Fertility Flash - Issue 6

F e Flash HIGHLIGHTS Endometrial Receptive Array Application in a Case of Repeated Implantation Failure Does the use of Human Growth Hormone in IVF enhance Egg or Embryo Quality and Outcome?

Pregnancy and the Postpartum Afford New Opportunity for Cardiovascular Risk Screening: Impact of the New American Hypertension Guidelines Concurrent use of Small Follicles—Blastocyst transfers may be the Treatment of Choice in Natural Cycle IVF Insulin May Be Toxic to the Placenta in Early Pregnancy International Evidence-Based Guideline for the Assessment and Management of Polycystic Ovary Syndrome 2018 Association between Maternal Body Mass Index and Telomere Function on In vitro Fertilization Outcome Impaired Decidual Trophoblast Invasion in Pregnant Women with PCOS could affect the Serum PAPP-A Concentrations

ISSUE

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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 - 1 Endometrial Receptive Array Application in a Case of Repeated Implantation Failure

CASE REPORT - 2

CONTENTS

PREFACE

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

Does the use of Human Growth Hormone in IVF enhance Egg or Embryo Quality and Outcome?

1 3

EVIDENCE UPDATES Effectiveness and Safety of Blastocyst Derived from Small Follicles (SFs) vs Large Follicles (LFs) in IVF

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Insulin May Be Toxic to the Placenta in Early Pregnancy

IMAGES OF THE MONTH

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GUIDELINE International Evidence-Based Guideline for The Assessment and Management of Polycystic Ovary Syndrome 2018

DIAGNOSTIC UPDATE Association between Maternal Body Mass Index and Telomere Function on In vitro Fertilization Outcome

TRAZER HUNT

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CONFERENCE UPDATE Biochemical Parameters of First-Trimester Screening Test in Pregnant Women with Polycystic Ovary Theme: Ab 01 Maternal Fetal Health/Sub-Theme: Ab 1.1 Prenatal Diagnosis

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CONFERENCE CALENDER

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QUIZ

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F e Flash CASE REPORT - 1 Endometrial Receptive Array Application in a Case of Repeated Implantation Failure Contributed by:

Dr. Chirag Amin MD, DGO, DIP IN ENDO SURG Senior Consultant–Amins Hospitals, Honorary Endoscopic Surgeon in Gynecology Department —Sheth V.S. General Hospital, Consultant Obstetrician at High-risk Pregnancy Unit—Sterling Hospital, A Premier Multi Speciality Hospital, Ahmedabad.

Case Presentation A 36-year-old woman presented to the gynecology department with complaints of severe abdominal pain and heavy bleeding since 4 days. She reported to have been clinically diagnosed with endometriosis 3 years ago.

However, she expressed her wish to conceive a child and was unable to have so owing to her gynecological challenges.

Patient History The patient had severe endometriosis with bilateral chocolate cysts (Figure 1). She had severe dysmenorrhoea & continuous pelvic pain due to recurrent endometriosis. She had also developed multiple uterine fibroids. For endometriosis, she underwent laparoscopic surgery. This was followed by 12 cycles of IVF & repeated embryo transfers which had failed. Her husband was a perfectly fertile male with normal sperm parameters. Prior to receiving IVF cycles, she tried to conceive a child naturally for 4 years.

Management The patient was given proper counseling about a detailed plan for the management of endometriosis as well as the next IVF protocol. Primarily, the pain due to endometriosis was managed by initiation with a GnRh analogue for 4 months. This led to the down-regulation and inhibition of the pituitary-gonadal axis.

Post the 4th month GnRh analog treatment, the patient underwent ovarian hyperstimulation with injectable recombinant FSH. After this, they could retrieve eggs from 6 follicles from which only 2 high quality day 5 embryos developed. Post the retrieval of eggs, a decision was taken to freeze the embryos in separate cryotops. Despite having low progesterone level of 0.3, the doctor with the patients consent decided for an all freeze cycle.

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Figure 1: (A) Ultrasound showing bilateral chocolate cysts. (B) Ultrasound showing uterine fibroids.

A

B

Following the retrieval, the patient underwent endometrial receptivity array (ERA) after 2 cycles since the patient had a history was of repeated implantation failures. An endometrial biopsy was performed HRT cycle in which estradiol valerate started in a dose of 2 mg; this was increased to 6 mg till an appropriate endometrial thickness of 7.8 mm was achieved. The ERA result was post-receptive (p+4.5 receptive) and it was advised to performthe blastocyst transfer 12 hours prior to the scheduled time. Injectable uterine 50 mg daily along with vaginal micronized progesterone 400mg bd was administered as a luteal phase support.

