IVF and Fertility Treatments

Understanding your medical treatment empowers you to take a much more proactive role in your fertility journey and helps ensure things go smoothly. It also allows you make the right choices for you based on sound knowledge. In this section we look at:

• Do I need IVF?
• What is IVF?
• Preparing for IVF
• What are gonadotrophins?
• How IVF works
• Stimulation of the ovaries
• Agonist or long stimulation protocol
• Disadvantages of the long protocol
• Antagonist or short stimulation protocol
• Advantages of the short protocol
• Ovarian reserve and predicting response to stimulation
• Ultrasound monitoring
• Egg (oocyte) collection
• Embryo transfer
• Single versus double embryo transfers
• Luteal support
• Intracytoplasmic Sperm Injection (ICSI)
• Frozen embryo transfers
• Freeze-all IVF cycles
• Intrauterine Insemination (IUI)

Do I need IVF?

If you have been diagnosed with blocked tubes, unexplained infertility, male factor infertility or polycystic ovary syndrome (PCOS) that hasn’t responded to treatment to stimulate ovulation (ovulation induction), the next step in your medical journey is assisted conception. For most people, this usually means in vitro fertilisation (IVF), though there are other options that are less commonly used, mainly for unexplained infertility. However, couples sometimes start IVF before all other treatments have been exhausted. While we do not encourage unnecessary delay, particularly in older patients, the notion that IVF is the high-tech modern answer to every couple’s subfertility is incorrect. The stresses of IVF (and other assisted conception procedures) can be huge, and the treatment has risks and complications (for example, ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy. Some like to proceed to fertility treatments quickly and others prefer to avoid high-tech treatments for as long as possible, however, in women over 35 years, we do believe that IVF should be offered as first-line therapy for unexplained infertility.

What is IVF?

‘In vitro fertilisation’ literally means fertilisation in glass. In practice, this means we collect eggs and sperm, prepare them in the laboratory and mix them in a Petri dish to ensure they are brought close together to give maximum opportunity for fertilisation before transferring the embryos that are created back into the womb, usually one at a time. IVF has revolutionised the treatment of infertility and given people who once would never have been able to conceive the chance to have their own children. Reproductive medicine is still a rapidly evolving branch of healthcare that is subject to intense scrutiny and regulation as it involves cutting-edge science. If you have got to this point, you will have been on a long journey, which can be challenging emotionally. We hope that by helping you understand your medical treatment in this ever-changing field, it will make the journey a little easier.

Preparing for IVF

Whether you’re providing eggs or sperm to your fertility treatment, or are to carry the pregnancy, you can prepare for IVF by following a preconception care programme ideally for 3-6 months before treatment. The preconception health of both the father and the mother has the potential to impact outcomes, including egg and sperm quality, the health of the pregnancy and the health of the baby. Many women enter pregnancy with low levels of key nutrients needed for the development of the baby, so having the appropriate tests and taking supplements where needed is an important aspect of your care. Following a Mediterranean diet has been associated with improved outcomes following fertility treatment in numerous studies. We cover the many dietary and lifestyle factors that are important in helping you prepare for a healthy pregnancy in our Fertility and Preconception Care course.

What are gonadotrophins?

Gonadotrophins are hormones that act on the gonads (ovaries and testes). Gonadotrophin is the collective term for the two hormones produced by the pituitary: follicle-stimulating hormone (FSH) and luteinising hormone (LH). Together they help coordinate the growth of the follicle, the maturation of the egg within it and the production of the ovarian hormones (testosterone, oestrogen and progesterone) that prepare the uterus (womb) for a pregnancy. These hormones therefore all work together to synchronise your menstrual cycle and the development of follicles in the ovary.

How IVF works

IVF involves five main stages:

1. stimulation of the ovaries
2. ultrasound monitoring
3. egg collection
4. embryo transfer
5. luteal support

Sperm preparation is also needed, whether preparing a fresh sample provided on the day of egg collection or thawing of a frozen sample.

1. Stimulation of the ovaries

The first stage of your IVF treatment is to stimulate the ovaries to capture all the follicles that are growing at the start of the cycle (so called ‘superovulation’) rather than with a natural cycle, where normal levels of the main hormone FSH generally only enables a single follicle to grow and ovulate. To stimulate the ovaries to allow more eggs to be collected as part of your IVF, higher doses of FSH are given than in a natural cycle. The aim is to stimulate 10–15 follicles, and collect mature eggs from the majority of them.

