In Vitro Fertilization
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Introduction
Many couples faced with infertility are still unable to become pregnant after first line therapy such as ovulation induction, intrauterine insemination, or reproductive surgery. For these couples, the logical next step is to explore the Assisted Reproductive Technologies (ART).
In vitro fertilisation is a demanding procedure with emotional, physical and financial consequences. Couples are often only considered for IVF, if surgery, drug therapy and IUI have not been successful. Previously, only couples whose fertility problem was the result of blocked fallopian tubes were considered for IVF. However today, its use has extended to include couples affected by endometriosis, severe male infertility and long-term unexplained infertility.
It is important not to underestimate the demands of IVF. However as long as you prepare yourselves properly as a couple and talk about it openly and honestly, the chances are greater that you will come through the treatment well, irrespective of the outcome. The information in this section provides greater insight into the world of IVF. In this way, you will arm yourself with knowledge, which you can use to find your way in this difficult, but possibly worthwhile process.
Most IVF clinics have extensive information about IVF treatment. Make sure you read this as details of the treatment can vary from clinic to clinic. Once you have been selected for IVF treatment, it is important to find out as much as you can about the way IVF is performed at your clinic. As soon as it becomes apparent that IVF is appropriate for your situation, you can be placed on the waiting list for treatment. This waiting list can vary greatly from clinic to clinic. However, it is generally preferable to undergo treatment at the fertility clinic you are already attending due to the relationship that you have built up with the people treating you to date, or, if not available there, locally because of the travelling time associated with the frequent checkups.
The IVF Process
IVF treatment is made up of the following key phases
Stimulation of the ovaries: As several egg cells are required for IVF to maximize the chances of fertilization, the ovaries are stimulated with drug therapy.
The outcome
2 weeks later you will find out whether treatment has succeeded.
Preparation :
As soon as you are put on the waiting list for IVF an extensive consultation will take place. This will include a verbal explanation of the procedure (supported by written information) where obviously you will have the opportunity to ask questions. It is critical that everything is clear to both partners before beginning treatment. You will also be told how to use the various drug therapies needed and, where appropriate, you will be taught how to administer them. The preliminary examinations that have to take place will also be discussed with you. These might include, for example, an extra blood test (for infectious diseases or hormone assessment), or another semen analysis. Additional heredity tests (chromosomal studies) on a blood sample from the man in the case of ICSI treatment. You will also be given further information on daily practice in your clinic; it is essential that you know whom to contact, and when, if you have questions or problems. IVF treatment not only takes up a lot of time, but also demands considerable flexibility. The course and duration of the stimulation is not easy to predict, as a result of which follow-up checks and even the day of the puncture to collect the eggs can only be scheduled shortly in advance. It is important that you bear this in mind during the month of your treatment.
Treatment Plan :
There are different types and brands of the drugs that may be prescribed to you. The precise drug therapies you use will depend on your personal situation and the clinic’s general policy. Usually the women’s own hormone production must be suppressed initially. Various methods are available for this.The woman then begins daily injections to stimulate the ovaries to produce a number of egg cells. Ideally the aim is to obtain 10 (5 – 15) egg cells. The quantity of drugs (dosage) required for this is estimated in advance. Do not expect from the start, however, to always be able to predict how the ovaries will react. If there are too many egg cells, your treatment may have to be cancelled. If the reaction is moderate, the dosage can sometimes be increased during the treatment, but a treatment may also be cancelled if there are too few egg cells. Although disappointing, you can at least take some solace from the fact that this experience can be used to improve the chance of success for a possible subsequent IVF treatment.
Checkups :
The egg cells are found in fluid-filled follicles in the ovaries. The size of a follicle provides an indication of the maturity of the egg cell. During the treatment, you will have frequent checkups at the outpatients department to track the reaction of the ovaries to drug therapy using vaginal ultrasonography. The size of the follicles and the viscosity (thickness) of the cervical mucus are measured at each check-up to determine the right time for the puncture. Blood may also be taken to measure the hormone levels.
Puncture :
At the point when the egg cells are almost mature, ovulation is artificially induced by means of an injection of human Chorionic Gonadotropin (hCG). It is crucial that this injection is carried out correctly and at exactly the stated time. This injection stimulates the final maturation of the egg cells so that they are released from the follicles. The egg cells are removed from the body by needle biopsy (puncture) 35 hours after the injection.
Puncturing the follicles is called follicle puncture. The puncture is carried out via the vagina with the aid of vaginal ultrasonography. You are generally given an anaesthetic for this, although practice may vary from clinic to clinic. The vaginal ultrasonic probe is fitted with a thin needle holder. A special hollow needle is then inserted into this holder. Both the needle and the follicles are visible using ultrasonography on the monitor. The follicles are punctured with the needle one at a time and aspirated (collected). You can follow the procedure yourself on the screen.
The egg cells and surrounding fluid are drawn into a tube, which is then transferred to the embryo laboratory. The whole procedure generally takes about half an hour. The puncture itself lasts approximately five or ten minutes depending, among other things, on the number and position of the follicles. You will only find out whether egg cells have been obtained during the puncture, and if so how many there are, after the embryologist has been able to examine the fluid obtained. The number of egg cells may be lower than the number of follicles punctured, either because not all the follicles contain an egg cell or some egg cells are not fully mature.