Two weeks after the procedure the patient had a positive urine pregnancy test. Ultrasound scan one week later showed a single intrauterine pregnancy with a gestational sac diameter corresponding to 5 weeks 6 days. The patient had an uneventful pregnancy and she delivered a healthy baby boy through Cesarean section at 36 weeks.

Discussion Repeated implantation failure (RIF) is attributed to several factors such as endometriosis, undetected genetic defects, and various uterine pathologies. In RIF, unindentified abnormalities or a damaged endometrium do not allow even the initial stages of embryo implantation.1 Endometrial receptivity array is a customized microarray which shows the window of inception and when the human endometrium is receptive to blastocyte adhesion. The accuracy and consistency of ERA make it a good diagnostic tool. In IVF techniques, ERA enables a personalized embryo transfer through the identification of WOI. In patients with RIF, ERA can improve the reproductive performance.2 References 1. Timeva T, Shterev A, & Kyurkchiev S. Recurrent implantation failure: The role of the endometrium. Journal of reproduction & infertility.2014; 15(4),173–83.

2. Mahajan N. Endometrial receptivity array: Clinical application. Journal of human reproductive sciences. 2015; 8(3), 121–9.

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F e Flash CASE REPORT - 2 Does the use of Human Growth Hormone in IVF Enhance Egg or Embryo Quality and Outcome?

Contributed by:

Dr. Sweta Agarwal MBBS, MS (Obs & Gyn), FRANZCOG (Australia), Masters–Reproductive Medicine (Australia), Director—Fertility & Gynecology, Southern Gem Hospitals, Hyderabad.

Case Presentation Mrs R.M, 39 year old married lady had presented to our centre with a history of 10 years of primary infertility.

Her menstrual cycles had been regular, with normal flow and no dysmenorrhea.

She had history of hypothyroidism since 3 years and was on regular Thyronorm 25mcg daily.

Prior to consulting us, she had undergone 3 cycle of ovulation induction and IUI. Unfortunately, she didn't conceive. Subsequently, she underwent one cycle of IVF/ICSI, during which she had 16 eggs collected, out of which 5 mature eggs had ICSI, 3 were fertilized and two Day 3 embryos of average quality were transferred.

Unfortunately, she did not get pregnant. She was told that her egg quality was poor.

Following consultation with us, she decided to proceed with preliminary investigations and hysteroscopy.

Her D2 FSH was 3.03mIU/ml, LH was 3.62mIU/ml, Prolactin 21.71ng/ml and TSH was 2.05uIU/ml. Her AMH was 1.03 ng/ml and on ultrasound her AFC was less than 5.

She had hysteroscopy which showed a normal uterine cavity and endometrial biopsy which was negative for hyperplasia, atypia or neoplasia. The real time PCR on gene expert platform was negative for any mycobacterium tuberculosis infection.

Her husband was 38 years old, non-smoker. He took alcohol socially, otherwise healthy. His semen analysis showed sperm count 43 million/ml, 43% total motility and 10% normal morphology.

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In the above case, our assessment was that the underlying cause of subfertility was poor ovarian reserve. She fits into Poseidon criteria, Group 4 with age (> 35 years) with prestimulation parameters of AFC < 5 and AMH < 1.2 ng/ml.

The couple agreed for the proposed option of Human growth hormone (HGH) during IVF cycle, for improvement of egg quality. The stimulation was started with 300 IU recombinant FSH and 150 IU of HMG (Human Menopausal Gonadotropin) on D2 of the cycle along with 6 IU of HGH injection in an antagonist protocol. Following 11 days of controlled ovarian stimulation, she had egg retrieval, where in 3 eggs were collected. Two of the eggs were mature and one was immature. Both mature eggs were fertilized and on Day 3, two grade 1 embryos were obtained. PGS was done which revealed that the embryos were chromosomally normal. These embryos were than frozen.

In the subsequent cycle, she had FET –HRT (frozen embryo transfer) where both the embryos were thawed and transferred. Two weeks later her B-HCG was 377 mIU/ml.

On the six weeks scan, a single live intrauterine

pregnancy was noted.

