ART = assisted reproduction technology; CI = confidence interval; HDS = high DNA stainability; ICSI = intracytoplasmic sperm injection; IVF= in vitro fertilization; OR = odds ratio; Ref = reference value. a The AOR was obtained using female age, body mass index, and DNA fragmentation index as covariates. P<.05 was considered statistically significant.

Jerre. Sperm SCSA HDS and miscarriage risk. Fertil Steril 2019.

≤15%. For HDS >15%, compared with HDS ≤15%, the OR was statistically significantly increased (OR 1.41; 95% CI, 1.07–1.85; P<.014), and the miscarriage rates were 361 (30%) of 1,220 and 129 (34%) of 382, respectively. Statistical analysis was performed using IBM SPSS Statistics 25 software (SPSS Inc.). Primarily, using linear regression, the levels of HDS were compared between the groups (+) versus early miscarriage (-). This was done for the entire group as well as for ICSI and IVF, separately.

As a result, this study found that HDS above the level of 15% was associated with an approximately 5% increase in risk of early miscarriage when using ICSI. For IVF patients no such increase was seen. These study findings suggest that HDS can be used as a predictor of an elevated risk of miscarriage in ICSI treatments. SCSA analysis might be an additional tool in deciding the right treatment strategy. High HDS in cases of ICSI pregnancies terminated by early miscarriages might lead to considering standard IVF as alternative option.

Source: : Jerre E, Bungum M, Evenson D et al. Sperm chromatin structure assay high DNA stain ability sperm as a marker of early miscarriage after intracytoplasmic sperm injection. Fertil Steril. 2019;112(1):46-53.e2.

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Combination of Follicle Stimulating Hormone and Human Chorionic Gonadotropin Effective in Improving Pregnancy Rate The success rates of assisted reproduction technology (ART) had extremely became better in the recent years. This improvement is due to the new developments in laboratory techniques along with the enhancement of ovarian stimulation protocols. Follicle-stimulating hormone (FSH) is an important part of the reproductive system, which is responsible for the growth of ovarian follicles. Follicles produce estrogen and progesterone in the ovaries and help maintain the menstrual cycles in women. In men, FSH is a part of the development of the gonads as well as sperm production. The human chorionic gonadotropin (hCG) hormone is produced during pregnancy. It is made by cells formed in the placenta, which nourishes the egg after it has been fertilized and becomes attached to the uterine wall. Several studies have suggested a possible biological role for FSH rising at the time of final oocyte maturation. hCG is a gold standard for triggering final oocyte maturation, mimicking the effects of the natural mid-cycle LH surge. The following study was aimed to investigate the oocyte maturation, fertilization and pregnancy rates among infertile women, by concomitant FSH administration with hCG trigger, compared to hCG trigger alone.

In this prospective randomized Table 1: ART outcome of "FSH+hCG" group versus "hCG only" groups controlled trial performed at Yazd Reproductive Sciences Institute p value hCG only FSH+hCG Variables between August and November of n=45 n=44 2017, 109 infertile women between the ages of 20 and 40 years, received 0.066* 0.84 ± 0.19 0.75 ± 0.26 Oocyte recovery rate gonadotropin-releasing hormone 0.004* 0.87 ± 0.16 0.77 ± 0.19 Oocyte maturity rate (GnRH) antagonist and fresh embryo 0.001* 0.65 ± 0.20 0.51 ± 0.22 Fertilization proportion transfer. Following the procedure, 0.124* 0.75 ± 0.19 0.68 ± 0.25 the subjects were randomly divided Fertilization rate 0.244** 12/84 (14.2) 7/82 (8.5) into two groups on the oocyte- Implantation rate 0.231** 9 (20.5) triggering day. In the experimental Chemical pregnancy rate 14 (32.6) 0.203** 12 (27.9) 7 (15.9) group (54 subjects), final oocyte Clinical pregnancy rate maturation was achieved by 5000 IU Data are presented as mean ± SD and number (%). "FSH+hCG" group versus "hCG only" group hCG plus 450 IU FSH. In the control using *; Mann-Whitney U test, **; Chi-squared test, ART; Assisted reproductive technology, group (55 subjects), however, oocyte FSH; Follicle stimulating hormone, and hCG; Human chorionic gonadotropin. triggering was performed by 5000 IU hCG, only. The primary outcome was clinical pregnancy, defined as the observation of fetal heart activity by transvaginal ultrasound 2-3 weeks after positive β-hCG test and the secondary outcomes included oocyte recovery rate, oocyte maturity rate, fertilization proportion rate, fertilization rate, implantation rate and chemical pregnancy rate. Ovarian hyperstimulation syndrome (OHSS) development was also considered as a secondary outcome.