You also need to be given a second hormone (either a gonadotrophin-releasing hormone (GnRH) agonist or antagonist) to prevent ovulation, so that the eggs cannot be released and lost before they are physically collected from the ovaries during your egg collection.

IVF stimulation protocols have become increasingly simplified in recent years and there are different drug options for your clinic to choose for your treatment using either GnRH agonists or antagonists.

Agonist or long stimulation protocol

The ‘long’ protocol uses a GnRH agonist to switch off the natural menstrual cycle – known as pituitary desensitisation or down-regulation. This usually takes 10–14 days. GnRH agonists can be delivered by a nasal spray or as a short-acting daily or long-acting monthly subcutaneous (just under the skin) injection. You will be assessed by an ultrasound scan which will show that the endometrium is thin (< 5mm) and the ovaries are inactive. Some clinics measure hormones in the blood and start the next treatment when LH is < 5IU/L and oestradiol is < 150pmol/L (progesterone, if measured, should be < 3nmol/L). Most clinics, however, go by the scan alone.

Treatment with hormone injections containing FSH to stimulate your ovaries then starts at the beginning of your period (either day 1 or 2). Daily injections of the GnRH antagonist then follow on day 5 or 6 of stimulation or once the largest follicle(s) has reached a diameter of 14mm. The GnRH antagonist acts immediately to stop you ovulating by inhibiting natural production of FSH and LH. Follicles will grow at different rates and we usually like to see at least three that are larger than 17mm in diameter. Any follicle bigger than 14mm is likely to contain mature eggs. Once the follicles have grown appropriately, the egg collection can be timed precisely 35–36 hours after an hCG injection. If the egg collection doesn’t take place, the ovaries would be expected to release the eggs about 40–44 hours after the hCG injection.

Disadvantages of the long protocol

A disadvantage of the long protocol using GnRH agonists is the 10–14 days lead-in to treatment before stimulation can start. Not only does this extend the treatment cycle, but pituitary down-regulation (switching off the natural menstrual cycle) causes menopausal symptoms due to oestrogen deficiency (including hot sweats, mood changes and vaginal dryness). Some clinics prefer to start GnRH agonist therapy on day 21 of your cycle. They believe that desensitisation happens more rapidly than if it is commenced on day 2 of menstruation in the following cycle. A day 21 start, however, carries the risk of ‘rescuing’ a corpus luteum (the remnant of the follicle after ovulation) from the last natural ovulation. This can cause an ovarian cyst that can then disrupt treatment. Also a day 2 start virtually guarantees you are not pregnant (although GnRH agonists are not harmful to take if you are).

Antagonist or short stimulation protocol

Antagonist cycles are shorter and more popular than longer protocols as they are newer forms of treatment that are kinder on the body. Treatment can also be scheduled more easily as the combined oral contraceptive pill (COCP) or progesterone can be given for a short time to delay your period and therefore the start of stimulation. You may therefore be given one of these drugs before you start stimulation, which simply allows your egg collection to be scheduled more accurately – often to suit your clinic’s timetable. The use of COCP or progesterone is usually stopped three to five days before stimulation commences.

The next stage is stimulation of the ovaries, and this part of the treatment is the same as for the long protocol above, including using the same criteria when monitoring the maturation of the eggs. Egg collection is then performed 35–36 hours later.

A single shot of a GnRH agonist can be used as an alternative to hCG in a short GnRH antagonist cycle. This strategy reduces the risk of OHSS because of the shorter time (‘half-life’) the agonist stays active in the body compared with hCG. If this approach is taken, luteal support (described below) has to be modified with either the combined use of progesterone and oestrogen supplementation or additional hCG in the luteal phase (at a low dose in order to minimise the risk of OHSS).

Advantages of the short protocol

GnRH antagonists in a ‘short protocol’ are a more recent development that have enabled us to skip the 10–14 days of down-regulation of the long protocol. Women usually prefer these protocols as they are shorter and have fewer side effects (for example, avoidance of symptoms of oestrogen deficiency during pituitary desensitisation). Furthermore, there is a similar probability of a live birth when either GnRH agonists or antagonists are used.

Ovarian reserve and predicting response to stimulation

Predicting an individual woman’s response to stimulation is the hardest part of fertility treatment: young women and those with polycystic ovaries tend to respond well (and may over-respond), while older patients and those with reduced ovarian reserve respond less well. How you may respond to stimulation is based on your ovarian reserve and this is done by assessing your antral follicle count (AFC) and measuring your anti-Müllerian hormone (AMH). Your specialist will plan the starting dose of the stimulation based on these results.

