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n The Leeds Teaching Hospitals NHS Trust

Pre-implantation (PGT), (IVF), Intracytoplasmic Injection (ICSI) & Frozen EmbryoTransfer (FET)

Information for patients This booklet informs you how a PGT cycle is managed at Leeds (LF). It includes information about PGT, and also about the IVF and ICSI processes and the frozen transfer (FET) cycle.

You can find further information at: www.leedsfertilityclinic.co.uk and at our regular, free, New Patients’ Information Open Evenings (see website or Reception notice board for up-coming dates and details).

How to contact us Please turn to page 84 of this booklet for urgent and non-urgent contact details.

2 Contents Page 08 What is PGT? Page 09 The PGT-SR/M Process Page 10 The PGT-SR/M Process step by step Page 11 How do I access PGT-SR/M-IVF treatment? Page 11 Referral and funding Page 12 PGT-SR/M pathway Page 13 Understanding genetics Page 14 PGT-SR for Chromosomal changes Page 15 What is the relationship between chromosomal aneuploidy and the ’s age? Page 16 PGT-M for Single Gene Conditions Page 16 What is a gene change? Page 16 Which single gene conditions can be tested for? Page 17 Does PGT-M for single gene conditions detect any other gene problems? Page 17 Does PGT-M for single gene conditions detect whether the number of chromosomes is correct? Page 18 Alternatives to PGT-SR/M Page 18 Fertility background information Page 19 Natural conception and fertility Page 21 The IVF Process

3 Page 22 The IVF Process step by step Page 23 Embryo storage Page 23 Success rates Page 24 What can I do to prepare for healthy and boost my chances of success? Page 24 General lifestyle issues Page 26 Preparing for treatment: tests and support Page 30 Abstaining from unprotected intercourse Page 31 Designing your specific PGT-SR/M test Page 32 What happens during a PGT-SR/M-IVF cycle? Page 32 Treatment cycle summary: order of events Page 32 Nurse consultation Page 34 Treatment protocols Page 36 Egg collection Page 37 Laboratory phase Page 38 Time Lapse Imaging Page 40 Embryo biopsy Page 41 What happens during an embryo biopsy Page 42 PGT-SR/M analysis of Page 42 PGT-SR for chromosomal changes Page 42 PGT-M for single gene conditions

4 Page 43 Aneuploidy Screening and Pre-implantation Genetic Testing-A (PGT-A) Page 43 What happens if an embryo has an incorrect number of chromosomes? Page 44 Comparing normal and abnormal numbers of chromosomes Page 45 What information does PGT-A provide? Page 46 What is the relationship between chromosomal aneuploidy and the mother’s age? Page 47 Studies into PGT-A Page 48 Results Page 48 What happens to the biopsied cells? Page 49 Frozen (FET) Page 49 Background information Page 50 Starting the FET cycle Page 51 Starting your FET cycle immediately following your PGT-SR/M-IVF cycle Page 51 Delay to starting your FET cycle following your PGT-SR/M-IVF cycle Page 51 Joint follow up and FET Nurse Consultation Page 53 How many embryos to thaw? Page 54 Embryo transfer Page 54 Two-week wait

5 Page 55 Page 56 Prenatal diagnosis Page 56 Follow-up Page 57 Treatment Risks Page 57 Risks of PGT-SR/M Page 59 Risks of IVF Page 60 Risks of the egg collection surgical procedure Page 61 Other risks Page 61 Risks of ICSI Page 62 Pregnancy Risks Page 62 Multiple pregnancy and the One at a Time initiative Page 63 Page 64 Page 65 Treatment failure Page 65 Possible reasons Page 65 Failure of the embryos to survive the freeze-thaw process Page 67 General Risks Page 67 Legal aspects of treatment: HFEA, confidentiality, consent, welfare of the child Page 68 HFEA register

6 Page 68 Confidentiality of fertility treatment Page 69 Welfare of future children Page 70 Consents Page 71 Consent to fresh IVF treatment Page 71 Consent to freeze sperm Page 72 Consent to freeze embryos Page 72 Consent to Page 73 Consent to egg / sperm / embryo research Page 73 Consent to training of scientists at Leeds Fertility Page 74 Consent to humane discarding of spare embryos Page 74 Consent to the use of eggs / sperm / embryos after death Page 75 Glossary Page 81 Useful resources Page 84 Contact us

7 What is PGT? Pre-implantation Genetic Testing (PGT) is used alongside IVF by couples who have a risk of passing on a serious genetic condition.

PGT was previously known as Pre-implantation Genetic Diagnosis (PGD). There are two specific types of PGT that are offered when there is a specific genetic condition that couples wish to avoid passing on. PGT-SR is used when there is a structural chromosomal change (“SR” stands for structural) (see page 14). PGT-M is used when there is a single gene condition (“M” stands for monogenic) (see page 16). PGT-A, which was previously known as Pre-implantation Genetic Screening (PGS) is used to identify abnormal numbers of chromosomes, and can be used as further testing after embryos have undergone PGT-M testing, which is discussed in this booklet (see page 43). (“A” stands for aneuplody). (PGT-SR already includes a check of the number of chromosomes in the embryo, although you may opt out of having this information reported). PGT-A can also be used on its own (please see separate information booklet).

PGT-SR/M is a technique that allows couples with a particular inherited condition in their family to avoid passing it on to their children. PGT-SR/M is only used when a couple has a known risk of passing on a genetic or chromosomal change. It is not used to screen embryos for common chromosomal changes in the absence of a significant family history.

8 A test is performed on an embryo created through IVF (please see page 21 for information about IVF) to find out if it has also inherited the genetic or chromosomal change. This can be done on several embryos, with the aim of selecting an unaffected embryo that can be transferred to the womb and hopefully result in the birth of an unaffected baby.

You may be offered PGT-SR/M if: •• You have a child with a serious genetic condition or you have had a previous pregnancy affected with a serious genetic condition •• You or your partner has a serious genetic condition. •• You and your partner are both carriers of a serious recessive genetic condition, even if there is no family history. In the UK it is illegal to use this testing to select embryos on the basis of their sex for social or family balancing reasons, but may be considered for sex-linked disorders in some circumstances.

The PGT-SR/M Process There are a number of steps involved in the PGT-SR/M process, and the aim of this booklet is to give you information about each step.

9 The PGT-SR/M Process step by step

1 2 Appointment at Leeds Fertility (LF) A doctor will take a detailed fertility history and arrange fertility tests to check if PGT-SR/M-IVF is suitable.

3 License and DNA tests Genetic Counselling If there are no fertility concerns, both parents (and Prospective parents sometimes other family memebers) will have DNA speak with a genetic tests sent to the PGT laboratory. If a license is not counsellor and discuss already in place, this can be applied for. PGT-SR/M in detail.

4 PGT-SR/M test preparation 6 The PGT lab designs a test Embryo Biopsy unique to each family. An embryologist carefully removes a small cell sample from each embryo and the 5 IVF and ICSI embryos are then frozen. IVF and ICSI is performed and the resulting embryos are incubated.

8 Frozen Embryo Transfer (FET)

7 An unaffected PGT-SR/M embryo is transferred. Samples are sent to the PGT Remaining unaffected laboratory, testing is performed, embryos can be kept and results are sent to LF. frozen for future use.

10 How do I access PGT-SR/M-IVF treatment? Referral and funding In most cases you will be referred to Leeds Fertility by a genetic counsellor who has discussed the option of PGT-SR/M with you. Occasionally you may be referred directly by another health care professional, in which case you will be referred for genetic counselling by Leeds Fertility. PGT-SR/M and IVF involving eggs, sperm and embryos require a special license from the Human Fertilisation and Embryology Authority (HFEA) and there are limited clinics available with the required facilities (see legal aspects section - page 67). Leeds Fertility is a large unit receiving referrals from a wide area. We treat both NHS and self-funding patients under the same roof because of the legal requirements of the facility. PGT-SR/M-IVF may be funded by the NHS. Leeds Fertility and the genetic counsellors will be able to tell you if you meet the criteria for NHS-funded treatment. Funding criteria are subject to change and so we have not listed them here. However, the important factors that we will need to consider include; female partner’s age, female partner’s (BMI) and whether you and your partner already have healthy children together. Both partners must be non-smokers. All patients are entitled to an NHS consultation and investigations as are felt to be appropriate. We will provide you with the current price list for your treatment if needed. (See website: www.leedsfertilityclinic.co.uk).

11 PGT-SR/M pathway After your genetics appointment the genetic counsellor will clarify that your specific condition can be tested for using PGT-SR/M and if this is the case, refer you to see a doctor at Leeds Fertility. You will then need two appointments, and both partners need to attend. During the first visit the doctor will ask you about your general and fertility health, and you may also undergo a vaginal ultrasound scan, and be requested to provide a for analysis. Several tests will be requested, and the results of these will be given to you at the second appointment; it may be possible for your second appointment to be a telephone / virtual consultation (see preparing for treatment: tests and support - page 26). If the tests show that it is appropriate to go ahead with PGT-SR/M-IVF, the doctor will inform the PGT laboratory, and their genetic counsellors will contact you by telephone to confirm you understand the processes involved and ask you to sign a specific consent form. They will also ask you to help obtain cheek swab DNA samples from a number of your relatives. They will then arrange for the PGT lab to develop your specific PGT-SR/M test. This usually takes just a few weeks but in some circumstances it can take several months. If PGT-SR/M is not yet licensed for your specific condition, the team will then apply to the HFEA for a license. This can take more than 6 months. Once the PGT lab has designed your specific PGT- SR/M test and an HFEA license is in place, you will have a nurse consultation with a specialist PGT nurse who will plan your cycle (see Nurse consultation - page 32). You will then undergo the IVF cycle; embryos will be sampled and frozen and you will return at a later date for a frozen embryo transfer (FET) cycle, where anunaffected embryo can be replaced into your womb.