The Statistical Package for the Social Science version 20 for Windows (SPSS Inc, Chicago. IL, USA) was applied for data analysis. Differences between continuous variables without normal distribution were measured by MannWhitney U test. The Chi-square test was used to compare categorical variables. When compared to hCG alone group, women in the FSH group had a significantly higher metaphase II (MII) oocyte (7.17 ± 3.50 vs. 5.87 ± 3.19), 6

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2 pronuclear embryos (2PNs) (5.44 ± 3.20 vs. 3.74 ± 2.30) and total embryos (4.57 ± 2.82 vs. 3.29 ± 2.13).

Table 2: OHSS occurrence in "FSH+hCG" group versus "hCG only" groups

OHSS occurrence

FSH+hCG n=52

hCG only n=54

p value

Besides, fertilization rate (0.75 ± 0.19 No OHSS 45 (86.5) 46 (85.2) 0.968 vs. 0.68 ± 0.25), implantation rate Mild 5 (9.6) 6 (11.1) (14.2 vs. 8.5%) as well as clinical (27.9 Moderate 2 (3.8) 2 (3.7) vs. 15.9%) and chemical (32.6 vs. Severe --20.5%) pregnancy rates (see Table 1) Data are presented as number (%). "FSH+hCG" group versus "hCG only" group using Chi-squared were higher in the FSH group. test. FSH; Follicle stimulating hormone, hCG; Human chorionic gonadotropin, and OHSS; However there was no statistical Ovarian hyper stimulation syndrome. difference found between the groups (P>0.05). Proportion of mild and moderate OHSS development was similar between the two groups (P>0.05). There was no case of severe OHSS in either group (Table 2). Results showed that co-administration of a bolus dose of FSH and hCG for oocyte triggering improves the number of MII oocytes, 2 PNs, embryos, as well as oocyte maturity rate and fertilization proportion, compared to hCG injection only.

The study summarizes that, FSH given with hCG for oocyte triggering enhances oocyte maturity and fertilization proportion rates without rising the chances of implantation, chemical and clinical pregnancy rates than hCG trigger alone.

Source: Dashti S, Aflatoonian A, Tabibnejad N et al. Comparison of Oocyte Maturation Trigger Using Follicle Stimulating Hormone Plus Human Chorionic Gonadotropin versus hCG Alone in Assisted Reproduction Technology Cycles. Int J Fertil Steril. 2019;13(2):102-107.

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F e Flash DIAGNOSTIC UPDATE The Induction of Acrosome Reaction in Human Spermatozoa

by GlcNAc-Neoglycoproteins Enhances Fertilizing Ability Human spermatozoa undergo sequential changes during capacitation in order to interact with and fertilize the oocyte. Capacitated spermatozoa bind to the zona pellucida in a process mediated by the latter with the consequent aggregation of specific receptors on the sperm membrane and the activation of ion fluxes, mainly calcium. These events trigger the fusion of sperm membranes leading to the Acrosome reaction (AR). Penetration of the zonapellucida then occurs and, finally, the sperm membrane fuses with the oolemma. AR is specifically induced by Neoglycoproteins with N-acetyl glucosamine residues (BSA-GlcNAc) in human spermatozoa. The goal of the following study was to investigate the relationship between this phenomenon and the invitro fertilization (IVF) rate.

In this study, the relationship between the results of the assay and the fertilization rate was studied on semen samples of 31 patients entering our assisted reproduction programme with the purpose of having IVF plus embryo transfer. The relationship between the proposed assay and sperm morphology (n = 30), progressive motility (n = 46), sperm penetration assay (n = 25) was also analyzed. In order to compare acrosome reaction after neoglycoprotein induction for responsive and non-responsive samples, the Mann-Whitney test was applied. Linear discriminant analysis was used to determine the value of the assay as a prognostic index of fertilization outcome.