Discussion Advancing female age is associated with progressive decline in ovarian reserve. This results in age-related decline in oocyte numbers and quality. There is also increase in the percentage of numerical chromosome irregularities (aneuploidy) in these women. ·An individualized protocol for ovarian stimulation, which can optimize the ovarian hormonal environment, can improve the oocyte numbers and quality and thereby reducing the risk of embryo aneuploidy in these women. It is in such cases that the use of human growth hormone (HGH) can play a valuable role. ·Several researchers have shown that the HGH, as an adjunct to controlled ovarian stimulation in IVF cycles, enhances the follicle response and helps in optimizing the oocyte numbers and quality in older women and those with diminished ovarian reserve. ·Two basic mechanisms have been proposed: 1) improving the response to gonadotropin therapy by up-regulating the FSH receptors on the granulosa cells that form the inner lining of follicles and, 2) through a direct enhancing effect of HGH on the egg's mitochondrial activity. ·In my own experience of over 8 years of using HGH, selectively prescribing HGH as an adjuvant to controlled ovarian stimulation in IVF, to women with diminished ovarian reserve, older women and those with unexplained poor oocyte quality deficits, it enhances the oocyte and embryo quality and better IVF outcome.

References 1. The use of human growth hormone (HGH) in poor prognosis patients improves euploidy and implantation rates. a patient-controlled trial. , M. Fernandez et al.

Fertility Sterility September 2015 Vol 104, Issue 3, Supplement 2. Growth hormone in IVF cycles: any hope? Hart, Roger J et al Current Opinion in Obstetrics and Gynecology: June 2017 - Volume 29 - Issue 3 - p 119–125 3. Growth hormone supplementation improves implantation and pregnancy productivity rates for poor-prognosis patients undertaking IVF. John L. Yovich, James D Stanger. July 2010 Vol 21, Issue 1, Pages 37–49 RBM online

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F e Flash EVIDENCE UPDATES Effectiveness and Safety of Blastocyst Derived from Small Follicles (SFs) vs Large Follicles (LFs) in IVF The purpose of this study was to clarify the effectiveness and safety of small follicles (SFs) for use in natural cycle in vitro fertilization (IVF). A retrospective cohort study compared the efficacy and safety of blastocyst transfer derived from small follicles (SF; ≤10 mm) and large follicles (LF; ≥11 mm). A total of 1072 patients aged 30-40 years who underwent blastocyst transfer between January 2012 and December 2014 were enrolled in the study.

For all patients where IVF was indicated as mode of treatment, natural cycle IVF was offered as the initial mode of IVF treatment. Women enrolled in the study reported history of infertility and of them about 30.2% experienced IVF-ET failures. As reported previously, about 292 cycles (128 SF-BTs and 164 LF-BTs) overlapped with the cycles. By reviewing medical records, pregnancy outcomes were assessed. Obstetric and neonatal outcomes were recorded based on a patient-reported outcome questionnaire that was returned by mail.

Using conventional method or intracytoplasmic sperm injection, oocytes retrieved during a modified natural cycle from both LF and SF were fertilized. The blastocysts were frozen, thawed, and transferred one by one in the following spontaneous ovulatory cycles or hormone replacement cycles. Blastocyst transfer (BT) resulted in live births and major congenital anomalies.

A total of 597 SF-derived BTs (SF-BTs) and 650 LF-derived BTs (LF-BTs) were conducted. The germinal vesicle–derived blastocysts were 55 (9.2%) and 2 (0.3%) of SF-BTs and LF-BTs, respectively (see Table 1). SF-BTs (n =597) yielded 55 chemical abortions (9.2%), 73 clinical abortions (12.2%), 261 live births (43.8%), and 263 live babies, including two sets of twin births.

Table 1: Pregnancy outcomes of blastocyst transfers Outcome hCG <10 IU/L Chemical abortion Clinical abortion • Ectopic pregnancy • Artificial abortion Live birthb Live baby No. of twin pregnancies

SF-BT (n=597)

LF-BT (n=650)

P value

Relative risk (95% CI)

No. of ETs

%ET

No. of ETs

%ET

208 55 73 2 0 261 263c 2

34.8 9.2 12.2

195 71 73 1 1a 311 313c 2

30.0 10.9 11.2

0.07 0.32 0.57

1.11 (0.99–1.26) 0.90 (0.73–1.11) 1.09 (0.81–1.48)

47.9

0.14

0.92 (0.82–1.03)

43.8

Note: Values represent the number of patients unless otherwise indicated.

One artificial abortion due to cystic hygroma at 13 weeks of pregnancy. bIncludes twin births. cNumber of babies.