12 Understanding genetics DNA, or deoxyribonucleic acid, is the hereditary material that provides important instructions for the human body. Our DNA is divided up into genes. Genes are the instructions that tell the body how to make proteins that allow the body to develop, grow and function. DNA is tightly wound and compacted in structures called chromosomes, which are found in the nucleus of our cells. Healthy people typically have 23 pairs of chromosomes in each cell. One chromosome in each pair is inherited from the mother (purple) and the other from the (blue).

DNA

Chromosomes

Chromosomes and Y determine if you are female () or male (Y)

PGT-SR/M is a technique that can be used to distinguish between embryos that may have a chromosomal change (PGT-SR) or an altered gene (PGT-M) (affected embryos) and healthy (unaffected) embryos, and select only unaffected embryos to be transferred to the womb.

13 PGT-SR for Chromosomal changes What is a chromosomal change? Extra or missing chromosomes, or pieces of chromosomes, can impact overall growth and development. PGT-SR can be used for carriers of balanced reciprocal translocations, Robertsonian translocations, inversions, and other complex chromosome rearrangements. Carriers of these chromosomal rearrangements are usually healthy, but they may produce embryos with the incorrect amount of chromosomal material, or the incorrect number of chromosomes (aneuploidy). If a whole chromosome, or significant part of a chromosome is lost or duplicated, the genetic instructions no longer make sense and the embryo will be unable to develop into a healthy baby. Most embryos with a major chromosomal change fail to in the womb or miscarry during pregnancy. However, sometimes a pregnancy can reach full term and the baby is born with a genetic condition e.g. an unbalanced chromosome translocation. An embryo with missing or duplicated chromosomal material may grow at a normal rate in its early stages. It therefore cannot be differentiated from a normal embryo in a standard IVF cycle.

14 What is the relationship between chromosomal aneuploidy and the mother’s age? The risk of having an embryo affected by a chromosomal aneuploidy (extra or missing chromosomes) is influenced by the age of the mother. The older the woman is, the higher the chance of having an affected pregnancy. This is separate from the risk of chromosomal changes due to the chromosomal translocation or rearrangement that one of the parents carries, which has no association with the mother’s age. PGT-SR can be used to see if there is an unbalanced translocation (or other complex rearrangement). It can also be used to detect aneuploidy (PGT-A). Embryos with a usual number of chromosomes can therefore be selected for transfer. There is, however, a risk that no embryos will progress to the stage for biopsy, or no embryos will have a normal number of chromosomes and no transfer will be performed. It is usually not possible to distinguish a normal embryo from an embryo with a balanced translocation (for example) but they can still be used for future treatment. It is only the ‘unbalanced’ or aneuploid embryos that cannot be used.

15 PGT-M for Single Gene Conditions What is a gene change? Changes within the genes are also called mutations. Some changes are passed down from parents and others happen spontaneously. Gene changes make us unique; while many changes cause harmless variation in traits like hair and eye colour, others can affect health.

Which single gene conditions can be tested for? It is a legal requirement that there is a specific HFEA license in place for each different genetic condition for which PGT-M is offered. If this has not already been granted, the team can apply for a new license. For a license to be granted we have to prove that the genetic condition is serious. The HFEA have a list of all licensed genetic conditions that can be tested for (http://guide.hfea.gov.uk/pgd/).

16 Does PGT-M for single gene conditions detect any other gene problems? PGT-M will only be used to assess embryos for the single gene condition(s) you are known to be at risk of passing on to your children. PGT-M can be performed for >6000 single gene conditions, including: •• BRCA 1 & 2 •• Fragile X Syndrome •• Huntington’s Disease •• •• •• Sickle-Cell Disease If a couple are at risk of passing on more than one single gene condition, then it may still be possible to screen embryos but this must be reviewed individually.

Does PGT-M for single gene conditions detect whether the number of chromosomes is correct? Once the embryos have been tested for the single gene condition, it is then possible to test the unaffected embryos to find out whether the embryo has a usual number of chromosomes. If an unaffected embryo is shown to have an incorrect number of chromosomes it will not be used for future treatment. This test is performed routinely at Leeds Fertility, but if you do not wish for this to be carried out you need to let us know at your nurse consultation. More detail is provided about genetic testing on page 42.

17 Alternatives to PGT-SR/M If a couple have no fertility problems, they can conceive naturally and then consider (chorionic villous sampling (CVS) or ). For most couples this route actually gives the highest chance of having a healthy baby. However, it does mean that a couple may be faced with the very difficult decision about whether to continue an affected pregnancy, or have a termination of pregnancy. Some couples consider other options including use of donor eggs or sperm, or not having children. If you want to discuss all of these other options, you should contact your genetic counsellor.

For a discussion around the risks of PGT, including misdiagnosis risks, please see page 57.

Fertility background information PGT-SR/M can only be performed when embryos are created via IVF. In order to appreciate what happens and why in an IVF cycle, it is helpful to understand the natural cycle and how a natural pregnancy occurs.

18 Natural conception and fertility Assisted conception by IVF takes over the natural processes. During each natural female monthly cycle, a woman releases one egg from one from the fixed supply that she was born with. The egg takes two weeks to get ready to be released (ovulated) when it is picked up by the and carried towards the womb. It meets the sperm in the tube and fertilisation happens here. The embryo (fertilised egg) then attaches to the womb lining that has prepared to receive it. A baby then develops. The process is coordinated by hormones (natural chemical messages). A woman’s fertility is quite closely related to her age. She is most fertile in her 20s and early 30s. For all women, fertility naturally falls in their later 30’s and 40’s. This makes it harder to get pregnant naturally, and with IVF assistance, because the quality and number of the eggs is reduced. Some women have fewer eggs than average at birth and some women lose their eggs more rapidly in their younger years. There may be inherited (genetic) reasons for this and / or it can be caused by past illness or lifestyle choices such as smoking. There are tests that can help to predict a woman’s egg reserve and her likely response to / success with IVF treatment. In PGT-SR/M it is especially important that there are sufficient embryos generated that can be tested, as there will be a number that are affected and cannot be used for treatment. Therefore, testing for ovarian reserve is crucial in PGD cycles and occasionally it is inappropriate to proceed as the tests predict very few eggs will be produced (See Preparing for treatment: tests and support - page 26).

19 Natural conception FSH and LH hormones released from the brain into the blood

stream to stimulate egg development and

Oestrogen and released from the ovary into the blood stream to stimulate the womb lining

Sperm meet the egg in the Fallopian tube where fertilisation happens. The embryo travels into the womb to implant 5-7 days later

20 The IVF Process During IVF treatment, hormones taken by injections, cause the ovary to make several eggs at the same time. These are taken out of the woman’s body in a minor surgical procedure. The eggs are put together with her partner’s sperm in the laboratory for fertilisation to take place. This is when the sperm enters the egg and the contents of both are combined to create a unique being. ICSI is routinely performed in PGT-SR/M cycles as it prevents contamination from the DNA of excess sperm that sticks to the outside of the egg in standard IVF . During ICSI, the sperm are injected individually into each of the mature eggs collected. The laboratory allows the fertilised eggs, now called embryos, to grow under observation for five days, or sometimes six days. At this stage the embryos are called . On day 5 (or 6) a few cells are removed from each which are then immediately frozen. The cells are analysed at a specialised PGT laboratory who then inform Leeds Fertility which embryos (if any) are unaffected. You will be told this information by the Leeds Fertility PGT team at a clinic appointment. You will then return for a frozen embryo transfer (FET) cycle. This may happen the month later, but sometimes there is a delay as the genetic testing takes longer.

21 The IVF Process step by step

Egg retrieved 2 from ovary Sperm 3 sample 1 provided Egg production stimulated by hormone therapy

Sperm 4 injected into 5 Fertilisation egg (ICSI) 6 Embryos incubated 7 Day 5 “blastocyst” Cells sent to PGT lab embryo 8 for genetic analysis

9

Blastocyst embryos frozen

PGT lab informs LF which embryos 10 are unaffected (e.g. embryos 3 and 6) 11 Unaffected embryo (e.g. embryo 6) 1 2 3 4 5 6 is thawed and 6 introduced into the womb

22 Embryo storage Human embryos generally cope well with freezing and thawing (80% will survive) and this does not affect their ability to grow into a healthy child, regardless of how long they are frozen. (See Frozen Embryo Transfer cycles - page 49).

Success rates Please see our website for our latest figures and the HFEA website for the figures for babies born in the last year. About About 30-35% couples will have a clinical pregnancy (where a heart beat is seen on the first scan), following the thaw and transfer of a single blastocyst (day 5 or 6 embryo).

23 What can I do to prepare for healthy pregnancy and boost my chances of success? General lifestyle issues

•• Stop smoking completely. •• Reduce alcohol intake to a minimum for both men and women. No safe limit has been identified so no alcohol consumption is advised. •• Women should have been vaccinated against German measles (rubella) or have confirmed immunity. •• Women should have an up to date, normal cervical smear test. •• Women should be taking folic acid (vitamin B) supplement at 400micrograms daily before and during treatment, and for at least the first three months of pregnancy. Occasionally a higher dose is recommended.

