Hospital Reports Europe – Personalised Medicine in Fertility Patients

SPECIAL REPORT

Personalised Medicine in Fertility Patients Personalised Medicine in Fertility What is Personalised Medicine? Fad or Future?

Application to IVF Being Fertile and the Opposite IVF, Safe IVF – What Can Go Wrong?

And How to Prevent or Reduce That Risk The National Institute for Clinical Excellence (NICE) Fertility Guidance and the Future

Published by Global Business Media

Women’s IVF journeys are personal.

Patients can now benefit from evidence-based personalised medicine, with individualised gonadotrophin dosing from the start of the first stimulation cycle.

Rekovelle® allows you to individualise their dose, based on your patient’s AMH level* and weight.

This medicinal product is subject to additional monitoring

*AMH level measured by the diagnostic test from Roche: ELECSYS AMH Plus immunoassay. REK/2621/2017/UK. Date of preparation November 2017.

Rekovelle® is indicated for controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technologies (ART) such as an in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycle.

Prescribing Information: Rekovelle® (follitropin delta) recombinant human folliclestimulating hormone (FSH) 12 micrograms/0.36 ml, 36 micrograms/1.08 ml and 72 micrograms/2.16 ml solution for injection.

Please consult the full Summary of Product Characteristics before prescribing.

Name of Product: Rekovelle solution for injection available in Multidose cartridges containing 12, 36 and 72 micrograms (mcg) follitropin delta. 1ml of solution contains 33.3mcg of follitropin delta (FSH produced in a human cell line (PER.C6) by recombinant DNA technology).

Composition: Rekovelle 12mcg/0.36ml. One cartridge contains 12mcg follitropin delta in 0.36ml solution. Rekovelle 36mcg/1.08ml. One cartridge contains 36mcg follitropin delta in 1.08ml solution. Rekovelle 72 mcg/2.16ml. One cartridge contains 72mcg follitropin delta in 2.16ml solution. Indications: Controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technologies such as an in vitro fertilisation or intracytoplasmic sperm injection cycle.

There is no clinical trial experience with Rekovelle in the long GnRH agonist protocol.

Dosage and administration: Rekovelle is dosed in mcg and is individualised for each patient. For the first treatment cycle, the daily dose is determined on the basis of the woman’s body weight and serum anti-Müllerian hormone (AMH) concentration based on a recent determination of AMH (i.e. within the last 12 months) measured by the Roche ELECSYS AMH Plus immunoassay. The individual daily dose is to be maintained throughout the stimulation period. For women with AMH <15 pmol/L the daily dose is 12mcg, irrespective of body weight. For women with AMH ≥15 pmol/L the daily dose decreases from 0.19 to 0.10mcg/kg by increasing AMH concentration. The maximum daily dose for the first treatment cycle is 12mcg. Treatment should be initiated day 2 or 3 after start of menstrual bleeding and should be continued until adequate follicular development has been achieved followed by 250mcg recombinant human chorionic gonadotropin (hCG) or 5,000 IU hCG. For subsequent treatment cycles, the daily dose of Rekovelle should be maintained or modified according to the patient’s ovarian response in the previous cycle. If the patient had adequate ovarian response in the previous cycle without developing OHSS, the same daily dose should be used. In case of ovarian hypo-response in the previous cycle, the daily dose in the subsequent cycle should be increased by 25% or 50%, according to the extent of response observed. In case of ovarian hyper-response in the previous cycle, the daily dose in the subsequent cycle

should be decreased by 20% or 33%, according to the extent of response observed.

The maximum daily dose is 24mcg. Contraindications: Tumours of the hypothalamus or pituitary gland; ovarian enlargement or ovarian cyst not due to polycystic ovarian syndrome; gynaecological haemorrhages of unknown aetiology; ovarian, uterine or mammary carcinoma; hypersensitivity to the active substance or to any of the active substance. Special Warnings and Precautions: Should only be used by physicians thoroughly familiar with infertility management. The first injection of Rekovelle should be performed under direct medical supervision. Use of results obtained with assays other than the ELECSYS AMH Plus for Rekovelle dose determination is not recommended, as there is currently no standardisation of available AMH assays. Patients undergoing stimulation of follicular growth may experience ovarian enlargement and may be at risk of developing OHSS. Rekovelle has not been studied in patients with moderate/ severe renal or hepatic impairment. Side effects: Common: Headache, nausea, OHSS, pelvic pain, adnexa uterine pain, pelvic discomfort, fatigue. Uncommon: Mood swings, somnolence, dizziness, diarrhoea, vomiting, constipation, abdominal discomfort, vaginal haemorrhage, breast pain, breast tenderness. Presentation: Rekovelle 12mcg/0.36 ml: 3ml multidose cartridge; each cartridge contains 0.36ml of solution.

Pack size of 1 cartridge and 3 injection needles. Rekovelle 36 mcg/1.08 ml: 3 ml Multidose cartridge; each cartridge contains 1.08 ml of solution. Pack size of 1 cartridge and 6 injection needles. Rekovelle 72mcg/2.16 ml: 3ml multidose cartridge; each cartridge contains 2.16ml of solution. Pack size of 1 cartridge and 9 injection needles.

All cartridges to be used with the Rekovelle injection pen. Marketing Authorisation Number: EU/1/16/1150/001–12mcg; EU/1/16/1150/002–36mcg; EU/1/16/1150/003– 72mcg. Marketing Authorisation Holder: Ferring Pharmaceuticals A/S, Kay Fiskers Plads 11, 2300 Copenhagen S, Denmark. Legal category: POM. Basic NHS price: Rekovelle 12mcg/0.36ml £118.31; Rekovelle 36mcg/1.08ml £354.94; Rekovelle 72 mcg/2.16ml £709.89 Date of preparation: May 2017. Rekovelle is a registered trademark. PI Job Code: REK/156/2017/UKa(1) Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard.