The pain or discomfort felt during the puncture may vary from patient to patient, but is generally well-tolerated. You may also feel some discomfort after the procedure. It is therefore sensible not to make any other plans for that day. Just as with every other medical intervention, puncture carries a small risk of complications. Haemorrhages and infection are two possible complications, but are relatively rare. In general, the recovery period is short.
Fertilisation :
In the laboratory, embryologists then examine the fluid removed from the ovary for egg cells. The egg cells are graded according to their maturity, to see whether they are suitable for fertilisation. If fresh sperm is used, the male partner is asked to supply sperm. A semen analysis is then carried out and the sample is washed with a special nutrient solution to isolate the more motile sperm.
Then comes fertilisation. Exactly which process is used depends on the clinic and the type of infertility involved. In standard IVF, the sperm is placed in a dish along with the egg cells.
Within 18 hours the embryologist can tell whether fertilisation has occurred.
Within 24 to 72 hours the embryologist can tell whether the embryos are growing.
The sperm and the egg cells are placed in growth media; special nutrient solutions to give them the maximum chance to fertilise or to be fertilised. In conventional IVF, every dish containing an egg is filled with at least 50,000 sperms. In the laboratory, the embryos are then left, for between 2 – 5 days, to grow and divide into several cells. This is called an embryo culture.
Embryo Transfer :
After the puncture, the woman is often prescribed drugs to prepare the uterus (womb) for embryo transfer. Embryo transfer usually occurs two to three days after fertilisation. There are special criteria against which the quality of an embryo can be assessed.
Embryos can be classified into different quality categories. A good or perfect embryo is an embryo that the embryologist believes has a good chance of implantation. If an embryo is classified as “bad”, the theoretical chances of implantation are indeed smaller, but implantation is not ruled out. If this type of embryo does implant, it can develop into a normal pregnancy and a healthy baby.
However, embryos can usually only be assessed on external features. In some cases, closer examination of the embryo’s hereditary material can be done prior to the embryo transfer.
The best embryo, or the three best embryos at most, are placed in the woman’s uterus. The embryos are transferred into the uterus by inserting a thin tube, or catheter, through the cervix. The depth of the uterus is measured in advance to determine the right place for the transfer.
Transferring several embryos increases the risk of multiple births. A strict transfer policy (see below), is therefore adopted to try and limit the number of twins and multiple births due to the increased chance of complications. The maximum safe number depends on the age of the woman, the quality of the embryos and the success rate of the programme concerned. In Singapore, a maximum of three embryos are replaced in the woman’s uterus.
The embryo is sometimes transferred after five to seven days. As a result, the embryo has had more time to develop and is referred to as a blastocyst. During this extra time, embryologists can better identify the best quality embryos for transfer. By transferring fewer but better quality embryos, the chances of success are improved and the risk of a multiple pregnancy is reduced. Not all embryos that begin the fertilisation process grow into a blastocyst. On average, 40 to 50% of the fertilised embryos develop into blastocysts so delaying transfer allows the “survival of the fittest”.
Frozen Embryos (Cryopreservation) :
In the event that embryos remain after transfer, they may possibly be frozen in the laboratory. Freezing is only possible with good-quality embryos. The embryos have to be able to be frozen and, after thawing, replaced in a later cycle. For this reason there is strict selection procedure, which means only 10-15% of the remaining embryos are usually of sufficient quality to be frozen.
After thawing, the frozen embryos can be transferred in a normal menstrual cycle or in what is called a “cryo-cycle”, in which the woman takes hormone tablets to prepare the uterus for possible implantation. However, you must bear in mind that, once the embryos have been thawed and if the quality is insufficient, they may no longer be suitable for implantation.
The chances of success with transferring frozen embryos is lower than with replacing “fresh” embryos, but it is still an extra chance with less stress for the woman.How you and your partner feel about the freezing and storing of embryos is a very personal matter. The ethical aspects are sometimes a source of discussion and it is important that you both reach an agreement about whether you would like to use this opportunity before you start an IVF/ICSI treatment. Prior to commencement of the treatment, the centre will require a written instruction from you and your partner in which the conditions for storage are all set.
Suitable candidates for IVF are
Tube pathology
If both fallopian tubes are completely blocked, IVF is directly indicated. If the function of the fallopian tubes is reduced, IVF is only considered after other treatments. Endometriosis Depending on the severity, drug or surgical treatment will be the indicated treatment in the first instance. IVF is considered if a pregnancy has not occurred after treatment. For mild forms of endometriosis, the guidelines for unexplained subfertility are applied.
Male subfertility
ICSI is also considered in severe cases of subfertility. In less severe forms, IVF is considered after a number of IUI cycles.