24 •• Vitamin D supplements (10micrograms daily) are also recommended throughout pregnancy. Over-the-counter multivitamins for pregnancy will cover both needs. If your levels are low, then you may need a three month high dose course of Vitamin D. •• Both partners should aim for normal body weight for their height. Women in particular should aim for a body mass index ideally under 25kg/m2, and absolutely under 30kg/m2 to access NHS-funding. Treatment is less successful and riskier at heavier weights. Pregnancy is also less healthy with a higher risk of blood pressure problems and diabetes in heavier . (See separate weight management guidance booklet or online). •• A healthy, varied diet and regular physical exercise are helpful for overall health, weight management and stress reduction. •• Discuss any other medication you take with your GP and specialist (s) to ensure any risks to yourself (from other medical conditions) and to your up-coming pregnancy / baby are minimised. •• Consider carefully the use of complimentary therapies, and please inform us what you are using / doing. is not known to be harmful and many patients find it helpful with managing stress. Other supplements that have not undergone conventional.

25 Preparing for treatment: tests and support •• Sperm analysis: This is always done as part of the investigations work-up in the out-patient clinic. Even if you have had a sperm analysis done before (e.g. at your GP or District Hospital), it is often necessary to repeat it in the IVF clinic as our test is more detailed. Our samples are produced on site in discrete private rooms, by into a small sterile pot, which will be provided. If you are concerned that you may have difficulty producing a sample on the day of egg collection (not an uncommon anxiety) please ask about freezing a sample in advance as a back-up. •• Hormone blood tests for the woman: Day 1-3 of a cycle (whilst bleeding) Follicle stimulating hormone (FSH), (LH), Oestradiol (E2) are required within six months of treatment starting (GP test). Anytime in the cycle Antimüllerian hormone (AMH) is useful to guide the dose of hormones needed to stimulate your . This blood sample must be taken at Leeds Fertility and sent to a specialist lab for testing. It is not covered by the NHS and will incur a charge if you choose to have it (see price list).

26 •• Pelvic ultrasound baseline scan: This is a screening scan that is performed internally (vaginally) to make sure there are no interfering factors such as fibroids (swellings in the muscle of the womb), polyps (overgrowths of womb lining), ovarian cysts (such as ) or swollen fallopian tubes. Any such findings may need further treatment before your IVF cycle can begin, in order to give you the highest chance of success. The scan will also assess ovarian reserve by looking for egg sacs (follicles) that are getting ready to develop mature eggs in the coming months. Polycystic ovaries have very many of these (more than 12 each side) and this makes them particularly sensitive to the IVF hormones. Women with polycystic ovaries will have a specially tailored treatment course to minimize the risk of producing too many eggs at once (ovarian hyperstimulation syndrome - see page 59).

•• Sexual health screen: Both men and women are offered screening for common sexually transmitted infections and non-sexually transmitted vaginal infections that can reduce the chance of IVF treatment success if they are not treated. Often these infections can be present without obvious symptoms. We may refer on to the Sexual Health Service if necessary.

27 •• HIV, , C and syphilis screen: We must screen all patients whose sperm and eggs will pass through our treatment laboratories and / or into our freezing tanks in order to protect all patients from any possible contamination or new infection. No case of infection has ever occurred in this way but we continue to take precautions. Any patients found to have one of these infections will be counselled and referred to the appropriate specialist for on-going care. Leeds Fertility can not conduct the laboratory part of the cycle for these patients, and you may be referred to another unit. •• Medical health assessment: If you have a specific genetic condition, which may be associated with various medical concerns, you may require additional tests e.g. heart scan or lung function tests. You may also need an anaesthetic assessment to prepare for the egg collection, or an obstetric assessment so a plan is in place to provide you with the best care if you do become pregnant. •• New Patients Information Presentation: All patients are kindly asked to listen to this talk that we provide just before your treatment cycle starts. You can access this, free of charge, in person at Leeds Fertility (see Reception or Notice Board or website for dates & time) or via the link on the website homepage. The talk will give you a rough time line and point out some important things that you need to understand clearly for your treatment to run smoothly. We will do all we can to support and help you to keep your treatment on track at home, in between the visits to Leeds Fertility. Please note that this presentation is not specific to PGT-SR/M.

28 •• Counselling and patient-to-patient support: We aim to provide supportive care for both partners through this process, regardless of the outcome. We have a highly-skilled team of fertility counsellors who are all professionally registered. (British Counsellors Association: www.bica.net). •• They provide support in dealing with the social and emotional aspects of fertility problems and help to find ways to cope with the on-going situation. Counselling is free and usually delivered on Leeds Fertility premises. Some counsellors offer evening appointments. Please call 0113 206 3100 if you would like to make an appointment, or request a referral from the doctor or nurse attending to you.

•• You may also seek support from your genetic counsellor. •• Some patients choose to support each other through social media and there is a private Facebook page for patients from Leeds Fertility. •• Infertility Network UK (www.infertilitynetworkuk.com) is the leading national charity for people having difficulty conceiving. They also offer emotional and practical support with a wealth of personal experience.

29 There are circumstances where the clinical team calls upon the Leeds Fertility counsellors to discuss the implications of some of our treatments e.g. the use of donated eggs or sperm with the intended recipients. This is a legal requirement of our License and addresses some important issues you may not have thought of by yourselves. The Leeds Fertility counsellors are also occasionally asked to meet with couples or individuals when a circumstance has given us cause to seek assurance, as far as we can do, as to the welfare of the child who may result from our treatment, within the intended family unit. Again, it is a legal requirement of our License to consider the wellbeing of the child who does not yet have a voice, and do all that we can to ensure that child will not be at risk of harm. The clinic does have the right to refuse treatment, having considered evidence from a wide variety of sources if necessary.

Please speak to your consultant if you have any concerns in this area. Our Standard Operating Procedure is available on request.

Abstaining from unprotected intercourse Once the decision has been confirmed that you are going to proceed with PGT-SR/M, it is critical that you avoid sexual intercourse or use barrier contraception until the pregnancy test.

This is required to prevent a natural pregnancy which could interfere with the PGT-SR/M process and confuse interpretation of results.

30 Designing your specific PGT-SR/M test Once we have confirmed that you are suitable to come through for PGT-SR/M-IVF (your fertility assessment is adequate, the genetic condition is licensed and the PGT laboratory are able to test for the genetic condition) the PGT laboratory genetic counselling team will contact you by telephone to answer any questions, complete a specific laboratory PGT-SR/M consent form and organise the collection of DNA samples. A DNA sample will be required from both partners (who are providing the sperm and eggs) AND in the case of PGT-M for single gene conditions, other family members (usually another person who has the same genetic condition). DNA can be found in the cells lining the inside of the cheek, and so is easily obtained with a special swab. Occasionally blood tests may be needed. The PGT laboratory genetic counsellors will arrange for these to be sent in the post. If the DNA samples are available from all relevant family members then a test called Karyomapping can be performed. Test development takes about 4 weeks and you cannot book for PGT-SR/M treatment until the test has been agreed.

If you are unable to provide family samples, then it may still be possible to offer PGT-M by ‘direct embryo’ testing but further analysis of chromosomes cannot be performed. The development of this type of test will take several months and can delay the start of your treatment.

For further information about the tests used in PGT-SR/M see PGT-SR/M analysis of embryos - page 42.

31 What happens during a PGT-SR/M-IVF cycle? Treatment cycle summary: order of events •• Nurse consultation •• Stimulation •• Egg Collection •• Laboratory phase (fertilisation and embryo monitoring, embryo biopsy, embryo freezing) •• PGD analysis of embryos •• Frozen embryo transfer •• ‘Two week wait’ to pregnancy test •• Follow-up (pregnancy scan or clinic appointment) Nurse consultation This one hour long appointment with a nurse specialist is the gateway into your treatment cycle. Both partners must attend.

Tasks: 1. Planning calender: You will be given a Treatment Diary explaining your individually-tailored treatment program and the expected dates when key parts of the process should fall. Please be aware that our bodies do not always ‘read the textbook’ and sometimes we have to reschedule for minor delays such as a period coming later than expected. This is quite normal and the service will stretch to fit you in.

32 Please bring your treatment diary to every visit after this.

2. Medication injection teach: The woman will be using medicines on a daily basis, some by injection. We will teach you both how to do this properly and safely. Many patients find this worrying to start with, but get the hang of it very quickly. The medicines are dispensed by a home-delivery pharmacy who will bring them to the address of your choice.

The nurse will show you examples of what will arrive and advise you how to store them. More information is available on our website e.g. injection teaching video.

3. Consents: This is the part that takes the longest. The consents are lengthy, detailed legal documents but it is critical that they are completed correctly and truly express your wishes. You will receive an e-mail link to your consents before your nurse consultation and it is helpful for you to have read through them before meeting with the nurse and you may sign those you feel confident with. 33 At the nurse consultation these will be completed and you will take a copy away for your own records. There are consent forms that are specific to PGT-SR/M, and in particular you will need to consider what you would like to be done with any affected embryos e.g. humanely discarding or donating these embryos to training. These embryos can be a valuable resource for research and improving PGT techniques.

Settlement of Invoice: If you are paying for your treatment, we respectfully ask that the bill is settled by the time of the nurse consultation. This can be done by card over the telephone (0113 206 3157) or in person on the day, with the Business Support Team on the unit.

Treatment protocols The principle of IVF requires stimulation of the ovaries with hormone injections under the skin to produce many eggs at once. Egg release (ovulation) is controlled so that the eggs can be collected and removed from the body. There are two commonly used ways of doing this, and a third process (the flare protocol) which is used less often: 1. Short protocol This is where natural ovulation is prevented for about five to ten days. This is the commonest protocol used in PGT- SR/M-IVF cycles. 2. Long protocol This is where the natural ovulation mechanism is switched off for two to four weeks.