Adverse events should also be reported to Ferring Pharmaceuticals Ltd. Tel: 0844 931 0050. Email: medical@ferring.com

SPECIAL REPORT: PERSONALISED MEDICINE IN FERTILITY PATIENTS

SPECIAL REPORT

Personalised Medicine in Fertility Patients Personalised Medicine in Fertility What is Personalised Medicine? Fad or Future?

Application to IVF

Contents

Being Fertile and the Opposite IVF, Safe IVF – What Can Go Wrong?

And How to Prevent or Reduce That Risk The National Institute for Clinical Excellence (NICE) Fertility Guidance and the Future

Foreword

2

Dr Charles Easmon, Editor

Personalised Medicine in Fertility

3

Sesh K Sunkara MBBS, MD, MRCOG, Consultant Gynaecologist and Sub-specialist in Reproductive Medicine, Barking Havering Redbridge University Hospitals, Essex, UK

Published by Global Business Media

Published by Global Business Media Global Business Media Limited 62 The Street Ashtead Surrey KT21 1AT United Kingdom Switchboard: +44 (0)1737 850 939 Fax: +44 (0)1737 851 952 Email: info@globalbusinessmedia.org Website: www.globalbusinessmedia.org Publisher Kevin Bell Business Development Director Marie-Anne Brooks Editor Dr Charles Easmon MBBS MRCP MSc Public Health DTM&H DOccMed Senior Project Manager Steve Banks Advertising Executives Michael McCarthy Abigail Coombes Production Manager Paul Davies For further information visit: www.globalbusinessmedia.org

The opinions and views expressed in the editorial content in this publication are those of the authors alone and do not necessarily represent the views of any organisation with which they may be associated.

Material in advertisements and promotional features may be considered to represent the views of the advertisers and promoters. The views and opinions expressed in this publication do not necessarily express the views of the Publishers or the Editor.

While every care has been taken in the preparation of this publication, neither the Publishers nor the Editor are responsible for such opinions and views or for any inaccuracies in the articles. © 2017. The entire contents of this publication are protected by copyright. Full details are available from the Publishers. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical photocopying, recording or otherwise, without the prior permission of the copyright owner.

Variations in Ovarian Reserve Advances in Ovarian Stimulation Regimes Advances in Reproductive Medicine

What is Personalised Medicine? Fad or Future?

6 Application to IVF Joanna Simpson, Medical Correspondent

Benefits of Personalised Medicine Pharmacogenetics, Genetics and Personalised Medicine Personalised Medicine and IVF Summary

Being Fertile and the Opposite

9

Dr Charles Easmon, Editor

Identifying Problems The 5 Basic Steps of IVF Summary

IVF, Safe IVF – What Can Go Wrong?

11 And How to Prevent or Reduce That Risk

Joanna Simpson, Medical Correspondent

Transformative Technology Get the Timing Right The Range of Physical Problems Not an Unlimited Supply

The National Institute for Clinical Excellence (NICE) Fertility Guidance and the Future

13

Dr Charles Easmon, Editor

The Positive and the Negative Chances for Success (NICE Data ) The Age Cliff Edge and Fertility The General Practitioner and the Woman Considering IVF and NICE Advice The Woman’s Gynaecological Structure The Men The Couple Helping the Woman Understand the Health Issue if it is Hers and not His A Summary of IVF Techniques for Success as Recommended by The Royal College of Obstetricians and Gynaecologists (RCOG)

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SPECIAL REPORT: PERSONALISED MEDICINE IN FERTILITY PATIENTS

Foreword

I

T SEEMS strange and even absurd to us now

egg numbers. Egg numbers need to be boosted

that IVF is less than 50 years old. The parents

as a matter of fact for success, but too many is

of Louise Brown, first IVF child, were sent abusive

harmful to the woman, painful and risks the chance

1

messages by religious zealots who decried the

of successful conception. So the question arises

‘unnatural’ and ‘ungodly’ process required to bring

of how to stimulate eggs enough for success but

her into the world. In today’s days of Twitter and

not too many for problems? Fortunately, we now

Internet trolls3, we can only imagine how unpleasant

have personalised medicine as a solution – tailor

the abuse might have become.

the dosage of stimulation of eggs to the individual

2

Prior to the advent of this technology, women who could not have children for various reason

woman based on her weight and egg reserve, using artificially DNA produced hormone.

was condemned to accept the fact and move on in

When two technologies collide, the world can

despair or acceptance. A lot has changed and we

become a better place. DNA recombinant6 technology

now almost take this amazing technology for granted.

combined with IVF offers an exciting personalised

4

It is a technology that is not always successful and

solution to a significant global fertility problem.

it is a technology that has risks. Some are the risks of normal pregnancy and conception and others are risks specific to IVF’s requirements and processes.

Amongst the risk areas is hyper stimulation of the 5

Dr Charles Easmon Editor

Dr Charlie Easmon, is a medical doctor with 30 years’ experience in the public and private sectors. After qualifying as a physician, he developed his interests in occupational medicine, public health and travel diseases.

References: https://www.biography.com/people/louise-brown-9542072#! Accessed 18/12/17

1

http://bit.ly/2p9YT6y Accessed 18/12/17

2

3

https://nypost.com/2017/02/07/twitter-is-taking-another-crack-at-stopping-internet-trolls/ Accessed 18/12/17

4

http://bit.ly/2DnnAQ9 Accessed 18/12/17

5

http://mayocl.in/2kUX0Fw Accessed 18/12/17

6

https://www.britannica.com/science/recombinant-DNA-technology Accessed 18/12/17

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SPECIAL REPORT: PERSONALISED MEDICINE IN FERTILITY PATIENTS

Personalised Medicine in Fertility Sesh K Sunkara MBBS, MD, MRCOG, Consultant Gynaecologist and Sub-specialist in Reproductive Medicine, Barking Havering Redbridge University Hospitals, Essex, UK

Current fertility practice, more so with in vitro fertilisation (IVF) treatment can be described as a form

T

HE CONCEPT of personalised medicine is not new, dating to the time of Hippocrates.