Teramoto. Small follicle–derived blastocyst. Fertil Steril. 2018. a

Except the live birth ratio which was approximately 4% less in SF-BT compared with in LF-BT, the remaining pregnancy outcomes were similar between both the groups. SF-BTs resulted in a 0.09–0.11 higher relative risk of negative hCG (no implantation) ratio and clinical abortion ratio and a 0.08 lower relative risk in the live birth ratio 5

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Table 2: Perinatal outcomes of live birth babies Variable

SF-derived babies (n=263)

LF-derived babies (n=313)

P value

RR (95% CI)

Male-to-female ratio (no. of males)a Duration of pregnancy (wk)b

1.25 (145) 36.5 ± 1.7

1.16 (167) 36.5 ± 2.0

0.67 0.94

1.04 [0.87–1.24]

Body weight (g)b

3,099 ± 466

3,047 ± 455

0.18

49.3 ± 2.4

49.2 ± 2.8

0.45

263 4 (1.5) 5 (1.9)

314d 4 (1.3)d 4 (1.3)

1.00 0.74

Length (cm)b Congenital anomalies (%)c • No. of major anomalies • No. of minor anomalies

1.10 [0.55–2.21] 1.22 [0.68–2.21]

a

Both groups included two pairs of monozygotic twins. The sex of the twin pregnancies was counted once for the male-to-female ratio. bMean+SD. Denominators are the number of live births and pregnancies terminated before 22 weeks. dIncludes one case of artificial abortion at 13 weeks because of fetal cystic hygroma.

Teramoto. Small follicle–derived blastocyst. Fertil Steril. 2018.

c

(see Table 2). This incidences were not statistically different between SF- and LF-derived Bts. The SF- and LF-derived spontaneous abortions reported similar incidence of abnormal karyotypes with no statistical difference (71% [39/55] vs. 72% [40/55], respectively). Both SF-and LF-derived pregnancies reported similar incidence of major congenital anomalies in neonates (1.5% and 1.3%, respectively; relative risk=1.10, 95% confidence interval [0.55-3.21]).

This study indicated that SF-derived blastocysts are as competent as LF-derived blastocysts. The live birth ratio of SF-BT was over 40%, which corresponds to that of LF-BT.

Blasto cysts from SFs ar derived e equ to tho iva se de rived lent LFs w from it achie h respect t ving l o and s ive births afety neona for tes.

Source: Teramoto S, Osada H, Sato Y, et al. Pregnancy and neonatal outcomes of small follicle-derived blastocyst transfer in modified natural cycle in vitro fertilization. Fertil Steril. 2019 Feb 27. pii: S0015-0282(18)32239-8.

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F e Flash

Insulin May Be Toxic to the Placenta in Early Pregnancy Insulin may be toxic to the placenta during early pregnancy, causing DNA damage, decreased cell survival, and apoptosis, but the toxic effects appear to be prevented with metformin, according to findings from an experimental in vitro study published in the Journal “Fertility and Sterility”. Collectively these results demonstrate that insulin itself may be directly toxic to the early human placenta but that metformin can prevent these deleterious effects.

Researchers cultivated trophoblast cells from three healthy women scheduled for manual vacuum aspiration during the first trimester of pregnancy to study the effects of insulin exposure alone, while trophoblast cells were cultured from a different set of women for the insulin and metformin follow-up experiments. The researchers tested each experiment against a control group of cultivated lung fibroblast cells. Insulin was measured in doses of 0.2 nmol, 1 nmol, and 5 nmol, while metformin was measured at 10 micromol. The primary outcome measures examined were gamma-H2AX for DNA damage, cell proliferation assay for cell survival, and cleaved caspase-3 for apoptosis.

Results from the study reported that within 48 hours, the cultures showed DNA damage and induction of apoptosis when exposed to 1 nmol of insulin, but researchers said pretreatment with metformin prevented these effects. Exposing cells to metformin after insulin reduced but did not eliminate the effects of insulin. Culture of purified primary trophoblast cells in the presence of insulin at levels as low as 1 nM resulted in a 386% increase in

Figure 1: Metformin prevents insulin-induced DNA damage, apoptosis, and decreased cell survival in trophoblasts.

(A) Representative immunoblots using antibodies recognizing cleaved caspase-3 protein and g-H2AX in primary human trophoblast cell lines after being treated with vehicle only (lane 1), metformin for 48 hours (lane 2), metformin for 72 hours (lane 3), insulin for 48 hours (lane 4), metformin+insulin for 48 hours (lane 5), or metformin for 24 hours then metformin þ insulin for 48 hours (lane 6). (B) Bar graph showing the percentage decrease in cell survival of primary human trophoblast cells and IMR-90 cells cultured in the presence of metformin for 48 hours (orange), metformin for 72 hours (light blue), insulin for 48 hours (blue), metformin+insulin for 48 hours (blue and orange hatched), or metformin for 24 hours then metformin+insulin for 48 hours (blue and light blue hatched).