34 3. Flare protocol The natural ovulation mechanism is switched off for a medium time period. The doctor will decide which one would suit your circumstances best. There are medical and safety reasons why one might be chosen over another and this will be tailored to your needs and explained individually.

We recommend that you choose a time of day to take your medicines and stick to it. Ideally, 21:00-22:00 is advised as it enables dose adjustment to take place in a daytime clinic appointment in time for that night’s dose. In a short protocol you will have a second injection to prevent ovulation and we suggest that you do this injection in the morning.

Your medication plan will be carefully explained at your nurse consultation. Your personalised diary will set out your specific instructions. Please be prepared for some instructions to change depending on your response as the cycle progresses. The treatment diary also contains further important information such as the use of other medicines, food intake (fasting), make-up, period of abstinence (no ejaculation) for the male partner before the treatment sperm is required. If you are particularly anxious, you may request a tranquilizer tablet to help you sleep the night before and remain calm on the day of the egg collection procedure.

35 Egg collection The doctor reaches the eggs through the skin at the top of the using the same kind of ultrasound machine that we use in the clinic to monitor egg development, but with a needle attached to a gentle suction pump.

The egg collection procedure is done with fast-acting painkillers and sedatives given in to a vein. It takes about half an hour. Most women do not remember the procedure happening (they are relaxed and comfortable) although they are not unconscious. This is not a general anaesthetic, which means that you can recover more quickly and get home sooner. A consultant anaesthetist will be close by, managing your comfort level. You can expect to be heading home within four hours of the procedure once you have recovered and eaten, and the 31 laboratory have reported the sperm sample to be satisfactory. It is normal to experience some lower tummy discomfort (not severe pain or breaking through paracetamol pain-relief) and some light vaginal bleeding. Please call the Leeds Fertility emergency phone if you are concerned and need advice (see page 84 for details).

36 Laboratory phase In all PGT-SR/M cycles, ICSI (sperm injection) is needed. This is not necessarily because the sperm sample is abnormal, but to prevent contamination from the DNA of extra sperm which usually stick to the outside of an egg following standard mixing of eggs and sperm (insemination). The issues surrounding ICSI are detailed later. (See Risks of ICSI - page 61).

37 Fertilisation happens during that night. Usually about 70% of eggs accept the sperm. After this time, if they have not, there is no further chance of fertilisation. These eggs will be discarded the next morning at the fertilisation check. You will receive a telephone call from the embryologist informing you how many of your eggs have fertilised, and therefore how many embryos are now in the culture incubator.

Time Lapse Imaging Leeds Fertility is pleased to be able to offer Embryoscope time-lapse imaging incubators. These machines allow the embryos to be cultured in a closed system (no opening of the ‘oven’ door while the ‘cake is rising’) because they have built in cameras (microscopes) taking pictures of the embryos every ten minutes. This means that details of the individual embryo’s development can be monitored throughout the culture period and pieced together in a short video clip. Without this technology, embryos are removed from a standard incubator and checked at snap shot time points (fertilisation, day three and day five). The development in-between is never seen. As we come to understand more about the details of embryo development, so we expect to be able to select ‘good quality’ embryos more accurately and increase the success of treatment. The embryoscope will not be able to detect embryos that may be affected by the genetic condition you are undergoing PGT-SR/M for. It will help in the selection process when deciding which embryo to thaw and transfer in the FET cycle. The maximum number of embryo slots available per couple is 12.

38 Day 2: 2-cell Day 3: 8-cell Day 5: expanded embryo* embryo* blastocyst*

* Images courtesy of The Association of Clinical Embryologists

39 Embryo biopsy On their fifth or sixth day the embryo is called a “blastocyst”. Each blastocyst is assessed and those that have developed normally will be biopsied. This means that a few trophoectoderm (TE) cells will be removed from the blastocyst. These cells are “extra-embryonic” and produce tissues such as the . The inner cell mass (ICM) is the group of cells that becomes the baby. There are over 100 Expanded blastocyst (Image courtesy of The Association of trophoectoderm cells in a Clinical Embryologists) blastocyst so the removal of very few of these cells rarely impacts the embryo. These cells are tested in a PGT laboratory, who predict whether or not the embryo is affected by the genetic condition. During a PGT-SR/M cycle ALL embryos are cultured to blastocyst regardless of their quality on day 3. If embryos do not reach blastocyst stage, then it is likely these are abnormal embryos and unlikely to result in a successful pregnancy. Embryos that do not reach a suitable blastocyst stage cannot be biopsied for technical reasons. Embryos that are slower to develop into a blastocyst can be cultured on to day 6 and if they reach a suitable stage can be biopsied then.

40 What happens during an embryo biopsy

Embryo A few cells are held sampled and sent stable to the PGT lab TE ICM Cells

Straight after the biopsy procedure the embryos will be frozen to await the result of the test. There will be no embryo transfer in that cycle. An unaffected (or in some cases carrier) embryo will be selected for transfer in a frozen embryo transfer (FET) cycle. This may happen the month later, but sometimes there is a delay as the genetic testing takes longer. You will be given a clinic appointment with the PGT team for about two to three weeks following your egg collection where we will let you know how many of the embryos which are frozen are unaffected and can be transferred at a later date. This will be followed by a nurse consultation to plan the FET cycle. If there are no embryos suitable for transfer, you will be offered a consultation with a member of the medical team to discuss the cycle and the future treatment options for you. Legally we also need your consent to allow the abnormal embryos to perish or be used for training. This is included in the PGT-SR/M consent form but we will confirm with you over the phone that you give your consent for this to happen.

41 PGT-SR/M analysis of embryos The specific test which will be performed on the cells removed from your embryos will depend upon the genetic condition you are having PGT-SR/M for: PGT-SR for chromosomal changes One test used to detect embryos affected by chromosomal rearrangements is NGS (next generation sequencing). This test analyses the entire set of chromosomes of the embryos. In some cases we can use HRaCGH (High Resolution array Comparative Genomic Hybridisation) which uses very similar technology. PGT-M for single gene conditions The PGT-M test for the embryos has previously been designed by karyomapping. This means the laboratory know the “genetic fingerprint” surrounding the genetic change that causes the condition in the family. Each tested embryo can then be classified as affected or unaffected.

42 Aneuploidy Screening and Pre-implantation Genetic Testing-A (PGT-A) Embryos which are unaffected by the specific gene condition will be routinely screened to check whether they are aneuploid, unless you specifically ask for us not to do this. This is a test known as Pre-implantation Genetic Testing-A (PGT-A).

PGT-A is a technique that can be used to distinguish between embryos that may have an abnormal number of chromosomes (affected embryos) and embryos with a normal number of chromosomes (unaffected-embryos), and select only unaffected embryos to be transferred to the womb.

What happens if an embryo has an incorrect number of chromosomes? Research has shown that many embryos have an incorrect number of chromosomes in their cells, a condition known as aneuploidy (extra or missing chromosomes). If a chromosome is lost, or one of them is duplicated, the genetic instructions no longer make sense and the embryo is unable to form a healthy baby. Most aneuploid embryos fail to implant in the or miscarry during pregnancy. However, there are very few situations where a pregnancy can reach full term and a baby is born e.g. Down’s Syndrome.

43 Comparing normal and abnormal numbers of chromosomes

Normal number of Abnormal number of chromosomes chromosomes

In this example there is an extra chromosome number 10. When there is an extra chromosome, this is known as a trisomy. Down’s Syndrome is when there is an extra chromosome 21. Sometimes, a chromosome is missing and this is known as monosomy.

An embryo with missing or duplicated chromosomes may grow at a normal rate in its early stages. It is therefore possible to select an embryo for transfer that looks normal but actually contains faulty chromosomes. This is an important reason why IVF treatment is not always successful.

44 What information does PGT-A provide? PGT-A provides information about the make-up of each embryo and helps with the selection of the healthiest one(s). Embryos can be categorized in three ways based on their chromosomal health: euploid, aneuploid or .

Euploid Aneuploid Mosaic

Low level High level

Mixed Number of (Some normal and chromosomes Normal Abnormal some abnormal) per cell Mainly Mainly normal abnormal

Likelihood of Reduced, Very producing a High Very but unlikely successful unlikely possible pregnancy

Considered if no Recommended Yes No euploid No for transfer embryos available

45 What is the relationship between chromosomal aneuploidy and the mother’s age? The risk of having an embryo affected by a chromosomal aneuploidy is influenced by the age of the female partner.

The older the woman is, the higher the chance of having an affected pregnancy. There is a simultaneous decrease in the rate of implantation (chance of an embryo implanting).

• For women in their early thirties, about 35% of embryos are aneuploid • Over the age of forty years, it is typical for at least 75% of embryos to be aneuploid

Studies into PGT-A In the past, the test used in the laboratory to find out whether cells contained the correct number of chromosomes was a technique that had limited value as it only examined one or two cells from very early embryos and looked at a only a few chromosomes. Early studies looking at the value of PGT-A using these older techniques did not show there was a benefit in selecting a healthy embryo in terms of pregnancy rates. Technology has since improved, with the biopsy being performed at a later stage in embryo development, and more cells being sampled, so the genetics laboratory is now able to use tests that detect ALL of the chromosomes and are therefore more effective at selecting an embryo which has the best potential for the birth of a healthy baby.