The notion however has gained increased application in recent years with scientific breakthroughs in the understanding of disease processes and approaches to precision treatments. Personalised medicine has also extended into infertility management.

One widespread practice is the application of prediction models for the treatment of anovulatory infertility and polycystic ovary syndrome (Imani et al., 1998). Current fertility practice, more so with in vitro fertilisation (IVF) treatment can be described as a form of stratified medicine, whereby treatments are matched to specific patient population characteristics using clinical biomarkers.

There is a constant endeavour by clinicians, embryologists and scientists to provide tailored or individualised IVF treatments with the goal of maximising success rates and safety. For ease of application, modalities towards personalised IVF can be considered along the events of the treatment pathway starting with (1) pre-treatment prediction models, (2) individualised controlled ovarian stimulation (iCOS) regimens, (3) advanced technologies for selecting embryos with the

of stratified medicine, best implantation potential and (4) the ideal luteal phase support.

Variations in Ovarian Reserve Several prediction models have already been developed for IVF treatments (Leushuis et al., 2009). These models use clinical characteristics, medical history such as age, body mass index (BMI), duration of subfertility, type, cause of subfertility and biomarkers of ovarian reserve.

The human ovary contains a fixed number of non-growing follicles (the ovarian reserve) established before birth that declines with increasing age until the menopause when the follicle pool is completely depleted (Wallace and Kelsey 2010). However, ovarian reserve at birth can vary substantially between women based on individual biology, which consequently influences the rate of depletion and ovarian reserve of individual women. Dynamic biomarkers, such as anti-mullerian hormone (AMH) and antral follicle count (AFC) can be used to accurately evaluate ovarian reserve, made possible by the fact that AMH is produced by granulosa cells in pre-antral and antral follicles which reflects the primordial follicle pool (Karkanaki et al., 2011). Anti-mullerian hormone and AFC are the most sensitive ovarian reserve tests (ORTs)

whereby treatments are matched to specific patient population characteristics using clinical biomarkers

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SPECIAL REPORT: PERSONALISED MEDICINE IN FERTILITY PATIENTS

There is a constant endeavour by clinicians, embryologists and scientists to providing tailored or individualised IVF treatments with the goal of maximising success rates and safety

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for the prediction of response following ovarian stimulation (Broer at al., 2013a, Broer at al., 2013b).

Advances in Ovarian Stimulation Regimes Controlled ovarian stimulation regimens have undergone significant developments involving evolution of gonadotrophins from human-derived compounds to highly purified and recombinant products, development of several pituitary suppression regimens using either GnRH agonists or GnRH antagonists, use of different approaches to oocyte maturation and triggering, such as hCG or GnRH agonist administration. While these advances have improved the efficiency of ART, the rapid progress in our understanding of clinical biomarkers of ovarian reserve means that there is a renewed focus on personalised care in reproductive health, particularly with respect to individualising gonadotrophin dosage (La Marca and Sunkara 2014). There has also been a significant reduction in the risk of ovarian hyperstimulation syndrome (OHSS) with iCOS by avoiding very high gonadotrophin doses, use of GnRH antagonist regimen and GnRH agonist trigger for oocyte maturation. Validated

models have been developed incorporating clinical characteristics and ovarian reserve biomarkers to individualise gonadotrophin doses demonstrating clinical benefit (Allegra et al., 2017). A further extension has been innovative models incorporating AMH as a companion diagnostic along with body weight to derive the ideal personalised gonadotrophin dosing (Andersen et al., 2016). The aim of such tested models is a move towards precision treatments to ultimately increase the efficacy and safety of ART. Advances in Reproductive Medicine Although personalisation in ART has been heavily focussed with COS regimens, it has extended beyond COS to laboratory procedures such as use of morphokinetics, preimplantation genetic screening (PGS) for embryo selection and personalised embryo transfer with use of endometrial receptivity array (ERA) based on gene expression. Furthermore, improvements in cryopreservation techniques such as vitrification has made possible the notion of cycle segmentation in IVF. Reproductive Medicine, particularly ART is a dynamic field with fast moving innovations. However, all such should be evaluated with robust clinical trials before routine clinical application.

SPECIAL REPORT: PERSONALISED MEDICINE IN FERTILITY PATIENTS

References: Allegra A, Marino A, Volpes A, Coffaro F, Scaglione P, Gullo S, La Marca A. A randomized controlled trial investigating the use of a predictive nomogram for the selection of the FSH starting dose in IVF/ ICSI cycles. Reprod Biomed Online. 2017 Apr;34(4):429-438.

Broer SL, van Disseldorp J, Broeze KA, Dolleman M, Opmeer BC, Bossuyt P, Eijkemans MJ, Mol BW, Broekmans FJ; IMPORT study group. Added value of ovarian reserve testing on patient characteristics in the prediction of ovarian response and ongoing pregnancy: an individual patient data approach. Hum Reprod Update. 2013 Jan-Feb;19(1):26-36.

Broer SL, Dólleman M, van Disseldorp J, Broeze KA, Opmeer BC, Bossuyt PM, Eijkemans MJ, Mol BW, Broekmans FJ; IPD-EXPORT Study Group. Prediction of an excessive response in in vitro fertilization from patient characteristics and ovarian reserve tests and comparison in subgroups: an individual patient data meta-analysis. Fertil Steril. 2013 Aug;100(2):420-9.

Devroey P, Polyzos NP, Blockeel C. An OHSS-Free Clinic by segmentation of IVF treatment. Hum Reprod. 2011 Oct;26(10):2593-7.

Imani B, Eijkemans MJ, te Velde ER, Habbema JD, Fauser BC. Predictors of patients remaining anovulatory during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J Clin Endocrinol Metab. 1998 Jul;83(7):2361-5.

Improvements in cryopreservation techniques such as vitrification has made possible the notion of cycle segmentation in IVF

Karkanaki A, Vosnakis C, Panidis D. The clinical significance of anti-Müllerian hormone evaluation in gynecological endocrinology. Hormones (Athens). 2011 Apr-Jun;10(2):95-103.