Sensitivity is defined as the ratio between the number of samples predicted as positive (present assay) to the number of samples actually positive (fertilization). Specificity is the ratio between the number of samples predicted as negative to the number of samples actually negative. Sperm suspensions from IVF protocols were incubated with BSA-GlcNAc (t), using calcium ionophore (i) or medium alone (c) as positive or negative controls. A positive correlation was found (r = 0.46, P < Figure 1: Average fertilization rates of spermatozoa from group of 0.01), when the normalized AR percentage patient responsive to BSA-GlcNAc induction of acrosome reaction ratio (STIM) (% ARt-%ARc):(%ARi-%ARc) was (STIM > 0.2 and non-responsive (STIM < 0.2). Results are the compared with fertilization rate in 31 couples mean ± SEM of 22 and nine samples respectively (*p<0.0003). from our IVF programme. The fertilization rate 100 in patients with STIM > or = 0.2 was higher 80 IVF Rate (%)

than in non-responders (STIM < 0.2); 72 ± 7% compared with 5 ± 3% (Fig 1). The overall predictive value of this test for adequate fertilization rate (>30%) was 87%, sensitivity 91% and specificity 78%. False positives were 9% and false negatives 22%. For successful fertilization rates (>60%), the results were: overall predictive value, 84%; sensitivity 100%; specificity 64% (Table 1). False positives were 23% and no false negatives were found. These results show that this assay can be used to predict sperm fertilizing ability. Analysis of the

60 40 20 0 S < 0.2

S > 0.2

STIM

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distribution of our subject population as a function of their performance in IVF suggested that the use of a cut-off value of STIM = 0.2 as a threshold Table 1: Linear discriminate analysis of fertilization rates versus helped to discriminate between N-acetylglucosamine residues (BSA-GlcNAc)-induced acrosome reaction from 31 in-vitro fertilization (IVF) patients groups with different prognosis in IVF. STIMa The data shown in the present work suggest that binding sites for GlcNAc residues are coupled to the acrosome reaction and might better reflect the presence of functional zona pellucid receptors on spermatozoa. The induction of AR in human spermatozoa by GlcNAcneoglycoproteins could be used to predict their fertilizing ability in vitro.

IVF rate (%)

<0.2

>0.2

Total

<60

9

5

14

>60

0

17

17

9

22

31

<30

7

2

9

>30

2

20

22

9

22

31

Total

Total a

Values are the number of patients with STIM value (percentage of stimulation of the acrosome reaction) lower or higher than the cut-off value of 0.2 and IVF rates above or below the limits indicated (30 or 60%)

Source: Brandelli A, Miranda PV, Añón-Vazquez MG et al. A new predictive test for in-vitro fertilization based on the induction of sperm acrosome reaction by N-acetylglucosamine-neoglycoprotein. Hum Reprod. 1995 Jul;10(7):1751-6.

Answers for TRAZER HUNT: Across: (1) Ventouse (3) Dystocia (7) Puerperal (9) Postpartum (12) Dysmenorrhoea (14) Hemorrhage (15) Prolapse (17) Vault (18) Induction (20) Abruption (21) Menorrhagia (22) Incontinence (23) Distress Down: (2) Ectopic (4) Amenorrhoea (5) Preeclampsia (6) Hysterectomy (8) Laparoscopy (10) Prolapsed (11) Infertility (13) Oophorectomy (16) Caesarean (19) Forceps

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F e Flash ESHRE 2019 ABSTRACTS Bio-Molecular Components in Follicular-Fluid Influence Embryo Development and Pregnancy Outcomes in IVF Cycles The study was aimed to evaluate bio-molecular components in follicular-fluid and assess if they share dynamic correlationships to influence embryo development and pregnancy outcomes in IVF cycles. It has been already known that, the molecular mechanisms controlling endometrial receptivity have remained an enigma because apart from the ovarian steroids estrogen and progesterone, cyclical remodeling of endometrium is also regulated at paracrine level by myriad growth-factors, cytokines and proteases. Hence, no factor has yet univocally been established as a predictive-marker. Study investigators predicted that 'follicle-maturation' is the rate-determining step that sets off a cascade mechanism triggering oocyte-maturation, fertilization, embryo development, implantation, pregnancy. Consequently, investigators of study attempted the holistic approach of profiling representative biomarkers in the follicular-fluid microenvironment to not just obtain thresholds of individual biomarkers but also to assess if they share systematic correlations predictive of pregnancy-outcome.