46 More recent research indicates that the chances of an embryo with a confirmed normal number of chromosomes producing a healthy baby is more than 25% higher than when an embryo is selected for transfer based on the look of the embryo (morphology). PGT-A may also reduce the time it takes to get pregnant meaning that fewer IVF cycles are needed. It may also reduce the number of IVF that miscarry since we know the commonest cause of miscarriage is chromosomal fault. On the other hand, not all studies using modern techniques have found chromosome testing to be of benefit. Further robust clinical and laboratory trials are ongoing to work out whether PGT-A can significantly increase rates.

Potential benefits of PGT-A •• In most cases normal and abnormal (aneuploid) embryos look identical. Without genetic screening, an embryologist cannot differentiate between them and it is possible that chromosomally abnormal embryos could be inadvertently transferred to the uterus. •• It is believed that most abnormal embryos either do not implant or miscarry. By ensuring that embryos with a normal number of chromosomes are prioritized for transfer, the probability of conceiving a healthy child may increase with PGT-A. •• PGT-A will be carried out on the same cells tested in PGT-M, and so no extra biopsy of the embryos is needed.

If you do not wish for PGT-A on your unaffected embryos, you will need to inform us at the time of the nurse consultation.

47 Results A report is generated by the genetics laboratory, usually two to three weeks after the biopsy procedure. Usually we will arrange a joint follow up appointment followed by a Nurse Consultation to plan the FET Cycle. In certain situations, the results may take several months, and you will be informed of this during the planning of your treatment.

What happens to the biopsied cells? The cells to be tested will be destroyed during the process of the analysis. This will usually occur within 5 days of the biopsy and the DNA inside them will be retained for a minimum of one year. Leeds Fertility are keen to know how your pregnancy progresses, especially if any causes for concern are found.

48 Frozen Embryo Transfer (FET) Background information For how long can embryos be frozen? Embryos can be legally stored for a maximum of 10 years. There are individual circumstances where this period can be extended by special application. The embryos do not change or deteriorate because they have been frozen for a long period but it is important that their fate is determined in a timely way and that they are not left in limbo. Leeds Fertility keeps them safely frozen and maintains records for the Licensing Authority (HFEA). There is an annual fee to cover storage administration. (Please refer to the current price list). You must keep us updated with any change to your correspondence address. If we lose contact with you, or you do not keep up your storage fees, we have to allow your embryos to perish. Both partners must continue to consent to the on-going storage. If one partner withdraws consent, the embryos will have to be allowed to perish after a period of reflection of one year (cooling off period) if both partners do not agree.

What options are there for our embryos if we no longer wish to use them for our own treatment? You can advise us that you wish to allow the embryos to perish. They will be thawed and humanely discarded. Alternatively, you could donate embryos for training purposes at Leeds Fertility or you can donate them to medical research if a suitable project is currently available. Embryo research is carefully monitored by the HFEA and specific consent is

49 required for the specific project from both partners. Detailed explanations would be provided. You can offer to donate unaffected embryos to another couple. This would require at least one counselling session to cover the implications of this for yourselves, your existing child / children and the potential child / children. You will be required to have further tests to assist the appropriate with another couple (at no financial cost to you).

Starting the FET cycle Depending upon the type of PGT-SR/M test needed for your embryos, and the PGT-SR/M-IVF protocol used, it may be possible to start your FET cycle immediately following on from your egg collection. In certain situations, where a special test is needed, this is not possible, and there may be a delay of several months before the testing of the embryos is complete. Sometimes the FET cycle may need to be delayed for other reasons, e.g. you need a gynaecological procedure, such as a polypectomy or removal of your fallopian tubes, to give you the best chance of success. There is no pressure of time and you may wish to take a longer break between treatments. If your PGT-SR/M cycle is funded by the NHS, in most situations NHS England will continue to fund FET treatment until all the embryos created from the fresh cycle they funded have been used, or a baby has resulted. If you are self funding your FET cycle, the costs are outlined in the price list.

50 Starting your FET cycle immediately following your PGT-SR/M-IVF cycle An appointment for an FET nurse consultation will be arranged once the PGT laboratory have confirmed there are unaffected embryos available to be transferred. This will usually be within two to three weeks after your egg collection. It is normal to experience a bleed after your egg collection within two weeks. You may be asked to start taking the contraceptive pill on the day you start bleeding if this occurs before your appointment so you are ready to start the FET cycle.

Delay to starting your FET cycle following your PGT-SR/M-IVF cycle If your FET cycle cannot start immediately, once the PGT laboratory have confirmed unaffected embryos are available for transfer we will arrange an FET nurse consultation appointment for you.

Joint follow up and FET Nurse Consultation A member of the medical team and an embryologist will discuss the embryo outcomes with you followed by a nurse consultation. This 30-minute long appointment is the gateway into your FET treatment cycle. Both partners must attend. You will be prescribed your medications, given a Treatment Diary explaining your individually tailored treatment program and the expected dates when key parts of the process should fall. As with the PGT-SR/M-IVF cycle, please be aware that our bodies do not always ‘read the textbook’ and sometimes we have to reschedule for minor delays such as a period coming later than expected. This is quite normal and the service will stretch to fit you in.

51 Treatment Protocols The principle of FET requires the development of the womb lining () and the control of natural ovulation to enable the precise coordination of the embryo thaw and developmental stage of the lining. Most FET cycles at Leeds Fertility are managed with medication because this provides greater control and flexibility.

1. Medicated FET with GnRH antagonist (Short FET cycle): GnRH antagonist switches off the natural cycle and prevents a new egg from developing or ovulating. This is taken as a daily injection for a week. At the same time, you will also be prescribed oestrogen hormone taken either as tablets or patches (or both) which will thicken the endometrium. After 7 days you will stop the GnRH antagonist, but continue to take the oestrogen. On day 10-12 a scan will confirm adequate endometrial development for the embryo thaw to be planned. There is some flexibility at this stage to minimise inconvenience to the clinic schedule and your own plans.

2. Medicated FET with Prostap / Buserelin (Long FET cycle): Ovulation can be suppressed with prostap (one injection) or buserelin (daily injections) taken on day 1 or day 21 of the cycle, as an alternative to a GnRH antagonist. Your consultant will advise if this is more suitable for you. A scan ten days to two weeks later will confirm ‘down-regulation’ or shut-down of the natural mechanism. The womb lining will be thin and ready to be stimulated to thicken with oestrogen, as with the short protocol.

52 In both short and long FET protocols, progesterone hormone will be added to the oestrogen medication to precisely prepare the womb lining for the age of the embryo at the time of expected transfer. Progesterone can be given as vaginal pessaries (tablets) or by injections. Both the oestrogen and progesterone supplements will need to be taken together until the pregnancy test and for the full three months of pregnancy if the test is positive.

3. Natural cycle FET: It is possible to perform FET in time with natural ovulation but this is much less predictable and is not suitable if the is irregular, and is not possible in immediate FET cycles. There is also a greater risk of cancellation of treatment if ovulation is missed, or if the embryo thaw happens to fall on a weekend day. We limit the number of embryos thawed per day, for safety reasons, and avoid thawing embryos at the weekends for staffing reasons.

How many embryos to thaw? Following PGT-SR/M-IVF we routinely thaw one embryo initially with a view to transferring a single embryo. If the embryo selected fails to survive the thaw, a further embryo may be thawed on the same day.

See treatment risks to find out more about multiple pregnancies following the transfer of more than one embryo - page 62.

53 Embryo transfer Please bring your treatment diary with you. You will be called by the embryologist on the day of your transfer with news of your embryo development / quality and a recommendation of the proposed number of embryos to transfer.

You will be given a time to attend (usually early afternoon) and advised to be filling your bladder in anticipation of the procedure. A full bladder helps the passage of the fine tube () containing the embryo that makes the procedure easier, quicker and safer. The procedure itself does not require any pain relief or sedation. It is similar to having a smear test. We introduce the embryo through the vagina and , guided by an ultrasound scan through the tummy. Partners are welcome to support the woman and watch from the side. After the transfer, you may empty your bladder immediately if necessary. There is no need to lie down or rest. You will be given information about your pregnancy test timing and technique.

Two-week wait You will continue the medications you have been taking after the transfer up until the pregnancy test. The medication will continue for three full months if the pregnancy test is positive.

54 After the transfer and before the pregnancy test is often described as the hardest time of an IVF treatment cycle. We will not usually need to see you during this time and generally recommend that you continue with your normal activities, in order to keep your mind off the uncertainty of the result. If you wish to exercise, we recommend low impact activity and not to swim. Pregnancy test We will advise when your urine pregnancy test is due, depending on the timing of your transfer. Instructions will be provided after your transfer procedure. First pregnancy scan The first scan is done about five weeks after the transfer when the pregnancy sac, foetal pole (baby) and a heart beat should be visible.

If all is well at this stage, we will discharge you back to your GP to make arrangements with the and antenatal clinic, and if you wish for any further antenatal screening this can be arranged through the foetal medicine unit (see prenatal testing - page 56). We shall look forward to the news of your new arrival in due course, and will then complete the information on your treatment with the HFEA register.

55 Prenatal diagnosis PGT-SR/M is a ‘pre-implantation’ test which carries a small risk of misdiagnosis. Therefore, if you do become pregnant, conventional “prenatal” cytogenetic analysis is still highly recommended. The purpose of PGT-SR/M is to decrease the risk of transferring an embryo with the genetic or chromosomal change for which PGT-SR/M was requested. However, technical limitations mean that the detection and transfer of a chromosomally normal embryo cannot be 100% guaranteed. Your midwife or genetic counsellor can help you to access prenatal testing. Chorionic villous sampling (CVS), amniocentesis and ultrasound scans are used to confirm the chromosome content of the pregnancy. Non-invasive prenatal test (NIPT), which is a blood test in early pregnancy can also be used. This may not detect all the chromosomes, so is not as comprehensive as the PGT-SR/M or standard CVS/amniocentesis tests. Again, your midwife or genetic counsellor can help to advise you.