La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Hum Reprod Update. 2014 Jan-Feb;20(1):124-40.

Leushuis E, van der Steeg JW, Steures P, Bossuyt PM, Eijkemans MJ, van der Veen F, Mol BW, Hompes PG. Prediction models in reproductive medicine: a critical appraisal. Hum Reprod Update.

2009 Sep-Oct;15(5):537-52.

Nyboe Andersen A, Nelson SM, Fauser BC, García-Velasco JA, Klein BM, Arce JC; ESTHER-1 study group. Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial. Fertil Steril. 2017 Feb;107(2):387-396.

Wallace WH, Kelsey TW. Human ovarian reserve from conception to the menopause. PLoS One. 2010 Jan 27;5(1):e8772.

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SPECIAL REPORT: PERSONALISED MEDICINE IN FERTILITY PATIENTS

What is Personalised Medicine? Fad or Future?

Application to IVF Joanna Simpson, Medical Correspondent

Most medical treatments are designed for the “average patient” as a “one-size-fits-all-approach,” which may be successful for some patients but not for others. Precision medicine, sometimes known as “personalized medicine” is an innovative approach to tailoring disease prevention and treatment that takes into account differences in people’s genes, environments, and lifestyles. The goal of precision medicine is to target the right treatments to the right patients at the right time1.

Most clinical trials are done on healthy young men, but the evidence from this is then extrapolated to the old, the obese, women and, in more rare cases, children

I

N HIS excellent book ‘Sapiens: A Brief History of Humankind2’ author and academic Yuval Noah Harari excellently summarises 10,000 years of our existence. In his follow up book “Homo Deus: A Brief History of Tomorrow 3’ he explains that, compared to mankind of thousands of years ago, we have achieved the power of their mythical gods via satellites, computers, mobile communication, air and land transport as well as weather forecasting and manipulation. One area that we have advanced hugely in is that of personalised medicine.

Poison is in everything, and no thing is without poison. The dosage makes it either a poison or a remedy4. Paracelsus

Benefits of Personalised Medicine We are all unique and even identical twins are different despite exactly the same genetic code.

Historically, therapeutic regimes in the West (at least) have developed around a homogenisation of what must be good for the average, but this can lead to obvious distortions. Most clinical trials are done on healthy young men5, but the evidence from this is then extrapolated to the old, the obese, women and, in more rare cases, children. Clearly there is room for error and, as Paracelsus6 warned us, all medicine is poison depending on the dose administered.

So, if we could tailor medicine like a Saville Row suit to the individual, we would clearly get a better fit and lower the risks of complications.

Enter personalised medicine to the Western 6 |WWW.HOSPITALREPORTS.EU

cannon (it can be argued that those in the East and some alternative practitioners have been doing this for aeons).

Advocates claim amongst the following benefits for personalised medicine: • Shifting the emphasis in medicine from reaction to prevention • Directing targeted therapy and reducing trialand-error prescribing • Reducing adverse drug reactions • R evealing additional targeted uses for medicines and drug candidates • Increasing patient adherence to treatment • Reducing high-risk invasive testing procedures • Helping control the overall cost of health care7 In cancer, personalised medicine has gained a strong foothold. Examples include the use of Herceptin8, testing for BRCA1/BRCA2 9 genes and other tests that indicate either likelihood of chemotherapy response or even disease recurrence.

Pharmacogenetics, Genetics and Personalised Medicine Pharmacogenomics is the study of how genes affect a person’s response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person’s genetic makeup10.

Genetic tests remain expensive but like computing and Moore’s11 law these costs are reducing rapidly and allow now and in the future for individual risk assessments and preventative approaches to disease.

SPECIAL REPORT: PERSONALISED MEDICINE IN FERTILITY PATIENTS

Techniques such as whole Exome (the part of the genome consisting of exons that code information for protein synthesis12) sequencing can now be done in association with prestigious US institutions such as Yale and UCLA on just a sample of saliva.

As many as 22,000 genes can be tested, including all known cancer risk genes and every single genetic disorder (e.g.: Ophthalmological, cardiovascular, neurological, etc.).

Cardiovascular/Heart disorders covered include: Cardiomyopathies (34 genes) Cardiac arrhythmias (21 genes), Atrial fibrillation (13 genes), Hyperlipidemias (5 genes), Aortic Aneurysms (22 genes) Ophthalmological disorders covered include: Cataracts (65 genes), Hereditary Optical Atrophy (7 genes), Ectopia lentis (10 genes), Microphthalmia/Coloboma spectrum (57 genes), Ocular albinism (9 genes), Stickler syndrome/myopia (11 genes), Anterior chamber dysgenesis (14 genes).

Other syndromes covered include: Marfan syndrome, Intellectual disability, Seizures, heritable connective tissue disorders, cancer predisposition syndromes, short stature, hearing deficit, Ataxias, and other neurological disorders

Personalised Medicine and IVF In IVF, just 2 personalised parameters are needed to improve the chances of safe fertility.

Under dosing leads to Normally, a woman produces one egg per month. Some women who have trouble getting pregnant may be given medicines to help them produce and release eggs13.

inadequate stimulation

The first is the basic quantity and readiness of the eggs that the woman has, and this is measured by a proxy measure, which is the level of Anti Mullerian Hormone (AMH). The second is the woman’s weight (not her Body Mass Index).

Why the personalised medicine approach in IVF matters is that under dosing and over dosing of egg stimulation both cause significant problems and costs.

Under dosing leads to inadequate stimulation of enough eggs and reduces the chance of fertilisation and hence conception and, considering the extensive costs of IVF, this is a significant personal, emotional and financial cost to the individual and to society.