This prospective study included 1150 (power of study >85%) women (mean age 30.22±4.25 years, BMI 23.97±4.53, W/H ratio 0.88±0.06) undergoing antagonist stimulation protocol with r-FSH for IVF (September 2015-December 2018). On day of ovum pick-up, original aspirate per follicle was pooled per patient. Biomolecules like AMH, E2, DHEAS, IGF-1, PAI-1, G-CSF and GM-CSF were evaluated in pooled FF by radioimmunoassay/ ELISA as applicable, using diagnostic kits. Each protein-biomolecule was expressed as a ratio of total protein content. Elderly women (age >35 years), women with polycystic-ovaries, endometriosis were excluded. Embryo-transfer (ET) was done either at day 3-cleavage stage or day 5 blastocyst stage. Micronized progesterone was provided as luteal-phase support. All cycles were divided into low, high groups to study correlation of each FF-biomarker with individual embryonic parameters. All cycles were later divided into pregnant and non-pregnant groups to study biomarker inter-relations and their correlation with pregnancy. Major outcome measures are clinical pregnancy and live birth rate .

As a result, FF-AMH correlated with oocyte quality; lower-levels increased the odds of top-quality oocytes. FF-PAI1 correlated with oocyte-maturity, lower levels increased the odds of obtaining MII-oocytes. FF-DHEAS correlated with fertilization; higher-levels increased the odds of fertilization. FF-IGF-1 correlated with embryo-quality; higherlevels increased the odds of top-quality embryos. FF-GCSF and FF-GMCSF correlated with embryo quality.

Thresholds of FF-biomarkers for clinical pregnancy/live-births were: FF-AMH (<1.8 ng/mg protein; ROCAUC:85%); FF-PAI-1 (<504.4 ng/mg protein; ROCAUC:76%); FF-DHEAS (>1850ng/ml; ROCAUC:69%); FF-E2 (>160000 pg/ml; ROCAUC:69%); FF-IGF-1 (>60ng/mg protein; ROCAUC:78%). FF-AMH showed strong positive correlation with FFPAI-1 (Pearsonr = 0.66) whereas, these both inversely correlated with FF-E2 (Pearsonr = -0.43; Pearsonr = -0.046) and FF-IGF-1 (Pearsonr = -0.27; ns). FF-DHEAS and FFIGF- 1 shared strong positive correlation with FF-E2 (Pearsonr = 0.43 and Pearsonr = 0.58). FF-IGF-1 directly correlated with FF-GCSF (Pearsonr = 0.31) and FF-GMCSF (Pearsonr = 0.36). FF-AMH and FF-PAI-1 inversely correlated with serum E2 on day 7 (Pearsonr = -0.62; Pearsonr= -0.42) and day 14 (Pearsonr= -0.66; Pearsonr = -0.50) as well as serum progesterone on day 7 (Pearsonr= -0.51; Pearsonr = -0.68) and day 14 (Pearsonr = -0.63; Pearsonr = -0.80) post embryo-transfer. The likelihood of

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live-birth was highest when all biomarkers maintained their algorithmic thresholds; major deviations from threshold values of any parameter increased the odds of no-pregnancy, biochemical pregnancy, early pregnancy loss or miscarriage.

These findings suggests that, follicular-fluid is a metabolite reservoir, a medium for exchange of biologically active components responsible for follicular/oocyte growth, fertilization and embryonic development. Study results recommend that the dynamic interactions (probably initiated by AMH) within this micro-environment set off an algorithmic cascade for embryo-development, further triggering a receptive endometrium conducive for pregnancy. In the summary, evaluated bimolecular components in follicular-fluid correlate with individual embryonic parameters and also interact dynamically to set the algorithm for successful outcomes in IVF cycles.

Source: Chimote N, Chimote B, et al. Mapping the follicular fluid bio-molecular profile: Dynamic interactions set the algorithm for oocyte maturation, embryo development and successful outcomes in IVF cycles. ESHRE 2019, Abstract no O-003.

Image of the Month Isolated tortuosity of proximal descending aorta is a rare form of congenital disorder.

Its association with ductus arteriosus aneurysm (DAA) has not been reported in fetal life. The present article reported the utility of 4-dimensional spatiotemporal image correlation (4D STIC) rendering in diagnosing this rare association in a 23week fetus.