A

B Insulin

-

-

-

+

+

+

Metformin

-

+

-

-

+

+

Pretr. Metformin

-

-

+

-

-

+

CI. Caspase-3 g-H2AX GAPDH 1

2

3

4

5

6

Decrease in cell survival (%)

Trophoblast

25

Metformin Pretr. Metformin Insulin Metformin+Insulin Pretr. Metformin+Insulin

20 15 10 5 0 -5 -10 -15

Trophoblast

IMR-90 Cell line

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the number of cell with elevated γ-H2AX expression, a 66% reduction in cell survival and a marked increase of cleaved caspase-3 expression (see Fig. 1). Treatment with insulin and/or metformin had no effects on primary fibroblasts.

Researchers of the study concluded that elevated insulin levels are directly toxic to first trimester trophoblasts and result in increased DNA damage, apoptosis, and decreased cell survival. Trophoblast cells from early pregnancy are uniquely vulnerable to elevated levels of insulin. These findings, if confirmed in vivo, suggest that there may be a role for insulin resistance screening before attempting pregnancy and for focusing on prevention of hyperinsulinemia during early pregnancy.

Source: Vega M, Mauro M, Williams Z. Direct toxicity of insulin on the human placenta and protection by metformin. Fertil Steril. 2019;111(3):489–496.e5.

Images of the month Automated follicle count using three-dimensional ultrasound in polycystic ovarian morphology

Figure 1: Grayscale two-dimensional ultrasound images of right (a) and left (b) ovaries in 24-year-old nulligravida, showing numerous peripheral antral follicles surrounding a rather hyperechoic central ovarian stroma.

Figure 2: Automated follicle counting using Sonography-based Automated Volume Count software in three-dimensional volume of left ovary, depicting 67 antral follicles.

Source: Ultrasound Obstet Gynecol. 2018n;51(1):147–149.

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F e Flash GUIDELINE International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome 2018 PCOS is one of the most common conditions in reproductive aged women affecting 8-13% of reproductive-aged women with up to 70% of affected women remaining undiagnosed

Features of PCOS Psychological Anxiety Depression Ÿ Body image Ÿ

Ÿ

Reproductive

Metabolic

Irregular menstrual cycles Hirsutism Ÿ Infertility Ÿ Pregnancy complications

Insulin resistance Metabolic syndrome Ÿ Prediabetes Ÿ Type 2 diabetes (Dm2) Ÿ Cardiovascular risk factors

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Ÿ

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Definition normal in the first year post menarche as part of the pubertal transition > 1 to < 3 years post menarche: < 21 or > 45 days

Irregular cycles and ovulatory dysfunction

> 3 years post menarche to perimenopause < 21 or > 35 days or < 8 cycles per year

> 1 year post menarche > 90 days for any one cycle

Primary amenorrhea by age 15 or > 3 years post thelarche (breast developmen)

Specific Recommendations of relevance for the diagnosis of PCOS Ultrasound is now not recommended for the diagnosis of those within 8 years of menarche

Young women at risk can be identified, where diagnosis is unclear with follow-up reassessment

Diagnostic features are redefined to limit overlap with those without PCOS to improve diagnostic accuracy

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Recommendations for assessment of PCOS Assessment

Recommendation

Ultrasound and polycystic ovarian morphology

Ultrasound should not be used for the diagnosis of PCOS in those with a gynaecological age of < 8 years (< 8 years after menarche), due to the high incidence of multi-follicular ovaries in this life stage.

Anti-müllerian hormone (AMH)

Serum AMH levels should not yet be used as an alternative for the detection of PCOM or as a single test for the diagnosis of PCOS

Menopause life stage

Postmenopausal persistence of PCOS could be considered likely with continuing evidence of hyperandrogenism

Cardiovascular disease risk (CVD)

All women with PCOS should be assessed for cardiovascular risk factors and global CVD risk

Gestational diabetes, impaired glucose tolerance and type 2 diabetes

Glycaemic status should be assessed at baseline in all women with PCOS. Thereafter, assessment should be every one to three years, influenced by the presence of other diabetes risk factors

Obstructive sleep apnea (OSA)

Screening should only be considered for OSA in PCOS to identify and alleviate related symptoms

Laparoscopic surgery

Laparoscopic ovarian surgery could be second line therapy for women with PCOS, who are clomiphene citrate resistant, with anovulatory infertility and no other infertility factors

Bariatric surgery

Bariatric surgery should be considered an experimental therapy in women with PCOS, for the purpose of having a healthy baby, with risk to benefit ratios currently too uncertain to advocate this as fertility therapy.

In-vitro fertilisation (IVF)

In women with anovulatory PCOS, the use of IVF is effective and when elective single embryo transfer is used multiple pregnancies can be minimised.