Over dosing can lead to Ovarian Hyper Stimulation Syndrome (OHSS). Crudely, for the males in the readership, this would be like being given a hefty kick to both testicles such that swelling and pain soon become prominent features. Women with this condition are in severe pain and may need hospitalbased morphine. Their ovaries can swell up to ten times normal size and there is a pressure effect that adds to the pain. Symptoms can include ‘rapid weight gain, abdominal pain, vomiting and shortness of breath14’. The pain has to be resolved and leads to the loss of eggs and defeats the whole purpose of the egg stimulation process.

of fertilisation and

of enough eggs and reduces the chance hence conception

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SPECIAL REPORT: PERSONALISED MEDICINE IN FERTILITY PATIENTS

To understand OHSS and its management, one must first be aware of its various grades of severity, (1) mild OHSS, (2) moderate OHSS, and (3) severe OHSS. Mild OHSS is classified as follows: •G rade 1 Abdominal distension and discomfort • Grade 2 Grade 1 disease plus nausea, vomiting, and/or diarrhoea, as well as ovarian enlargement of 5-12 cm Moderate OHSS is classified as follows: •G rade 3 Features of mild OHSS plus ultrasonographic evidence of ascites Severe OHSS is classified as follows: •G rade 4 Features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax and breathing difficulties •G rade 5 All of the above plus a change in the blood volume, increased blood viscosity due to hemoconcentration, coagulation abnormalities, and diminished renal perfusion and function15

Personalised medicine as applied to IVF is not a fad. It is present, available, NICE

Summary Technological advances have helped us to help women to conceive using science. They now also help us reduce the side effects of this science and increase the chances of a successful outcome. Personalised medicine as applied to IVF is not a fad. It is present, available, NICE recommended16 and the future of a new generation of successful conceptions.

recommended and the future of a new generation of successful conceptions

References: https://www.fda.gov/ScienceResearch/SpecialTopics/PrecisionMedicine/default.htm Accessed 7/12/17

1

http://amzn.to/2BZRa0m Accessed 11/12/17

2

http://amzn.to/2BROsrn Accessed 11/12/17

3

http://www.azquotes.com/quote/224598 Accessed 11/12/17

4

http://www.bu.edu/today/2014/why-medical-research-often-ignores-women/ Accessed 11/12/17

5

https://www.britannica.com/biography/Paracelsus Accessed 11/12/17

6

http://www.personalizedmedicinecoalition.org/Resources Accessed 7/12/17

7

http://www.breastcancer.org/treatment/targeted_therapies/herceptin Accessed 11/12/17

8

https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet Accessed 11/12/17

9

https://ghr.nlm.nih.gov/primer/genomicresearch/pharmacogenomics Accessed 11/12/17

10

https://computer.howstuffworks.com/moores-law.htm Accessed 11/12/17

11

https://www.merriam-webster.com/dictionary/exome Accessed 11/12/17

12

https://medlineplus.gov/ency/article/007294.htm Accessed 8/12/17

13

http://mayocl.in/2kUX0Fw Accessed 8/12/17

14

https://emedicine.medscape.com/article/1343572-overview Accessed 8/12/17

15 16

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https://bnf.nice.org.uk/drug/follitropin-delta.html Accessed 11/12/17

SPECIAL REPORT: PERSONALISED MEDICINE IN FERTILITY PATIENTS

Being Fertile and the Opposite Dr Charles Easmon, Editor

I

N VITRO Fertilisation (IVF) costs the taxpayer at least £400 million per year1 – a small fraction of the more than £ 120 billion2 NHS England budget. Some debate whether this should be a private fee matter rather than an NHS funded activity and, even though it is NHS funded, the geographic distribution leads to a postcode lottery3, and some complain about the variation in costs across the United Kingdom4.

How did the technology, first successfully used in 19785, get us to this point and why?

Human eggs are a limited supply in each woman. Some are born with more and some are born with less, but no woman is born with an infinite supply. Every ‘period’ sheds more of the limited supply and after the age of 40 many women have no more eggs left for fertilisation.

Eggs are not in an immediate state to be fertilised since, for that, they need specific types of hormonal stimulation. But once they have this, they can then be fertilised and, if nothing goes wrong, a human embryo can result.

Identifying Problems The frustration for those who cannot conceive is to have to go through the various investigative processes to identify where the problem might lie. If the problem is with the male, specific techniques are required to achieve successful fertilisation. In this series of articles, we focus on the woman. The pathology pathway in terms of infertility can be summed up as to whether the issue is: • A total lack of eggs • A relative lack of eggs • Eggs present but not in a fertilisable state • Other factors affecting egg viability such as age and weight If eggs can be found, can they be harvested and preserved pre-fertilisation by whatever means works?

Fertility is associated with spring, new growth, new plant shoots and seasonal change. Human fertility has huge symbolic, cultural and existential meaning - without it you would not be reading this article. Historically women have been valued based on their ability to reproduce and many women take that basic ability as part of what defines them as women. So, a woman

who cannot conceive suffers at psychological, spiritual and sometimes physical levels. The question ‘why me?’ is often asked by those who cannot conceive. Those who have left the attempt at conception until after the age of 40 have a more obvious answer. However, the urge to have children can be so great that we have seen women conceive in their 60s and 70s6,7.

These are exceptional cases and have usually ocurred outside most regulatory and health and safety advice. Much more common are those who seek assisted conception. The private treatment market is part fuelled by what the NHS is, or is not, prepared to pay for in terms of cycles and women’s’ ages.

The 5 Basic Steps of IVF Step 1: More than one egg is required because not all eggs will develop or fertilise after retrieval. In this step, specific fertility medications are prescribed to stimulate multiple eggs. The hormone levels are checked by blood tests and transvaginal ultrasound ‘visualises’ the ovaries.

The frustration for those who cannot conceive is to have to go through the various investigative processes to identify where the problem might lie

Step 2: An ultrasound guided hollow needle is used to retrieve the eggs through the pelvic cavity.

To reduce and/or remove the pain/discomfort, medication is required.

Step 3: The male’s part is to produce the sample of sperm, which is then prepared for combining with the eggs.

Step 4: The sperm and eggs are mixed together (in a process called insemination), and stored in the relevant media to encourage fertilisation. The eggs need to be monitored to confirm that fertilisation and mitosis (cell division) are taking place. Dividing fertilised eggs are the embryos.