Follow-up If a miscarriage occurs, we ask that chromosome studies be carried out on the pregnancy tissue passed, especially if the miscarriage happens at a later stage. All results from genetic testing of the pregnancy or the child up to the age of one year should be sent to the Leeds Fertility PGT coordinator. This information will remain confidential and will be used to cross check outcomes of the PGT-SR/M program.

56 Treatment Risks Risks of PGT-SR/M Risk of the cell biopsy procedure It is not yet known whether embryos that have been biopsied have the same chance of implanting as embryos that have not been tested. The biopsy itself may lower the chance of the embryo implanting. However, any reduction in success may be more than made up for by identifying a normal embryo with no reason not to implant. If an embryo is damaged by the procedure, it may not produce an embryo suitable for transfer. The risk of damaging an embryo is less than 1%. Several thousand healthy babies have now been born from IVF with PGT-SR/M. These babies do not have any more congenital abnormalities (birth defects) than occur naturally in the general population (3-5%).

Risk of preparation of biopsied cells After the biopsy procedure, the cells are placed in a small test tube. The cells are no longer viable in any way after this process and can only be used for PGT-SR/M. A fraction of the cells may not yield a test result (<5%), some may not contain any genetic material, cells may be lost during the highly technical fixation process of the test, or may have suboptimal fixation meaning they cannot be used for this complex analysis.

Risk of the test giving the wrong result No scientific test is 100% perfect. There is a small chance that the test will report normal embryos as abnormal. This is called a false positive result and happens up to 15% of the time.

57 The consequence is that a normal embryo is not transferred when it could have resulted in a healthy baby. The chance of the test reporting an abnormal embryo as normal is lower (5%). The consequence of this is that an abnormal baby may result. It is for this reason that prenatal testing during pregnancy is recommended, even after PGT-SR/M, to double- check.

Risk of having nothing available for biopsy There is a chance that no embryos will be suitable for biopsy as they have not reached the correct stage of development. In these cases, it is highly likely that the embryos that have stopped developing are chromosomally abnormal and would not produce a viable pregnancy.

Risk of no unaffected embryos The test may find that none of the embryos are unaffected, in which case there may be no embryo transfer procedure. The likelihood that this will happen is influenced by a variety of factors; the most significant are advancing female age and having a small number of embryos to work with. If there are no unaffected embryos where all the cells have the correct number of chromosomes (euploid), we will consider transferring embryos that have a mixture of normal and abnormal chromosome numbers, whereby the majority of the cells are normal (low level mosaicism), as these have been shown to produce healthy pregnancies although at a lower rate than with euploid embryos. We will discuss this with you when we give you the biopsy results. We will not transfer embryos with high level mosaicism or aneuploid embryos.

58 Risk of no diagnosis/partial diagnosis Some embryos may have no diagnosis, due to the absence of chromosomes in the sample, or technical difficulties in the fixation process. In addition, sometimes the analysis may not be clear for one of the chromosomes tested. This will be discussed with you individually if this does occur. Current PGT-SR/M techniques are unable to provide a guarantee that the child will have a normal set of chromosomes after IVF and PGT-SR/M. Smaller chromosome changes will not be detected.

Risks of IVF Ovarian hyperstimulation syndrome (OHSS) The purpose of IVF is to generate multiple eggs at once. All patients experience a mild form of hyperstimulation. A few (about 1%) will get significant symptoms and need special help or alteration to their treatment program. Patients with polycystic ovaries are particularly vulnerable and we take a number of precautions in planning the treatment.

A risk of OHSS may become apparent during the early scanning phase before egg collection. Your medication may be altered. Very occasionally, the stimulation may be abandoned altogether to be started again at a later date on a much lower dose. This is unpleasant for the woman but also can be medically risky.

59 Severe OHSS has been associated with blood clots (), dehydration and kidney problems, on top of the bloating discomfort, nausea, vomiting and diarrhoea that occur with milder forms of the condition. Some women need hospital admission to manage the symptoms and prevent complications. Most can be managed as out-patients with regular monitoring at Leeds Fertility. The condition eventually rights itself over a period of weeks. Further written information will be provided if you appear to be at risk of OHSS or indeed have signs of the condition. See separate OHSS leaflet.

If you suspect you may have symptoms of OHSS, please contact us directly at Leeds Fertility for advice (not your local hospital or GP). See back cover for contact details.

Risks of the egg collection surgical procedure At the time of the egg collection a needle is carefully passed through the skin of the vagina into the ovary under ultrasound vision. These risks are rare: •• Infection: The needle can transfer germs from your vagina into the pelvis and lead to an infection. The risk of this is higher: •• If you already have infected tubes or an active vaginal or pelvic infection. •• If you have endometriosis and especially if it is affecting the ovary in a cyst. •• If you have internal scarring involving the bowel.

60 Pre treatment sexual health screening of both partners, Dalacin antibiotic vaginal cream and clean surgical technique all minimise the infection risk. • Bleeding or internal injury: The needle could also enter a blood vessel leading to internal bleeding or damage the bowel leading to internal infection. Further treatment, including surgery may be appropriate. The risk of this complication is quite remote and less than 0.001% Other risks Although it has been suggested that the use of IVF hormones may increase the risk of , these medicines have been used in treatment for over 50 years. There have not been any cases of ovarian cancer that can be directly liked to the use of fertility treatment hormones. The available evidence suggests that there is no increase in your risk over and above that which exists naturally. Risks of ICSI Intracytoplasmic sperm injection, ICSI has been used worldwide for over 20 years in the assistance of male factor infertility. When ICSI is used because there is male factor infertility, it may also use sperm that would not otherwise be able to fertilise an egg. For these reasons, concerns about the potential risks to children born as a result of ICSI have been raised. The concerns mostly involve the risk of passing on a genetic problem that would not be transmitted under normal conception circumstances. The potential result is a fertility problem in the child, especially if it is a boy. The studies of ICSI children published so far have involved relatively small numbers of children and do not yet include effects that may be seen in older children or in the next generation.

61 Work is on-going and we would encourage patients needing ICSI to participate in long term follow-up studies. These risks apply in PGT-SR/M-IVF when there is a sperm problem, but there is less of a concern if the sperm is normal. There is no clear evidence that ICSI results in more birth defects than occur randomly with natural conception. There is also no clear evidence to give cause for concern regarding the on-going physical and intellectual development of ICSI children.

Pregnancy Risks Multiple pregnancy and the One at a Time initiative It is our joint wish to achieve a healthy pregnancy and live birth. This is more likely with a single baby at a time, rather than or more. IVF has a poor reputation for producing multiple pregnancies and these can be complicated for both mother and babies, sometimes with tragic outcomes. It is not wise to take unnecessary risks by transferring more than one embryo at a time in couples with the highest chance of success. Therefore, it is our usual policy to transfer embryos singly in women under the age of 38 years, during the first or second cycle of treatment, where the embryo development has been good overall. This practice is consistent with the HFEA Code of Practice (www.hfea.gov.uk) and the One at a Time initiative (www.oneatatime.org.uk). The chance of a pregnancy is closely related to female age (and egg quality) at the time the egg was fertilised, and to the performance of the clinic as a whole.

62 Our figures show clearly that if we have two good quality day 5 blastocyst embryos, and we transfer both together, there is a 50% chance that if pregnancy results, it will be a implantation. If we only transfer one, the chance of a pregnancy resulting at all is less than 1% lower than if two were transferred. So the price paid for avoiding twins is very small relative to the high risk of seeing a twin pregnancy through to two healthy live births. The Law permits the transfer of a maximum of two embryos in women under 40 years of age. Over 40 years, the maximum number of embryos permitted is three at any time. We will be happy to discuss your embryo development and the context of your chances of pregnancy on the day of embryo transfer, if you have any concerns about the advice proposed.

Miscarriage Performing PGT-SR/M and having a normal embryo transferred does not, unfortunately, guarantee a positive pregnancy test, a viable early scan or a healthy live birth. As with all pregnancies there is also a risk of miscarriage. PGT-SR/M testing and replacement of a chromosomally normal embryo does not eliminate the risk of miscarriage; it can only serve to reduce the risk. The risk of miscarriage after a positive pregnancy test is approximately 20-30%, whether the pregnancy has been assisted through IVF / FET or occurred through natural means. If the number of chromosomes have been checked (PGT-A or PGT-SR), and a euploid embryo has been transferred, then the risk of miscarrying is lower than this. The risk of miscarrying can be as high as 50% if a mosaic embryo has been transferred.

63 Once the pregnancy sac has been seen and the heart beat identified then the risk of miscarriage falls (<5%). The risk of birth defects in babies born after IVF is no greater than in naturally conceived pregnancies. Your personal risk is more likely to relate to your age, your family history and whether or not you have a multiple pregnancy. We ask that if you have a miscarriage, if at all possible, for the pregnancy tissue to be sent for chromosome testing.

Ectopic pregnancy Embryos do not implant immediately upon transfer. There is a small chance that an embryo may wander up and settle in the Fallopian tube. This is an ectopic pregnancy which, if unidentified, may burst and cause serious internal bleeding. Women whose tubes have been identified to be less than perfect are at higher risk of ectopic pregnancy after natural or IVF conception. We will perform your first pregnancy scan early (6+ weeks) if you are at risk. The standard first pregnancy scan is done at 7 weeks (3 weeks after your pregnancy test).