As ovarian reserve declines, so too does the chromosomal integrity of the eggs that are ovulated, so that there is a fall in the development of healthy embryos and a rise in the rates of miscarriage and fetal chromosomal abnormalities.

Having polycystic ovaries, whether or not there is overt PCOS, means your ovaries are likely to respond sensitively to stimulation and produce lots of follicles. This does not necessarily mean you will get the same number of good-quality eggs, however. Patients with polycystic ovaries are also at the greatest risk of developing OHSS during treatment.

If you have polycystic ovaries (whether or not there are signs of PCOS), we recommend reducing the starting dose, depending upon age and previous response to stimulation, and starting ultrasound monitoring earlier (day 6 or 7 of stimulation). Your specialist may also reduce the dose of FSH as soon as follicles greater than 10mm in diameter have been recruited. Your response should be reviewed after each cycle of treatment and the dose of stimulation adjusted according to this response.

2. Ultrasound monitoring

After stimulation has started, your ovarian response will be monitored by ultrasound scans. The dimensions of the growing follicles are recorded either daily or every other day, from around day 8 of stimulation, together with a measurement of endometrial thickness. The daily measurement of oestrogen in the blood is of little help in predicting either success or the development of OHSS and adds to the cost of treatment. The hCG ‘trigger’ is usually given when the leading follicle is at least 17–18mm in diameter and there are at least three follicles greater than 17mm.

There is current interest in the measurement of progesterone on the day of hCG, as there is some evidence that if it is high at that point, the outcome of treatment is less good. In this case, there would be a case for freezing any embryos and using them in the future. This approach hasn’t been universally accepted and is an area of ongoing research.

3. Egg (oocyte) collection

The next stage of your IVF treatment is egg collection. You will usually have your ultrasound-guided oocyte retrieval (the ‘egg collection’) under light sedation with pain relief (combinations of benzodiazepines, midazolam, opiates and sometimes propofol are given intravenously). You may also be given a local anaesthetic into the top of the vagina. The procedure should be pain-free and you will be monitored during and after the egg collection. As you will be only lightly sedated, you may be shown the eggs on a closed-circuit video monitor attached to the embryologist’s microscope. Most clinics do not allow your partner to be present for the egg collection because of the overall stress of the situation, in an unfamiliar environment, seeing a partner sedated and having an invasive procedure. Both partners can, however, be present at the embryo transfer.

During the egg collection the ultrasound probe is inserted into the vagina. A long needle is passed through a needle guide; the needle is attached to plastic tubing which in turn has a pump attached to the end to suck the fluid from the follicles and obtain the eggs. It isn’t possible to see the eggs on the scan or with the naked eye and so the test tube with the fluid from the follicle is passed to an embryologist who can identify the eggs by looking down a microscope. Sometimes it is necessary to inject some fluid through the needle to flush the egg out of the follicle.

The egg retrieval procedure should take about 15–20 minutes and is relatively free of risks. Occasionally there may be bleeding from the point at which the needle passes through the vagina and you may need a stitch. Less commonly, the ovary may bleed after the procedure and this may very occasionally require an operation to stop the bleeding. Infection is also an uncommon occurrence and many clinics provide prophylactic antibiotics to minimise any risk.

After the egg retrieval, the semen is washed and prepared. Sperm is usually added 1–6 hours later with 50–200,000 motile sperm being placed with each oocyte; 16–18 hours later the oocytes are examined to ensure that normal fertilisation has happened. If intracytoplasmic sperm injection (ICSI) is needed, a single sperm is injected into each of the mature eggs.

Approximately 80–85 per cent of the eggs collected are expected to fertilise. They are then observed as they develop into embryos over the next five days. Traditionally, the dish containing the embryos was removed from the incubator on a daily basis to inspect their development. Nowadays we use a sophisticated incubator (known as an Embryoscope) which has a time-lapse camera within to take a photo of each embryo every ten minutes so that the precise timing of each cell division can be observed in order both to identify which embryos are developing normally and to avoid having to remove them from the incubator and disturb the environment in which they are growing. We have published data showing that the use of the Embryoscope has significantly improved the success rates in our clinic.

4. Embryo transfer

You will usually have an embryo transfer five days after the egg collection when the embryos have reached the blastocyst stage of development. A few years ago, the transfer was done on day 2 of development and then this was extended to day 3 and now to day 5. By this stage, we can better tell which are the highest quality embryos and so can choose either the best for transfer or freezing. Those embryos that do not develop normally are then discarded. Blastocyst transfer is thought to better mimic natural conception by synchronising the embryo development with the readiness of the endometrium for implantation. It also means that you have your embryo transfer when any uterine contractions following the egg collection have reduced.