Step 5: 3-5 days after the egg retrieval and fertilisation process the embryos are usually transferred into the woman’s uterus.

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SPECIAL REPORT: PERSONALISED MEDICINE IN FERTILITY PATIENTS

Human eggs are a limited supply in each woman. Some are born with more and some are born with less, but no woman is born with an infinite supply

With a successful procedure, implantation typically occurs around 6-10 days following egg retrieval.

After more than 35 years, IVF techniques for success8 are now known. The key factors are as follows: 1. R educe premature surges of Luteinising Hormone 2. C ontrol ovarian stimulation (not too much and not too little) 3. Trigger ovulation 4. Retrieve eggs 5. Use ultrasound-guided embryo transfer 6. E valuate embryo quality, at both cleavage and blastocyst stages9, 7. O ffer women progesterone for luteal phase support after IVF

Summary IVF is here to stay. Its funding will remain a matter of controversy and many will have no choice but to use private options. Age is a key factor for success, but the advance of personalised medicine also allows better dosing of egg stimulation.

References: http://www.dailymail.co.uk/health/article-193870/Can-NHS-afford-400m-IVF-bill.html Accessed 11/12/17

1

2

https://www.kingsfund.org.uk/projects/nhs-in-a-nutshell/nhs-budget Accessed 11/12/17 https://www.nice.org.uk/news/article/nice-calls-for-an-end-to-postcode-lottery-of-ivf-treatment Accessed 11/12/17

3

https://www.theguardian.com/lifeandstyle/2014/feb/21/robert-winston-ivf-questions-reproductive-health Accessed 11/12/17

4

5 6

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http://bit.ly/2p9YT6y Accessed 11/12/17

http://www.telegraph.co.uk/news/2016/05/10/indian-woman-gives-birth-at-70-with-help-of-ivf/ Accessed 11/12/17

7

http://bit.ly/2ByCkhT Accessed 11/12/17

8

https://www.nice.org.uk/guidance/cg156/evidence/full-guideline-188539453 Accessed 11/12/17

9

https://www.embryologists.org.uk/ Accessed 11/12/17

SPECIAL REPORT: PERSONALISED MEDICINE IN FERTILITY PATIENTS

IVF, Safe IVF – What Can Go Wrong? And How to Prevent or Reduce That Risk Joanna Simpson, Medical Correspondent

P

ROBL EMS OCCUR with natural conception from tubal pregnancy, eclampsia, pre- eclampsia, gestational diabetes, miscarriage, still birth and more. All of these can occur with in vitro fertilisation (IVF).

Transformative Technology IVF was pioneered in the UK. Oldham in 1978 was the place and date of birth of Louise Brown1, the first baby in the world born outside her mother’s womb. Since the initial work by Patrick Steptoe and Robert Edwards, the number of IVF conceptions has exceeded 5 million2.

IVF as fertility treatment involves an egg being fertilised with sperm in a laboratory process outside of the womb. The embryo (the fertilised egg) is then returned to the womb so that it can grow as in a normal pregnancy.

On the male side, IVF may be needed because the man has a low sperm count, antibodies harming the sperm or something unexplained.

On the female side IVF may be needed because of endometriosis, problems with the uterus of fallopian tubes, problems with ovulation, antibodies that harms eggs, or the sperm may be unable to penetrate or survive in the cervical mucus.

The hormones in IVF are needed to improve the mathematical probability of conception. Normally a woman produces one egg per month, but with hormones she will produce multiple eggs in each month.

Further medication is required to ‘ripen’ the developing eggs before they are retrieved.

Get the Timing Right Timing is a key skill in IVF since the eggs must be retrieved just before they emerge from follicles in the ovaries. Too early and too late are both bad timing since the egg development will not be normal.

Blood tests and ultrasound are used in IVF as the progress monitoring tools to make sure the eggs are at the right stage of development before retrieval.

Retrieval can be painful and, for this reason, the night before the procedure and the day of the procedure pain medication and/or sedation anaesthesia may be required.

Individuals can be affected physically, emotionally, socially and financially. Family, friends, relationships and work can all suffer. Feelings of depression, sadness, frustration, anger, helplessness and isolation are all common3.

Problems specific to IVF include the physical and the psychological. The psychological problems are substantial in that the couple are under enormous pressure in their attempt to have a successful conception whilst being regularly reviewed, tested, given medication and, in some cases, expected to have sexual intercourse within a prescribed frame of time.

The National Institute for Clinical Excellence (NICE) emphasises the importance of stress and psychological issues within IVF and recommends that early and continuing counselling be offered to both couples.

Normally a woman produces one egg per month, but with hormones she will produce multiple eggs in each month

When couples have fertility problems, both partners should be informed that stress in the male and/or female partner can affect the couple’s relationship and is likely to reduce libido and frequency of intercourse, which can contribute to the fertility problems.

People who experience fertility problems should be informed that they may find it helpful to contact a fertility support group.

People who experience fertility problems should be offered counselling because fertility problems themselves, and the investigation and treatment of fertility problems, can cause psychological stress.

Counselling should be offered before, during and after investigation and treatment, irrespective of the outcome of these procedures.

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Counselling should be provided by someone who is not directly involved in the management of the individual’s and/or couple’s fertility problems4.

The risk of miscarriages (15-25%), birth defects and ectopic pregnancies (2-5%)6 is estimated to be about the same as for non IVF pregnancies and, for both situations, increasing maternal age plays a role.

Can personalised medicine reduce the risk of OHSS (and any other associated risks)?

The simpler answer is – YES it can.

Not an Unlimited Supply

The Range of Physical Problems

The National Institute for Clinical Excellence (NICE) emphasises the importance of stress and psychological issues within IVF and recommends that early and continuing counselling be offered to both couples

The most significant problem in terms of risk to the woman and future pregnancy is Ovarian hyperstimulation syndrome5 (OHSS), which can include nausea, vomiting, decreased urinary frequency, shortness of breath, faintness, severe stomach pains, bloating and a 4-5 kilogram weight gain within three to five days.