Figure 1: Fetal descending aortic tortuosity with ductal aneurysm

A 26-year-old primigravida was referred for fetal echocardiography in view of suspicion of a retrocardiac vascular channel in midtrimester obstetric scan. It was a singleton pregnancy. Fetal echocardiography showed isolated tortuosity of proximal descending aorta with no other structural anomalies (Figure 1).

Source: Ultrasound Obstet Gynecol. 2019 Jul;54(1):142-144

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Reducing Follicle-Stimulating Hormone Concentration Could Diminish its Detrimental Effect on Oocytes during Human In Vitro Maturation Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland, and regulates the development, growth, pubertal maturation, and reproductive processes of the body. The purpose of this study is to find the optimal concentration of follicle-stimulating hormone (FSH) during human in vitro maturation (IVM) in terms of oocyte maturation rate.

It has been already known that exogenous FSH is generally used for ovarian stimulation in vivo over and above for oocyte maturation in vitro. Nevertheless, there is increasing evidence suggesting that elevated FSH levels can impair oocyte developmental capacity. To our knowledge, no study has defined the optimal FSH concentration for human IVM. Thus, the great number of immature oocytes recovered from the surplus medulla tissue of nonstimulated patients receiving ovarian tissue cryopreservation for fertility preservation will potentially be able to benefit patients and improve reproductive outcome. Additionally, patients that cannot receive ovarian stimulation may also benefit from optimized conditions for human IVM. Immature oocytes were recovered from surplus tissue of 22 patients (age 14- 40 years) who had one ovary excised for fertility preservation by ovarian tissue cryopreservation. Most oocytes derived from follicles with diameters below 3 mm. Immature oocytes with similar diameters and that did not show signs of degeneration, such as darkened cytoplasm, or misshapen zona pellucida, were selected and homogeneously distributed into culture media with different concentrations of FSH. A total of 566 immature oocytes were divided into three categories according to their cumulus mass: cumulus-oocyte complexes (COCs) with large cumulus mass (L-COCs), small cumulus mass (S-COCs) and naked oocytes (N-Oocytes), and then submitted to 48h IVM in the presence of increasing concentrations of recombinant FSH: 20 mIU/mL, 40 mIU/mL, 70 mIU/mL or 250 mIU/mL. Oocyte nuclear maturation and diameter were recorded as outcome parameters.

On average, 26 oocytes were recovered per ovary (range 8-73), being 42% L-COCs (N=239), 39% S-COCs (N=218), and 19% N-Oocytes (N=109). After IVM, mean oocyte diameters were similar (P >0.05) among all treatments (range 113.3-114.1 μm, zonapellucida not included). Including all oocyte categories (L-COCs, S-COCs, and NOocytes), the three treatments with FSH above 20 mIU/mL i.e., 40, 70, and 250 mIU/mL, significantly increased oocyte nuclear maturation (22% MII vs. 35% MII, respectively) (P <0.03). Regardless of the FSH concentration, oocyte maturation increased when increasing cumulus cell mass (18% N-Oocytes, 28% S-COCs, and 35% L-COCs) (P <0.01) and oocyte diameter (P <0.001). Thus, considering only oocytes with cumulus cells (S-COCs and L-COCs) (N=457), there was an increase in oocyte maturation of almost 13% when FSH exceeded 20 mIU/mL (from 24.7% to 37.4% MII) (P <0.03), resulting in an average of 8 MII oocytes per ovary. There were no significant differences in oocyte maturation when FSH concentration increased from 40 to 250 mIU/mL. Findings of study indicates that, similar maturation rates were achieved using 40 mIU/mL FSH to those described in non-stimulated patients with 75 mIU/mL FSH. Reducing FSH concentration could diminish its detrimental effect on oocytes. Using oocytes from small antral follicles (1-5 mm) can improve the fertility preservation of patients by complementing ovarian cortical tissue freezing. In the summary, the FSH concentration can be reduced to 40 mIU/mL without reducing the rate of oocyte maturation.

Source: Cadenas J, Zunigal LA, Ghezelayagh Z, et al. Optimizing follicle-stimulating hormone concentration during human IVM. ESHRE 2019, Abstract no O-011

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F e Flash GUIDELINES The Faculty of Sexual and Reproductive Healthcare (FSRH) Guidelines on Overweight, Obesity and Contraception This new guideline brings together evidence and expert opinion on the provision of contraception to women who are overweight and women with obesity. This guidance is most relevant to women of reproductive age who require contraception and have a body mass index of 25 kg/m2 or higher. The guidance is intended for use by health professionals who provide contraceptive advice or contraceptive supplies for women in community and hospital settings. A new evidence-based clinical guideline by the Faculty of Sexual and Reproductive Healthcare (FSRH) reminds healthcare professionals that there is a wide range of safe and effective contraceptive options for women who are overweight or have obesity.