The embryo transfer procedure usually takes five to ten minutes. A fine plastic catheter is inserted through the cervix into the uterus under ultrasound guidance. A narrower catheter is then inserted inside this which carries your precious embryo into your womb. This means the specialist can see it clearly as it enters the middle of the uterine cavity. After the embryo transfer it is fine to go about your normal daily activities. Indeed, it’s best to keep busy as the two weeks up to the pregnancy test are hard to cope with as you don’t have to attend the clinic for regular scans and monitoring.

Single versus double embryo transfers

The aim, whenever possible, is to transfer a single embryo, as there is good evidence that the transfer of more than one good-quality embryo does not increase the chance of a pregnancy developing, but instead significantly increases the risk of a twin pregnancy to as high as 50 per cent. In the UK, a maximum transfer of two embryos is permitted in women under the age of 40 and three in those older (although if frozen embryos or donated eggs are being used it is the age of the woman at the time the eggs were collected that is considered).

5. Luteal support

Progesterone treatment to support the second part of the cycle and early pregnancy if treatment is successful (known as luteal support) is started on the day of egg collection. It is usually given as pessaries or injections and continued until the day of the pregnancy test. Some clinics continue luteal support for up to 12 weeks of pregnancy, although this is unnecessary particularly if progesterone pessaries have been used. No one protocol or means of delivery of luteal support has been shown to be superior to another, though most women tend to prefer vaginal progesterone to injections. While a number of additional medications have been proposed to enhance implantation, such as aspirin and intralipid, there is no evidence for any benefit.

hCG injections can be given, but most clinics these days give progesterone. hCG should be avoided if there is any risk of OHSS as it will continue to stimulate the ovaries, while progesterone instead replaces the production of progesterone from the ovaries. Many clinics, including our own, have now stopped giving hCG because OHSS is not always easy to predict.

Intracytoplasmic Sperm Injection (ICSI)

For you to have standard IVF, you need to have a semen sample with a good sperm count for a reasonable chance of success. This means there needs to be more than 500,000 motile sperm in the total ejaculate. In cases where the sperm count is lower, lab techniques can be used to help things along. ICSI involves the injection of a single sperm cell (spermatozoon) directly into the cytoplasm (ooplasm) of the egg. ICSI revolutionised the management of male infertility. It now allows men whose partners previously would have needed donor insemination to be the biological fathers of their own children. ICSI is used not only for men with very low sperm counts but also for those with obstructive azoospermia, after microsurgical or direct aspiration of sperm from either the epididymis or the testis.

Fertilisation rates with ICSI are in the region of 60–70 per cent, irrespective of the origin of the sperm, providing 90 per cent of couples with an embryo transfer and chance of a pregnancy. Pregnancy rates after ICSI are the same as after IVF and so there is no advantage in using ICSI if there isn’t a problem with the sperm. ICSI is, however, sometimes offered to couples in whom fertilisation has failed during IVF in the absence of an apparent sperm problem.

Frozen embryo transfers

Many IVF cycles result in the creation of surplus good-quality embryos that can be frozen for future use. If you’re having a frozen embryo cycle, your embryo will be removed from storage in liquid nitrogen to thaw on the day of your transfer. Embryo survival is in the region of 80 per cent after freezing and thawing. You will usually have a thawed embryo transferred five days after ovulation in carefully monitored natural cycles. Most clinics, however, use a hormone-supported cycle as this is more predictable and also better for planning. If you’re having treatment in an artificial cycle, you will first have a GnRH agonist to switch off your cycle and then oestrogen (tablets) to develop the endometrium for at least 12 days. A scan is performed to ensure the endometrium has thickened, usually to at least 8mm and then progesterone is commenced (as either pessaries or injections, or a combination of both). The embryo transfer if planned after five days of progesterone if the embryos have been frozen at the blastocyst stage. The oestrogen and progesterone are continued until the pregnancy test two weeks later and then to twelve weeks’ gestation if the treatment is successful. Alternatively, in a shorter cycle you may be given a GnRH antagonist, instead of the GnRH agonist, during the first seven days of the treatment cycle.