Other effects after IVF can include, passing a small amount of fluid (may be clear or bloodtinged), mild cramping, mild bloating, constipation and breast tenderness.

Effects that require medical advice or intervention are those such as heavy vaginal bleeding, pelvic pain, blood in the urine or a fever over 38 °C. Some acknowledged side effects of fertility medications include headaches, mood swings, abdominal pain, hot flushes and abdominal bloating. Additional risks of IVF during cycles include bleeding, infection, and damage to the bowel or bladder during egg retrieval. Multiple pregnancies should be avoided to prevent or reduce the risk of premature delivery and/or low birth rate.

The ovarian reserve is a term that describes the fixed number of non-growing follicles that the ovaries contain from birth and this declines with ageing until the complete depletion post menopause. Human biology and variation is such that different women have different reserves to start with and, for successful IVF, this needs to be assessed as best as possible.

Anti-mullerian hormone (AMH) is one of two substances that can be used to assess accurately ovarian reserve. AMH is produced via granulosa cells in pre-antral and antral follicles and it is a sensitive ovarian reserve test (ORT).

Follicle stimulating hormone (FSH) is like the product sold for wood staining – it does what is says on the tin. However, technology has been needed to produce enough of it for IVF use.

The hormone is now produced by recombinant DNA7 – this is known as rFSH. The personalised element has come from regulator approved tests that show the dosing can be correctly managed to stimulate and NOT overstimulate follicles based on two elements of personal data 1) the weight of the individual and 2) the AMH levels of the individual.

Personalised medicine reduces the risk of multiple births and hence early labour and low birth weight.

References: 1

2

http://www.dailymail.co.uk/news/article-2515585/Louise-Brown-Worlds-test-tube-baby-paysemotional-tribute-parents.html Accessed 11/12/17 https://www.theguardian.com/society/2013/jul/12/story-ivf-five-million-babies Accessed 18/12/17

http://fertilitynetworkuk.org/for-those-trying-to-become-parents/ Accessed 9/12/17

3 4

http://bit.ly/2kEiFmh Accessed 18/12/17

https://www.rcog.org.uk/globalassets/documents/guidelines/green-top-guidelines/gtg_5_ohss.pdf Accessed 18/12/17

5

https://www.mayoclinic.org/tests-procedures/in-vitro-fertilization/about/pac-20384716 Accessed 18/12/17

6

https://rpi.edu/dept/chem-eng/Biotech-Environ/Projects00/rdna/rdna.html Accessed 15/12/17

7

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SPECIAL REPORT: PERSONALISED MEDICINE IN FERTILITY PATIENTS

The National Institute for Clinical Excellence (NICE) Fertility Guidance and the Future Dr Charles Easmon, Editor

Healthcare professionals should define infertility in practice as the period of time people have been trying to conceive without success after which formal investigation is justified and possible treatment implemented.

A woman of reproductive age, who has not conceived after 1 year of unprotected vaginal sexual intercourse, in the absence of any known cause of infertility, should be offered further clinical assessment and

The chances for IVF

investigation along with her partner.1

conception are not as

T

HE NATIONAL Institute for Clinical Excellence (NICE) provides excellent advice and recommendations with regard to In Vitro Fertilisation (IVF). IVF is an assisted reproductive technology2 (ART). The advice is about the man and the woman, their relationship, their interactions with medical professionals and what is evidence based and should be done and what is not evidence based and ideally should not been done.

The Positive and the Negative Chances for Success (NICE Data3) Couples who come to an IVF expert come with a sense of hope. For some this hope is realistic and for some it is not so. A positive message about natural (non IVF) intercourse gives an 80% chance of conception within 1 year if the woman is under 40 years of age, the couple have regular intercourse and they do not use contraception.

For the 20% who do not conceive in the first 12 months, the good news is that 50% will conceive in the second year (a cumulative pregnancy rate of over 90%).

The chances for IVF conception are not as good as that for natural conception but 50% of women under aged 40 years will conceive within 6 cycles of intrauterine insemination (IUI). Fresh sperm, not surprisingly, is better than frozen-thawed sperm. Of those who failed in the first year, 50% will succeed in the second year with a further 6 cycles (a cumulative pregnancy rate of over 75%).

The Age Cliff Edge and Fertility Some have described five ages of female fertility.

The 1st age is the teens when most women (as young girls) have begun to ovulate (around 14 years). The second age is when female fertility is at or reaching its peak (early 20s). The third age is when female fertility has already started to decline (late twenties). At the fourth age, female fertility has dropped steeply (mid-thirties). The fifth age is when the chances of becoming a biological mother are almost negligible (early 40s and above)4.

Women need to know as early as possible that there is a point beyond which natural or IVF conception becomes extremely unlikely and, with this knowledge, they can adapt their plans for a future family.

good as that for natural conception but 50% of women under aged 40 years will conceive within 6 cycles of intrauterine insemination (IUI)

In the United States, the live birth rate for each IVF cycle started is approximately: • 41-43% for women under age 35 • 33-36% for women ages 35 to 37 • 23-27% for women ages 38 to 40 • 13-18% for women ages over 405

The General Practitioner and the Woman Considering IVF and NICE Advice6 NICE advise you to start with her age as the initial predictor of success, naturally or via IVF. They then advise you to assess the likely ovarian response to gonadotrophin stimulation in IVF; the options to assess this include one of the following:

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SPECIAL REPORT: PERSONALISED MEDICINE IN FERTILITY PATIENTS

Women need to know as early as possible that there is a point beyond which natural or IVF conception becomes extremely unlikely and, with this knowledge, they can adapt their plans for a future family

1) The Antral Follicle count (Less than equal to 4 has a low response/Greater than 16 has a high response) 2) The anti-Müllerian hormone level (Less than or equal to 5.4 pmol/l has a low response/ Greater than or equal to 25.0 pmol/l has a high response) 3) The follicle-stimulating hormone (FSH) level (Greater than 8.9 IU/l has a low response/Less than 4 IU/l has a high response)

The Woman’s Gynaecological Structure NICE advise that you identify whether the woman has existing comorbidities ‘(such as pelvic inflammatory disease, previous ectopic pregnancy or endometriosis7)’ and those who do not have these should be offered hysterosalpingography (HSG) to screen for tubal occlusion because this is a reliable test for ruling out tubal occlusion, and it is less invasive and makes more efficient use of resources than laparoscopy.