Familiarity with FSRH guidelines is essential for any healthcare professional providing contraceptive care in the community, primary care and hospital settings. The new guideline reviews the current evidence on how weight impacts on contraceptive effectiveness and safety as well as the effect of contraceptive use on weight. The guideline also considers contraceptive use in relation to medical and surgical approaches to weight loss.

Key recommendations of this new FSRH guideline include: For women with a body mass index (BMI) of 35kg/m2 or greater, the potential health risks associated with use of combined hormonal contraception (the combined pill, patch and vaginal ring) generally outweigh the benefits: Ÿ

The effectiveness of the progestogen-only implant, progestogen-only pill and progestogen-only injectable are not affected by body weight or BMI

Ÿ

The progestogen-only implant is effective for three years of use for women of all weight categories; early replacement of the implant is not necessary

Women with raised weight or BMI do not need a double dose of the progestogen-only pill or more frequent contraceptive injections Progestogen-only implants Ÿ

The etonogestrel (ENG) implant is a highly effective method of contraception; efficacy is not affected by body weight or BMI.

Ÿ

The available evidence suggests that ENG is safe in women who are overweight or obese.

Ÿ

The licensed duration of the ENG implant is 3 years, and is the same for women of all weight categories.

Progestogen-only pill (POP) Ÿ

The available evidence suggests that effectiveness of POP is not affected by body weight or BMI, and that is a safe option for women who are overweight or obese.

Ÿ

Double-dose POP is not recommended for women who are overweight or obese.

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Ÿ

Women should be advised that the effectiveness of oral contraception, including oral emergency contraception, could be reduced during use of weight loss medications and after bariatric surgery; where possible, these should be avoided in favour of non-oral methods of contraception.

Emergency contraception (EC) Ÿ

Oral emergency contraception, particularly levonorgestrel, could be less effective for women who are overweight or have obesity.

Ÿ

The copper IUD is the most effective method of emergency contraception and is not affected by weight or BMI.

Ÿ

Ulipristal acetate EC (UPA-EC) may be less effective in women with BMI >30kg/m2 or weight >85kg.

Ÿ

In women with BMI >26kg/m2 or weight >70kg, consider UPA-EC, or if this is not suitable, double-dose (3mg) LNG-EC. The effectiveness of double-dose LNG-EC is not known.

Ÿ

Double-dose UPA-EC is not recommended for women of any body weight or BMI.

The guideline makes recommendations about effective contraception during use of weight loss medications and after weight loss surgery. FSRH guidance also sets out the current evidence on how the different contraceptive methods affect weight. This summary has been written as a quick reference guide to help busy clinicians give clear, safe advice when providing contraceptive care to women who are overweight (BMI ≥25–29.9 kg/m2) and women with obesity (BMI ≥30 kg/m2).

The guideline and its summary provide information and guidance on: Ÿ

The effect of overweight/obesity on safety and effectiveness of all contraceptive methods

Ÿ

The effect of contraceptive methods on weight for women with raised BMI/bodyweight

Ÿ

Special considerations for use of each contraceptive method by women with obesity

Source: Overweight, Obesity and Contraception. Faculty of Sexual & Reproductive Healthcare. April 2019; www.fsrh.org/documents/fsrh-clinical-guidance-overweight-and-obesity-april-2019.

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F e Flash TRAZER HUNT

1

3

2

4

5 6

7 9

9

10 11 12

13 14 16

15 17

18

19 20

21 22

23

Across 1.

3.

Down

A suction cap applied to the fetus' head during delivery

2.

A pregnancy when an embryo in the Fallopian tube

Where one of the fetus' shoulders becomes stuck during a vaginal birth

4.

Absent menstrual periods

5.

A disease during pregnancy related to maternal hypertension

7.

Sepsis infection of the uterus during or after labor

9.

The period following delivery

12.

Painful menstrual periods

14.

Happens in a number of disorders such as placenta previa

15.

The uterus falls down or slips out of place

11.

Inability to conceive

17.

Expanded region of the vaginal canal at the internal end

13.

Removal of ovaries

18.