Freeze-all IVF cycles

There has been a lot of interest in the elective freezing (cryopreservation) of all embryos and later transfer of embryos in a subsequent frozen embryo cycle – so-called ‘segmentation of IVF’. This is thought to help with healthy implantation when compared to the high hormone levels of a fresh cycle. This has also been shown to improve live birth rates in the subsequent frozen embryo cycles, particularly for those women with polycystic ovaries. This approach has yet to gain widespread popularity and, of course, relies upon a good-quality cryopreservation programme.

Intrauterine Insemination (IUI)

Intrauterine insemination (IUI) is a form of fertility treatment where a prepared sperm sample is inserted directly into the womb. Historically, IUI has been used to treat unexplained fertility but IVF is more commonly used as it is much more successful. You can be treated with IUI if you need to use donor sperm, however. IUI of a prepared sample of sperm became a popular treatment for ‘mild’ male infertility when the total motile count after preparation is greater than 1 x 106/ml. IUI may be performed in a natural cycle or with mild stimulation of the woman’s ovaries (which carries the risk of multiple pregnancy). Unfortunately, studies of both stimulated and unstimulated IUI for male infertility have failed to show any real benefit and so are no longer recommended.

It also used to be thought that clomiphene (a drug used to stimulate ovulation) enhanced fertility by correcting a subtle defect in ovarian function – either of follicular development or of the luteal phase. It appears more likely, however, that stimulation of ovulation works by increasing the number of follicles that develop and consequently the number of eggs that are released – indeed there is at least a 10% risk of multiple pregnancy. Overall, however, there is no clear evidence for the use of clomiphene in the treatment of unexplained infertility even if combined with IUI. Similarly, the use of gonadotrophin injections alone in the treatment of unexplained infertility appear to have limited benefit and again carries the risks of multiple pregnancy and also ovarian hyperstimulation syndrome (OHSS).

There has been quite a bit of controversy surrounding the use of IUI with gonadotrophin therapy, as some studies have shown no benefit over gonadotrophin therapy with monitoring and timed intercourse whilst others have demonstrated that the use of IUI improves the ongoing pregnancy rate. Overall IUI with ovarian stimulation appears to have a potential, albeit relatively limited role in the management of unexplained infertility. In the UK, however, the NICE guidelines do not recommend the use of IUI with ovarian stimulation because of the risk of multiple pregnancy, hence it is not funded by the Health Service and this has caused a lot of debate and unhappiness.

References

1. Adam Balen and Grace Dugdale. The Fertility Book: Your Definitive Guide to Achieving a Healthy Pregnancy. Penguin Random House (Vermilion) 2021
2. Preconception health 1: Judith Stephenson, Nicola Heslehurst, Jennifer Hall, Danielle A J M Schoenaker, Jayne Hutchinson, Janet E Cade, Lucilla Poston, Geraldine Barrett, Sarah R Crozier, Mary Barker, Kalyanaraman Kumaran, Chittaranjan S Yajnik, Janis Baird, Gita D Mishra. Before the beginning: nutrition and lifestyle in the preconception period and its importance for future health Lancet 2018; 391: 1830–41
3. Dimitrios Karayiannis, Meropi D Kontogianni, Christina Mendorou, Minas Mastrominas, Nikos Yiannakouris, Adherence to the Mediterranean diet and IVF success rate among non-obese women attempting fertility, Human Reproduction, Volume 33, Issue 3, March 2018, Pages 494–502
4. Salas-Huetos, A., Babio, N., Carrell, D.T. et al. Adherence to the Mediterranean diet is positively associated with sperm motility: A cross-sectional analysis. Sci Rep 9, 3389 (2019).
5. Thomsen, L. H., Kesmodel, U. S., Erb, K., Bungum, L., Pedersen, D., Hauge, B., Elbæk, H. O., Povlsen, B. B., Andersen, C. Y., & Humaidan, P. (2018). The impact of luteal serum progesterone levels on live birth rates – a prospective study of 602 IVF/ICSI cycles. Human Reproduction, 33(8), 1506–16.
6. Mascarenhas, M., Fox, S. J., Thompson, K., & Balen, A. H. (2019). Cumulative live birth rates and perinatal outcomes with the use of time‐lapse imaging incubators for embryo culture: A retrospective cohort study of 1882 ART cycles. BJOG: An International Journal of Obstetrics & Gynaecology, 126(2), 280–6.
7. Moolenaar, L. M., Cissen, M., De Bruin, J. P., Hompes, P. G., Repping, S., Van Der Veen, F., & Mol, B. W. J. (2015). Cost-effectiveness of assisted conception for male subfertility. Reproductive Biomedicine Online, 30(6), 659–66.

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