It is important to perform a pregnancy test even if you have bled, and attend for the scan after a positive test. If a pregnancy sac is not seen on scan, a blood test is taken to measure the pregnancy hormone (hCG) level in your blood. You may be asked to attend for more tests after a few days’ interval. If this hormone level is steady or slowly rising, then we may need to perform further investigations that may include a (surgery).

64 Treatment failure Possible reasons •• Failure to produce enough eggs in response to the hormone injections (weak ovaries). •• Failed release of the eggs before the egg collection (very uncommon). •• Unexpected illness in either of the partners. •• Failure of any eggs to fertilise: This may be due to problems with either the eggs, the sperm or both. •• Occasionally fertilised eggs fail to divide and continue their development. Not all fertilised eggs will divide to form embryos. •• Failure of PGT-SR/M process (see page 57). Although these circumstances do occasionally arise, they are not common.

Failure of the embryos to survive the freeze-thaw process. About 80% of embryos that were apparently good quality before they were frozen will survive the vitrification process. The majority will maintain their good quality features. Some will survive but have deteriorated. Good quality embryos can occasionally ‘repair’ themselves and still result in healthy pregnancies even if they do not score top grades at the time of the transfer. The chance of a cycle not resulting in a pregnancy is clearly higher if there are only one or two embryos available in storage and they do not survive the thaw intact.

65 It is more common for a pregnancy not to result, even when everything has apparently gone well. Sometimes we may not have an explanation for why a pregnancy fails to occur. We suspect that in most of these cases, the embryos have some sort of chromosomal change that is usually nothing to do with the reason PGT-SR/M was being performed. There is still much work to do to try to overcome what can often feel like a lottery. We welcome feedback on the various aspects of our service. We use it to ensure that we are maintaining a high standard of patient experience and to try to improve the service that we provide. We would be grateful if you would spend a few moments to complete our questionnaire once your cycle is over.

66 General Risks Risk of equipment failure Leeds Fertility maintains service contracts for all our equipment. There are also many safety checks in the laboratory to give early warning of any possible problems. Despite all our efforts, and very uncommonly, equipment failure may sometimes lead to loss of eggs or embryos. This is a ‘Category A’ incident that will be immediately notified to our licensing body (HFEA), the Leeds Teaching Hospitals Trust and to you. There would usually be a thorough investigation and steps taken to prevent a recurrence of similar problems. The HFEA also operates an Alert system which all clinics use to learn from incidents elsewhere and can then reduce risks locally.

Legal aspects of treatment: HFEA, confidentiality, consent, welfare of the child The Human Fertilisation and Embryology (HFE) Act (1990, amended 2008) and the HFE Authority (HFEA) regulate all treatments involving human eggs, sperm and embryos. The HFEA issues the Code of Practice that we work by and it inspects us regularly to ensure standards are maintained before renewing our License. All UK clinic results are reported to them and are publically available (www.hfea.gov.uk).

67 HFEA register The Authority keeps a confidential register of identifying information on all patients, their treatments, donors, recipients and children born after HFEA licensed treatments. Since 2008, adults may request information from the HFEA as to whether they were conceived with donor material and the HFEA may disclose such identifying information as was available at the time of the treatment.

Confidentiality of fertility treatment All information regarding your FERTILITY treatment is strictly confidential under our HFEA License and is subject to both the HFE Act and the general Data Protection Act. We may only communicate with your GP, referring consultant and other health care providers with your written consent. Once we have disclosed treatment information to individuals who are not subject to the HFEA License (e.g. your GP) such information can no longer be controlled by us in its onward travel. It will still be regulated by the Data Protection Act and General Law of Confidentiality, as for all private medical information. In general practice, information will be accessible to other GPs and staff working within the practice even if your consent specifically named only one of the several GPs in your practice. When changing GPs, your medical records will be transferred to your new GP practice without any regard for any specific named consent you gave us in the past. The General Law of Confidentiality will apply.

68 From time to time your notes may be inspected at Leeds Fertility for audit (standards checking) by other officials e.g. HFEA members, Care Quality Commission, Patient Safety Agency and National Care Standards Commission. You have the right to decline consent to share your fertility information but we need to consider your reasons for declining consent in our assessments. Generally, it is advisable for us to keep your GP informed of the progress of your treatment in case you need them in an emergency.

Welfare of future children The Law states that ‘a woman shall not be provided with treatment services unless account has been taken of the welfare of any child who may be born as a result of the treatment (including the need of that child for a father), and of any other child (other children in the household or the family) who may be affected by the birth’.

It is therefore our legal responsibility to have a written procedure for assessing the Welfare of the Future Child and that of any other existing child who may be affected by our treatment.

Factors considered in assessment include •• The couple’s commitment to having and bringing up a child. •• The couple’s ability to provide a stable and supportive environment for the child/children. •• The couple’s medical history and that of their families, considering factors that may risk the child’s wellbeing.

69 •• Both partner’s health (including their ages) and their ability to provide maternal and paternal nurturing to the child. •• The couple’s ability to meet the needs of the children in the event of a . •• Any risk of harm e.g. that of inherited disorders, transmissible disease, neglect or abuse. •• Any risk a new born may put on the welfare of the existing child with in the family. Our protocol has been approved by our local ethics committee. Under specific circumstances, we may also need to contact your GP, other medical specialists, authorities and agencies e.g. social workers, police etc. for information. This is to enable the members of the team at Leeds Fertility or the Clinical Ethics Committee in The Leeds Teaching Hospitals Trust to formally consider the welfare of the future child when appropriate.

Consents Fully informed consent to the different aspects of fertility treatment takes quite a long time but it is critical to ensuring you and we understand our respective responsibilities in all possible circumstances. Further relevant information will be provided through the process in written and spoken forms. Please do not sign until you are completely clear and satisfied with your stated . Both partners must sign all of the consent forms before we can proceed with your treatment. Your consent advises us of your informed choice but does not commit you to undergo any form of treatment. You have the right to change your mind until, but not after the event.

70 It is vital that all the issues are thoroughly considered beforehand and that snap decisions are not regretted afterwards. Both partners must consent to the use of their frozen embryos for the treatment of their current partner. The legal storage limit for embryos is 10 years from the date of freezing. The period of storage can be extended under exceptional clinical circumstances, with the agreement of a fertility specialist doctor. You also have to decide the fate of the embryos in the event of death or mental incapacitation. We strongly advise you to maintain current contact details with us and recommend that you consider replacement of your frozen embryos at the earliest opportunity.

Consent to fresh IVF treatment

Both partners must consent to the use of their eggs/sperm and creation of embryos with them, for the treatment of their current partner. Please note that you have to decide the fate of your spare eggs/sperm and /or spare embryos and that we act as per your written consents.

Consent to freeze sperm Your sperm may be in storage if it has been banked before treatment. Not all the sperm stored may be used in one treatment cycle leaving some surplus to your immediate needs.

71 Consent to freeze embryos All blastocyst embryos will be frozen, and at a later date it will be possible to distinguish between affected and unaffected embryos based on the PGT-SR/M testing of the cells removed. Embryo freezing can only be performed with your prior written consent. The legal storage limit for embryos is 10 years from the date of freezing. The period of storage can be extended under exceptional clinical circumstances, with the agreement of a fertility specialist doctor. You also have to decide the fate of the embryos in the event of death or mental incapacitation. We strongly advise you to maintain current contact details with us and recommend that you consider replacement of your frozen embryos at the earliest opportunity. Once we know which embryos are affected and unsuitable for transfer, you may opt to humanely discard them or donate them for training.

Consent to embryo donation You can consider donating your unaffected embryos to help another couple. Before we can accept them for this purpose, you would both be required to have counselling to ensure all the implications have been considered, and the necessary screening tests would need to be completed. You might opt to do this if / when you have completed your family, or decided not to pursue treatment further yourselves.

72 Consent to egg / sperm / embryo research All human embryo research requires specific permission (License) from the HFEA for the project in question. All research is experimental and embryos used or created during the project cannot be transferred for treatment after the project has finished. They must be allowed to perish. You may be offered the option to donate embryos for research, only if there is an active project running during the remaining time period available for your embryos to be in storage. Once the legal storage period is up, the embryos will have to be discarded. Embryos destined for research are anonymised which means that there will be no feedback to you of the outcome of the experiments. Occasionally, embryos may be specifically used in genetic projects. If the results could have implications for your or your family’s future, you will receive more information and counselling before you agree to your embryos taking part. Offering to take part in a research project is always voluntary and will never affect your own treatment. You can change your mind and pull out at any time before your embryos are used.

Consent to training of embryology scientists at Leeds Fertility Leeds Fertility is part of the Leeds Teaching Hospitals Trust and as such, is involved in the training of junior scientists. As part of training in techniques such as egg and embryo handling, freezing, thawing or injection, it is necessary to use real eggs, sperm and embryos. These will only ever be those that are not required for your treatment and would be otherwise discarded (e.g. unfertilised eggs, surplus sperm or poorly developed embryos or embryos that are chromosomally abnormal or affected by a gene mutation that has been tested for by PGT-SR/M).

73 Your consent will be requested for this, in order to train junior staff, improve our service and develop new techniques.

Consent to humane discarding of spare embryos Affected embryos can be either donated to research or for use to in training at Leeds Fertility, otherwise you must instruct us to humanely discard your spare embryos.

Consent to the use of eggs / sperm / embryos after death Men can opt to permit their female partner to use their sperm or embryos created with them after their death. There are ethical and legal concerns that you must consider very carefully before making this choice.

We strongly recommend that you have a discussion with the counsellor to consider the implications to all parties fully, if you are considering this.