A method of artiďŹ cially stimulating labor in women

20.

A placenta disorder where a patient can bleed to death if not managed properly

21.

Heavy menstrual periods

22.

Involuntary leakage of urine

23.

Where the fetus is compromised in the uterine environment

6.

Removal of the uterus

8.

Operation through small incisions with the aid of a camera

10.

Refers to a condition of the umbilical cord that risks of fetal suffocation

16.

A surgical procedure used to delivery a baby

19.

A hand held surgical instrument sometimes used in childbirth

Answers for TRAZER HUNT on page 9

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F e Flash CONFERENCE CALENDER September - November 2019 33rd AICC RCOG Conference Date: 5-7 Sept Place: ITC Royal Bengal, Kolkatta, India Fetal and Women's Imaging 2019: Advanced OB-GYN Ultrasound Date: 6-8 Sept Place: Seattle, Washington, United States AOFOG Reproductive Endocrinology Committee Date: 12-13 Sept Place: Mumbai, Maharashtra, India BIR Events — The BIR Gynaecology imaging update: Part 2 Date: 13 Sept Place: London, United Kingdom Gynecology and Infertility Chronicles Date: 14-15 Sept Place: Mumbai, Maharashtra, India BGGF / OEGGG – Kongress 2019 Date: 12-14 Sept Place: Munich, Germany FOGSI Managing Committee Meeting Date: 21-22 Sept Place: Mumbai, Maharashtra, India International Conference on Neonatology & Perinatology Date: 9-10 Oct2019 Place: Dubai, United Arab Emirates EOGC — The Emirates Obs & Gyne Congress (EOGC) Date: 17-19 Oct 2019 Place: TDubai, United Arab Emirates EMA - FOGSI Congress Date: 17-19 Oct 2019 Place: Dubai East Zone Yuva FOGSI Date: 1-3 Nov 2019 Place: Shillong, Meghalaya, India Survival Skills for Today's Gynecologist 2019 Fall Date: 1-3 Nov 2019 Place: Arlington, Virginia, United States World Conference on Conception to Delivery- C2D2 Date: 23-24 Nov 2019 Place: Mumbai, India

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and submit your quiz answers

Your Thought QUIZ 1. What should you suspect with a measured difference of >4 cm between the calculated gestational age and the fundal height? a) Inaccurate gestational age

b) Multifetal gestation

c) Hydramnios

d) All of the above

Source: CRB, Casanova R, Chuang A, et al. Chapter 13: Multifetal Gestation. Obstetrics and Gynecology. 7th ed. New York, New York: American College of Obstetricians and Gynecologists, and Wolters Kluwer, Lippincott William & Wilkins; 2014:145-149.

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2. The natural course of a tubal ectopic pregnancy, without intervention, will result in a) Tubal abortion

b) Tubal rupture

c) Spontaneous resolution

d) Any of the above

Source: CRB, Casanova R, Chuang A, et al. Chapter 19: Ectopic Pregnancy and Abortion. Obstetrics and Gynecology. 7th ed. New York, New York: American College of Obstetricians and Gynecologists, and Wolters Kluwer, Lippincott William & Wilkins; 2014:179-187.

3. The warning signs for preeclampsia, or toxemia, during pregnancy include all of the following EXCEPT:

a) High blood pressure

b) Swelling that doesn't subside

c) Vaginal spotting

d) Higher than normal amounts of protein in urine

Source: https://www.healthywomen.org/node/6182/take?quizkey=e2732bc68022431e233b939dcae80c1a

4. The use of vasopressin to reduce blood loss is often used in gynecologic surgery procedures including, but not limited to, which of the following? a) Hysterectomy

b)

Myomectomy

d) A and B

e)

All the above

c) Second trimester pregnancy termination

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Source: Robert L. Barbieri, MD , Gynecologists often use vasopressin to reduce surgical blood loss. Far fewer obstetricians use the same drug during difficult cesarean delivery surgery. It is time to close the gap. OBG Manag. 2016 November;28(11):8,10-11

5. Female patients older than 45 may not qualify for fertility preservation with which of the following procedures?

a) Egg/embryo freezing

b) Uterine preservation

c) A and B

Source: “Decision Support in Medicine: Fertility Preservation.” https://www.mdedge.com/obgyn/quiz/4080/reproductiveendocrinology/considerations-fertility-preservation?channel=287

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