Recommendations for management of PCOS Intervention

Recommendation

Non-Pharmacological Measures Behavioural strategies

Lifestyle interventions could include behavioural strategies such as: Goal-setting Self-monitoring Stimulus control Problem solving Assertiveness training Slower eating Reinforcing changes and Relapse prevention to optimise weight management, healthy lifestyle and emotional wellbeing in women with PCOS.

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Dietary intervention

A variety of balanced dietary approaches could be recommended to reduce dietary energy intake and induce weight loss in women with PCOS and overweight and obesity, as per general population recommendations

Exercise intervention

For prevention of weight gain and maintenance of health: In adults from 18 – 64 years, a minimum of 150 min/week of moderate intensity physical activity or 75 min/week of vigorous intensities or an equivalent combination of both, including muscle strengthening activities on 2 non-consecutive days/week Ÿ In adolescents, at least 60 minutes of moderate to vigorous intensity physical activity/day, including those that strengthen muscle and bone at least 3 times weekly Ÿ Activity be performed in at least 10-minute bouts or around 1000 steps, aiming to achieve at least 30 minutes daily on most days. Ÿ

For modest weight-loss, prevention of weight-regain and greater health benefits: A minimum of 250 min/week of moderate intensity activities or 150 min/week of vigorous intensity or an equivalent combination of both, and muscle strengthening activities involving major muscle groups on 2 non-consecutive days/ week Ÿ Minimised sedentary, screen or sitting time Ÿ

Obesity and weight assessment

All those with PCOS should be offered regular monitoring for weight changes and excess weight

Pharmacological treatment for non-fertility indications Pharmacological treatment principles in PCOS

When prescribing pharmacological therapy in PCOS, benefits, adverse effects and contraindications in PCOS and general populations need to be considered and discussed before commencement

Combined oral contraceptive pills (COCPs)

The COCP alone should be recommended in adult women and adolescents with PCOS for management of hyperandrogenism and/or irregular menstrual cycles.

Combined oral contraceptive pills in combination with metformin and/or antiandrogen pharmacological agents

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Metformin

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In combination with the COCP, metformin should be considered in women with PCOS for management of metabolic features where COCP and lifestyle changes do not achieve desired goals In combination with the COCP, metformin could be considered in adolescents with PCOS and BMI ≥25kg/m2 where COCP and lifestyle changes do not achieve desired goals.

In combination with the COCP, metformin may be most beneficial in high metabolic risk groups including those with diabetes risk factors, impaired glucose tolerance or high-risk ethnic groups Metformin in addition to lifestyle, could be recommended in adult women with PCOS, for the treatment of weight, hormonal and metabolic outcomes.

Metformin in addition to lifestyle, should be considered in adult women with PCOS with BMI ≥25kg/m2 for management of weight and metabolic outcomes

Anti-obesity pharmacological agents

Anti-obesity medications in addition to lifestyle, could be considered for the management of obesity in adults with PCOS after lifestyle intervention, as per general population recommendations.

Anti-androgen pharmacological agents

Where COCPs are contraindicated or poorly tolerated, in the presence of other effective forms of contraception, anti-androgens could be considered to treat hirsutism and androgen-related alopecia

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Assessment and treatment of infertility Assessment

Recommendation

Assessment of factors that may affect fertility, treatment response or pregnancy outcomes

Factors such as blood glucose, weight, blood pressure, smoking, alcohol, diet, exercise, sleep and mental, emotional and sexual health need to be optimised in women with PCOS, to improve reproductive and obstetric outcomes, aligned with recommendations in the general population

Ovulation induction principles

Unsuccessful, prolonged use of ovulation induction agents needs to be avoided, due to poor success rates

Letrozole

Letrozole should be considered first line pharmacological treatment for ovulation induction in women with PCOS with anovulatory infertility and no other infertility factors to improve ovulation, pregnancy and live birth rates

Clomiphene citrate and metformin

Clomiphene citrate could be used alone in women with PCOS with anovulatory infertility and no other infertility factors to improve ovulation and pregnancy rates.

Gonadotrophins

Gonadotrophins could be used as second line pharmacological agents in women with PCOS who have failed first line oral ovulation induction therapy and are anovulatory and infertile, with no other infertility factors

Anti-obesity agents

Pharmacological anti-obesity agents should be considered an experimental therapy in women with PCOS for the purpose of improving fertility, with risk to benefit ratios currently too uncertain to advocate this as fertility therapy

Laparoscopic surgery

Laparoscopic ovarian surgery could be second line therapy for women with PCOS, who are clomiphene citrate resistant, with anovulatory infertility and no other infertility factors

Bariatric surgery

Bariatric surgery should be considered an experimental therapy in women with PCOS, for the purpose of having a healthy baby, with risk to benefit ratios currently too uncertain to advocate this as fertility therapy.