74 Glossary •• Aneuploidy: extra or missing whole chromosomes. •• Biochemical pregnancy: This is a pregnancy where the embryo has tried to implant but has not continued to develop. Pregnancy hormone reaches the bloodstream and urine to make a pregnancy test positive but the level is invariably low / weak and falls to zero within days. •• Biopsy: the removal of one or several cells for examination or testing. •• Blastocyst: This is a particular stage of development of an embryo which should be reached by day 5-6 after egg collection. A blastocyst has 50-60 cells and they have begun to separate into those that will form the baby and those that will form the placenta (afterbirth). A small area of fluid separates the two types of cells. Shortly after this stage the embryo will hatch and should implant into the lining of the womb. •• Chromosome rearrangements: changes in the structure of a chromosome (see translocation and inversion). •• Chromosomes: structures of tightly wound and compacted DNA which allow for the genetic code to be stored within cells. •• Cleavage: Cleavage is the term used to describe the multiplication of the cells of the embryo. •• Deoxyribonucleic acid (DNA): biological molecule that contains genes; comprised of a sugar phosphate backbone and four nucleotide bases. •• Down-regulation: This is the first phase of treatment in a long cycle where the natural cycle is switched off. 75 •• Ectopic pregnancy: This is when the pregnancy implants somewhere other than the heart of the womb where it should be. The commonest location is in one of the fallopian tubes but ectopics can also occur in the cervix and the top corners of the womb where the tube comes into the main cavity (cornual ectopic) even when the tubes have been removed. •• Eggs: A woman’s lifetime supply of eggs is present in the ovary at birth. They reduce in number and quality with time. They pass on the woman’s half of the genetic instructions to the embryo / baby. •• Embryo: Once the fertilised egg begins to cleave (multiply its cells) it is called an embryo. •• Fertilisation: Fertilisation is when the genetic material from the egg and sperm combine to create a new and unique cell which may go on to develop into an embryo and then a baby. •• Follicles: These are the sacs in the ovary that contain the egg. One follicle develops in every natural monthly cycle. The IVF process should cause several to develop at the same time which makes the ovaries larger for a short time (several weeks). •• FSH: Follicle stimulating hormone causes the eggs to mature in the ovary. •• Genes: unique stretches of DNA which use a four letter alphabet of nucleotide bases to encode for protein creation.

76 •• Genetic counselling: the process of communicating with a specially trained professional (called a genetic counsellor) to review family and medical history within the context of genetic disease; genetic counsellors are trained to help patients determine the best health decisions for them and assist with the psychosocial adaptation of new knowledge regarding their genetic health. •• GnRH Agonist: A hormonal drug that first stimulates and then inactivates the pituitary gland e.g. Prostap, Buserelin, Naferelin. These can be used to block ovulation during long IVF cycles and cause ovulation in short IVF cycles. •• GnRH Antagonist: A hormonal drug that inactivates the pituitary gland e.g. Orgalutran, Cetrotide, only used to prevent ovulation in short IVF cycles. •• Gonadotrophins: Hormones produced naturally by the pituitary gland to stimulate the ovary to produce and release eggs e.g. FSH, LH. These drugs are produced as medicines to over-stimulate the ovary during IVF to get lots of eggs ready at once e.g. Meriofert, Menopur, Fostimon, Gonal F, Puregon. •• HCG: Human chorionic gonadotrophin is also a gonadotrophin but it is not produced in the pituitary. Normally, it is only produced by the placenta (afterbirth) during pregnancy. It is able to act like LH, but is stronger. We often use it in injection form to begin the ovulation process (trigger) before the egg collection. It can also help to prepare the womb lining for implantation. •• Inversion: a chromosome rearrangement in which a piece of a chromosome breaks off and reinserts within the chromosome in the reverse position.

77 •• Karyotype: a picture of a person’s complete chromosomal makeup. •• LH: Luteinising hormone is a gonadotrophin which causes the release of the egg at ovulation and prepares it for fertilisation by the sperm. •• Luteal phase: This is the phase after egg collection (or ovulation), including the embryo transfer, up until the pregnancy test. •• Miscarriage: Any positive pregnancy test which does not reach 24 weeks of pregnancy and the potential for a live- born child is a miscarriage. Miscarriage is as common after IVF as it is after natural conception. Bleeding in early pregnancy is not always bad news, especially if there is no cramping pain. Unfortunately, some pregnancies miscarry without any outward signs (bleeding) and are not identified until a scan is done. •• Mutation: a change in the sequence of nucleotide bases which may affect the function of a gene. •• Oestrogen: This hormone is naturally produced by the follicle in the ovary as the egg is growing. Its main job is to thicken the lining of the womb for the pregnancy to implant. It can also be given in tablet or skin patch form e.g. Progynova, Elleste. •• OHSS: Ovarian hyperstimulation syndrome is a risk of IVF treatment which can be serious if not recognised and treated. It happens when the ovaries are over-sensitive to the stimulation (FSH) injections and produce too many follicles. It can cause pain, abdominal bloating, sickness, diarrhoea, dehydration and rarely, serious blood clots. You will be warned if you are at risk, for the symptoms and signs to look out for and report to us for further advice.

78 •• Ovary: Stores all the woman’s eggs for her whole life and produces hormones. •• Pituitary gland: In the head, behind the nose, produces many hormones including those that control the ovary and testis. •• Preimplantation genetic testing for structural chromosome changes (PGT-SR): the process of testing embryos for for chromosome rearrangement prior to transfer. •• Preimplantation genetic testing for monogenic / single gene disorders (PGT-M): the process of testing embryos for for a specific single gene disorder prior to transfer. •• Preimplantation genetic testing for aneuploidy (PGT-A): the process of testing embryos for the number of chromosomes prior to transfer. •• Progesterone: This hormone is naturally produced by the follicle after ovulation and is also responsible for preparing the lining of the womb for implantation. It can also be given as a vaginal pessary e.g. Cyclogest or as an injection e.g. Gestone, Prontogest, Lubion. •• Recombination: the process by which chromosomal segments cross over to create a new combination of genetic material and thus generate diversity in the next generation. •• Sperm: The sperm develop in the man’s testes and continue to do so throughout adult life. They do not suffer the same deterioration with age as the woman’s eggs, as they are constantly being replaced. They pass on the man’s half of the genetic instructions to the embryo / baby. •• Stimulation: This is the phase where the daily injections stimulate the ovaries to produce multiple eggs.

79 •• Translocation: a chromosome rearrangement in which a piece of one chromosome breaks off and attaches to another chromosome. •• Trigger shot: (Also known as the “Late Night Injection”).This is usually hCG (5000-10,000 units) but can also be buserelin (0.5-1.0ml). This injection begins the release of the egg 35h before the egg collection. The timing is specific to you and you should follow your personalised instruction. •• Trisomy: the presence of a third chromosome copy.

80 Useful resources British Fertility Society •• www.britishfertilitysociety.org.uk The UK professional society promoting high quality practice and research.

British Infertility Counselling Association •• www.bica.net The professional association of infertility counsellors in the UK.

Endometriosis UK •• www.endometriosis-uk.org Leading UK charity providing information and support for those with endometriosis.

Fertility Network UK •• www.fertilitynetworkuk.org The UK’s leading infertility support network offering extensive information and support through treatment. They provide advice regarding funding and a variety of factsheets.

81 Health information for before and during pregnancy •• www.nhs.uk/conditions/pregnancy-and-baby/ This is a comprehensive NHS resource on preparing for and achieving a healthy pregnancy.

Human Fertilisation and Embryology Authority, HFEA •• www.hfea.gov.uk The regulatory body website has lots of information for patients.

Multiple birth matters •• www.oneatatime.org.uk This site provides information behind the drive to reduce multiple pregnancies during assisted conception treatments. •• www.multiplebirths.org.uk

•• www.tamba.org.uk These two sites offer a wealth of information on twins and multiple births / pregnancies.

Polycystic Ovary Syndrome (PCOS) •• www.nhs.uk/conditions/polycystic-ovarian-syndrome/ Pages/Introduction.aspx

•• www.verity-pcos.org.uk An NHS resource for information and a reputable patient support group.

82 The Daisy Network •• www.daisynetwork.org.uk This charity provides support and information for women who are facing premature ovarian insufficiency (premature ) and its consequences.

The Miscarriage Association •• www.miscarriageassociation.org.uk If you have been affected by miscarriage, ectopic pregnancy or molar pregnancy you will find information and support here.

83 Contact us

By post •• Leeds Fertility, Leeds Teaching Hospitals NHS Trust, Seacroft Hospital, York Road, Leeds, LS14 6UH By email •• [email protected] Online •• Web: www.leedsfertilityclinic.co.uk By telephone Mon-Fri 08.00-17.00: •• For all NHS appointments: 0113 206 3100 •• For clinical queries: 0113 206 3102 Sat-Sun 08.00-12.00 •• Clinical queries only: 0113 206 3102 In an Emergency During working hours •• Please call appointments or clinical queries as needed on the above numbers. Outside working hours •• Please call Leeds Teaching Hospitals switchboard on 0113 243 3144 and ask to be put through to the Duty Nurse / Doctor for Leeds Fertility. •• If necessary, attend your local Accident & Emergency department.

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87 © The Leeds Teaching Hospitals NHS Trust • 4th edition Ver 1 LN004204 Publication date Developed by Dr Nadine Ellissa Baskind - Consultant in Reproductive 10/2018 Medicine & Gynaecology Review date Produced by: Medical Illustration Services • MID code: 20180724_008/MH 10/2021