The Men NICE recommends that you advise the male partner to reduce their alcohol intake, stop smoking, not wear tight pants, reduce weight if obese and increase exercise to improve the chances of conception.

The Couple Both will need counselling, as IVF is a complex, emotionally-laden process.

Screen both for blood borne viruses (BBV) and Chlamydia.

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Helping the Woman Understand the Health Issue if it is Hers and not His NICE advise you to use the World Health Organization (WHO) classification of ovulation disorders8, recognising 3 groups: Group I: hypothalamic pituitary failure (hypothalamic amenorrhoea or hypogonadotrophic hypogonadism).

Group II: hypothalamic-pituitary-ovarian dysfunction (predominately polycystic ovary syndrome).

Group III: ovarian failure.

For those in Group I, NICE recommends that you advise them that they can improve their chance of regular ovulation, conception and an uncomplicated pregnancy by: increasing their body weight if they have a BMI of less than 19 and/or moderating their exercise levels if they undertake high levels of exercise. Such women should be offered pulsatile administration of gonadotrophin-releasing hormone or gonadotrophins with luteinising hormone activity to induce ovulation.

For those in Group II, NICE recommends that you advise them that they can improve their chance of regular ovulation, conception and an uncomplicated pregnancy by losing weight if they have a BMI of 30 or over. Such women should be offered the following treatments, taking into account potential adverse effects, ease and mode of use, the woman’s BMI, and the monitoring needed: clomifene citrate or metformin or a combination of the two.

SPECIAL REPORT: PERSONALISED MEDICINE IN FERTILITY PATIENTS

For women who are taking clomifene9 citrate, offer ultrasound monitoring during at least the first cycle of treatment to ensure that they are taking a dose that minimises the risk of multiple pregnancy. Do not continue treatment for longer than 6 months.

For women prescribed metformin, they should be informed of the side effects associated with its use (such as nausea, vomiting and other gastrointestinal disturbances).

In women with WHO Group II ovulation disorders who are known to be resistant to clomifene citrate, consider one of the following second-line treatments, depending on clinical circumstances and the woman’s preference: Laparoscopic ovarian drilling or combined treatment with clomifene citrate and metformin if not already offered as first-line treatment or gonadotrophins.

Women with polycystic ovary syndrome who are being treated with gonadotrophins should not be offered treatment with gonadotrophin releasing hormone agonist concomitantly because it does not improve pregnancy rates, and it is associated with an increased risk of ovarian hyperstimulation.

The use of adjuvant growth hormone treatment with gonadotrophin releasing hormone agonist and/or human menopausal gonadotrophin during ovulation induction in women with polycystic ovary syndrome who do not respond to clomifene citrate is not recommended because it does not improve pregnancy rates.

The effectiveness of pulsatile gonadotrophinreleasing hormone in women with clomifene

citrate-resistant polycystic ovary syndrome is uncertain and, therefore, is not recommended outside a research context.

For those with Group III ovarian failure the solution to be considered is donor eggs (oocytes)10.

A Summary of IVF Techniques for Success as Recommended by The Royal College of Obstetricians and Gynaecologists (RCOG)11 A full cycle is the term used to define a full IVF treatment, which should include 1 episode of ovarian stimulation and the transfer of any resultant fresh and frozen embryo(s). The key steps for success are: Firstly – reduce premature surges of Luteinising Hormone.

Secondly – control ovarian stimulation.

Third – trigger ovulation.

Fourth – retrieve eggs.

Fifth – use ultrasound-guided embryo transfer.

Sixth – evaluate embryo quality12, at both cleavage and blastocyst stages, according to the Association of Clinical Embryologists (ACE)13 and UK National External Quality Assessment Service (UK NEQAS14) for Reproductive Science Embryo and Blastocyst Grading schematics.

Seventh – offer women progesterone for luteal phase support after IVF. With all these steps in place, correctly managed and assisted by the advent of personalised medicine solutions, women in the right age brackets can hope for a successful conception, with reduced risk.

For women prescribed metformin, they should be informed of the side effects associated withits use (such as nausea, vomiting and other gastrointestinal disturbances)

References: https://www.guidelines.co.uk/NICE/Fertility-treatment/237921.article Accessed 18/12/17

1 2

https://www.cdc.gov/art/index.html Accessed 18/12/17

3

https://www.nice.org.uk/guidance/cg156 Accessed 18/12/17 http://fertilitynetworkuk.org/for-those-considering-their-future-fertility/the-five-ages-of-female-fertility/ Accessed 18/12/17

4

http://americanpregnancy.org/infertility/in-vitro-fertilization/ Accessed 18/12/17

5 6

https://www.nice.org.uk/guidance/cg156/chapter/Recommendations Accessed 18/12/17

7

http://bit.ly/2l0Vp1g Accessed 18/12/17

https://www.timeofcare.com/ovulation-disorders-world-health-organization-who-categorization/ Accessed 18/12/17

8

http://srh.bmj.com/content/familyplanning/38/1/48.full.pdf Accessed 18/12/17

9

https://www.nice.org.uk/guidance/cg11/documents/fertility-algorithm-second-consultation2 Accessed 18/12/17

10

11 12

https://www.nice.org.uk/guidance/cg156/evidence/full-guideline-188539453 Accessed 18/12/17

https://www.nice.org.uk/guidance/qs73/chapter/quality-statement-8-number-of-embryos-transferred Accessed 18/12/17

13 14

https://www.embryologists.org.uk/ Accessed 18/12/17 https://ukneqas.org.uk/ Accessed 18/12/17

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Notes

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