In-vitro fertilisation (IVF)

In women with anovulatory PCOS, the use of IVF is effective and when elective single embryo transfer is used multiple pregnancies can be minimised.

Source: https://www.monash.edu/__data/assets/pdf_file/0004/1412644/PCOS_Evidence-Based-Guidelines_20181009.pdf.

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F e Flash DIAGNOSTIC UPDATE Association between Maternal Body Mass Index and Telomere Function on In vitro Fertilization Outcome Telomeres are specific repetitive DNA sequences of TTAGGG that cap and stabilize the ends of chromosomes. They are located at the termini of chromosomes and consist of tandem repeats of the DNA sequence above. During mitotic and meiotic divisions, functional telomeres are essential for the normal segregation and maintenance of chromosomes integrity. The non-interventional prospective cohort study compared the telomere profile of female IVF patients with desirable weight (BMI <25) and overweight women (BMI >25). Besides, the association between telomere profile and the outcome of their IVF treatment was also assessed.

A total of 20 patients were enrolled, according to their BMI, patients were randomized to study group (n=10) with BMI >25 kg/m2 and the control group (n=10) included women with BMI under 25 kg/m2. Outcome measures were defined as number of aspirated oocytes, fertilization rate, embryo quality and pregnancy rate.

Results from the study reported that as expected, BMI and waist circumference were higher in this group.

No pregnancies were recorded in the group with raised BMI though treatment outcome did not differ statistically between the two groups (see Table 1). There was a direct relationship between telomere length and number of oocytes and between telomere length and fertilization rate. Higher embryo quality was observed in patients with increased telomerase activity. For pregnancy outcome, all telomere characteristics tended to fare better for the patients who achieved pregnancy, although with statistical significance only for the q13 test for telomere capture. For all telomere characteristics, there was a distinct trend towards shorter telomeres and activation of telomere shortening compensatory mechanisms in the study group (BMI >25), reaching a statistical significance only in the test for senescence (see Table 2).

Table 1: IVF outcome measures presented by study group (mean ± standard deviation, median or rate %)

Number of oocytes (mean ± SD, median)

BMI £25 (n=10)

BMI >25 (n=10)

p-Value*

6.1 ± 4.3, 4.5

7.1 ± 5.9, 5.5

0.739

Fertilisation (mean ± SD, median)

2.8 ± 1.9, 2.0

1.7 ± 1.8, 1.5

0.19

Quality of embryos (mean ± SD, median)

3.3 ± 0.4, 3.5

3.0 ± 1.0, 3.0

0.713

1.6 ± 0.7

1.1 ± 1.0

0.21

Number of embryos transferred *Mann-Whitney test/Fisher’s Exact test.

Table 2: Telomere function tests presented by study group (percentage)

PNA (% cells with short telomeres) Senescence (% cells in senescence) Telomere capture (% cells with telomere capture, chromosome 13) Telomere capture (% cells with telomere capture, chromosome 15) Telomerase activity (% cells with increased telomerase activity) Aggregates (% patients with aggregates, % of patients with big aggregates >10)

BMI £25 (n=10) 15.8 5.72 10.4 9.44 8.09 66.7, 33.3

BMI >25 (n=10) 16.98 12.52 15.06 13.36 11.44 70, 60

p-Value* 1 0.003 0.325 0.241 0.241 1, 0.37

*p in Fisher’s Exact test.

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Researchers opined that telomere shortening, rather than merely high BMI may provide an explanation for the reduced IVF performance in obese patients.

Further studies are required in order to validate this proposition and to test whether interventions can reverse these observations.

Source: Weeg N, Hershko Klement A, Haikin E, et al. The effect of maternal body mass index (BMI) and telomere function on in vitro fertilization (IVF) outcome: A preliminary cohort study. Hum Fertil (Camb).

2019:1–7.

Telo contr meres i assoc bute to the iation betwe obesi ty and en sub-o pti IVF re mal sults.

TRAZER HUNT Across 1

5.

The combining form “oophor/o-” means __________________________.

7.

The female__________________________ includes the ovaries, uterine tubes, uterus, and vagina.

9.

The combining form “galact/o-” means __________________________.

10.

The combining form “____________________” means “vulva.”

2

4

3 6

5

Down 8

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1.

The second phase of the menstrual cycle is the _________________________ phase.

2.

A surgical procedure that sutures a weakness in the vaginal wall is called a/an _____________.

3.

The outer layer of the uterus is called the __________________________.

4.

The ovaries are held in place by the ________________________ ligament.

6.

__________________________ is the most abundant and biologically active of the female hormones.

8.

The combining form “__________________________” means “seizure.”

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Answers for TRAZER HUNT on page 16

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F e Flash CONFERENCE UPDATE Biochemical Parameters of First-Trimester Screening Test in Pregnant Women with Polycystic Ovary Theme: Ab 01 Maternal Fetal Health/Sub-Theme: Ab 1.1 Prenatal Diagnosis Pregnancies with aneuploid fetuses are screened using biochemical markers the maternal serum levels of pregnancy-associated plasma protein-A (PAPP-A) and free β – human chorionic gonadotropin (β-h CG). The serum concentrations of both molecules are related with decidualization and placentation process. In pregnancies with polycystic ovary syndrome (PCOS), endothelial damage and impaired decidual trophoblast invasion were detected.

In pregnant women with PCOS, significant alterations in serum concentrations of PAPP-A and β-h CG are observed as demonstrated by several studies.

The prospective case-control study was conducted to assess the effect of polycystic ovarian syndrome on the biochemical components of first trimester combined aneuploidy screening test. A total of 489 women with singleton pregnancy in the first trimester (11+0–13+6 weeks) were enrolled at an academic tertiary care center between March 2014 and April 2017. Women enrolled were randomized to two groups, study group which constituted 124 women who met Rotterdam criteria for PCOS before pregnancy and control group with 365 women with proven absence of PCOS. In both groups, the maternal PAPP-A, free β-h CG, and fetal nuchal translucency (NT) were measured and compared.

Results from the study reported that in both groups, the data regarding to baseline characteristics including gestational and maternal age, gravity, parity, maternal weight, and BMI were similar. The multiple median (MOM) Resea rcher levels of serum PAPP-A were significantly decreased so decid ual tr pined that when compared with those of the control group opho impa pregn (ρ=0.02) in pregnant women with PCOS. Between both ant w blast invas ired could omen io PCOS group and the control group, there were no with P n in conce affect the C OS serum ntrati statistically significant differences in terms of the o P n A s. neede PP-A multiple median (MOM) levels of serum free b-h CG d in o Further st u r d d result ies ar er to and NT measurements. s an e con

Source: Ebrahimi M, Taraghi F, Rasekhjahromi A, et al. Fcs022 | Biochemical Parameters of First-Trimester Screening Test In Pregnant Women With Polycystic Ovary Theme: Ab 01 Maternal Fetal Health/ Sub-Theme: Ab 1.1 Prenatal Diagnosis.

da firm o facto ur r that dd PCOS a s a ris chang of bio k es th ch of firs emical com e results tt p aneup rimester co onents loidy mbin e scree ning t d est.

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F e Flash CONFERENCE CALENDER May - July 2019 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

8th International Congress Academy of Clinical Embryologists Date: 19-21 July Place: Chennai, India

Answers for TRAZER HUNT: Across: (5) Ovary (7) Internalgenitalia (9) Milk (10) Episio Down: (1) Proliferative (2) Colporrhaphy (3) Perimetrium (4) Broad (6) Estradiol (8) Eclampso

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Your Thought QUIZ 1. All of the following statements are true about reproduction in obese women EXCEPT: a) Ovulatory dysfunction is common among women with obesity b) Menstrual cycle abnormalities are more common among women with obesity c) Obesity has no influence on fecundity in women with normal menstrual cycles d) Assisted reproductive technology has lower success rates in women who are obese

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Source: OBG Manag. 2017;29(2):18–20, 22–26.

2. What is the critical period for folic acid supplementation in women who are planning or capable of pregnancy? a) Starting at least 2 weeks before conception and in 1st month of pregnancy b) Starting at least 3 weeks before conception and in 1st trimester of the pregnancy c) Starting at least 1 month before conception and in 1st & 2nd trimester of the pregnancy d) Starting at least 1 month before conception and throughout the pregnancy Source: JAMA. 2017;317(2):183–189.

3. In which patients would Day 3 FSH/estradiol testing be appropriate? a) Women with shorter intervals (i.e., 40 days) to their oligomenorrhea b) Women with longer intervals (i.e., months) to their oligomenorrhea c) Women with amenorrhea Source: https://www.ncbi.nlm.nih.gov/books/NBK279144/

4. Which approach is more effective for first-trimester aneuploidy screening of a singleton pregnancy? a) Nuchal translucency measurement alone b) Nuchal translucency measurement and biochemical markers c) None of the above

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Source: Obstet Gynecol. 2016;128:e241-56.

5. Women who are obese and conceive through IVF are at increased risk for: a) Cesarean delivery b) Preeclampsia c) Preterm delivery d) All of the above Source: OBG Manag. 2017;29(2):18-20, 22-26

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