Premature ovarian failure
Unexplained subfertility
No cause found after full investigation, at least 3 years of marriage, and having completed alternative approaches to fertility management for at least 1 year. However, this will not apply to female above 35 years old. Other conditions acceptable to the local obstetric/gynaecologic community. IVF shall only be carried out on a married woman and only with the consent of her husband, whether or not her husband’s semen is used. The most important reason for considering a couple for IVF at an earlier stage is the age of the woman: the chances of a pregnancy over the age of 35 rapidly reduce, and with them the chances of success after IVF. The doctor treating you will assess when and if IVF is an option for you. A strict selection is justified given that IVF is an invasive and intensive treatment with associated risks.
When does IVF not make sense?
Age
The success rate of an IVF treatment reduces with age. As the age of the woman increases, there is a greater chance that the ovaries will no longer react fully to the stimulation. This can be assessed from certain blood results, including the FSH level. In addition, the quality of the egg cells reduces and the risk of miscarriage is greater as age increases. This is therefore the reason why women over the age of 40 are generally no longer considered for IVF treatment.
Sperm Quality
Limitations caused by conditions relating to sperm quality have been enormously relaxed by the introduction of ICSI.
Risks
The advantage of any medical procedure must be balanced against the possible side effects and risks. The same applies to in-vitro fertilisation (IVF).
Because the IVF process involves various stages, patients can experience different side effects at different times.
The drugs used in IVF treatment can cause side effects such as mood swings and headaches. Besides side effects, risks are also associated with the use of these drugs. Because you are going to use drugs that have to stimulate the ovaries to produce several eggs, the ovaries may overreact. This can be assessed by ultrasound checks, as a result of which either too many follicles are seen or the ovaries have increased greatly in size. It is possible that, in the period following the puncture, the ovaries will be even more disturbed and release fluid into the abdominal cavity. This is called overstimulation. Fluid is released into the abdomen, which can lead to complaints of stomach ache, nausea, vomiting, serious weight gain (> 1 kg/day), breathlessness and reduced urine production (ovarian hyperstimulation syndrome, or OHSS). In severe cases, fluid may accumulate in the lungs causing breathing difficulties. If an ultrasound scan shows that the ovaries are overreacting, the treatment is stopped. If the reaction is still acceptable, but there is a risk of overstimulation, you will be given separate instructions. If any of the symptoms described above occur, you must contact your doctor directly. The doctor will perform an ultrasound scan to determine the size of the ovaries and to see if there are cysts (fluid-filled blisters) in them. The doctor will also look to see if there is free fluid in the abdominal cavity and carry out blood tests. Generally you should wait, rest and drink plenty of fluid, although admission to hospital may be required once in a while.
Although the risks of the rupture are slight, occasionally haemorrhage or very rarely infections can occur. Organs in the vicinity of the ovaries, such as the bladder or the intestines, are rarely damaged during the puncture.
Although the work on egg cells, sperm and embryos is done with the greatest care in the laboratory, IVF remains the work of humans – and subject to human error. Fortunately human errors are made very rarely.
There is a chance of a multiple pregnancy. A strict transfer policy is operated in order to maximise the chance of a pregnancy but minimise the chances of a multiple pregnancy. Even if a single embryo is transferred, a (single-egg) twin can result, just as in a natural course of events. If two embryos are replaced, the chances of having twins are 25% and for triplets 1%, which is why the risk of complications as a result of multiple pregnancies (such as miscarriage, premature birth or diabetes) is kept as low as possible.
While a positive pregnancy test is a promising sign of a successful treatment, pregnancy goes wrong in approximately 25% of cases. There is a 20% chance of a miscarriage and a 5% chance of an ectopic pregnancy.
At the present time, no increased risks have been demonstrated in the incidence of hereditary defects in children conceived through IVF. If there is an indication of this, for example, the age of the woman (36 years or older), or hereditary defects in the family, prenatal diagnoses can be carried out.
Finally, the IVF process can be psychologically stressful. Patients are well advised to take steps to reduce stress, such as keeping good health, using relaxation techniques and seeking help and support from family or professionals.
Weight
Being seriously overweight not only has an effect on fertility, but also on general health and therefore on a possible pregnancy. In addition, ovaries for IVF have to be accessible for puncture. Sometimes this is scarcely possible in heavier women. Therefore, weight loss is a necessity in some cases before a possible treatment.
Pregnancy
The woman has to be able to carry a pregnancy to term.
The IVF clinic concerned will carefully map out your situation, after which it will decide whether you can be considered for IVF.
Success Rates
How great are the chances of success?
In an IVF treatment, the chance of pregnancy per cycle is around 20% on average. However, this is highly dependent on individual circumstances such as age, sperm quality and the number and quality of the embryos. In addition, not all pregnancies lead to a live-born child. 1/4 of all pregnancies begun end in a miscarriage (20% of the total) or in an ectopic pregnancy (5%).
Because there are new chances with every cycle, half the couples on average return home with one child or more after three attempts.IVF results can be displayed in various ways. The following definitions have been used:
Started cycle
IVF attempt, from the start of the drugs to stimulate follicle growth.
Follicle puncture
Ovary puncture with the aim of obtaining egg cells.
Embryo Transfer
Placing of embryos in the uterine cavity.
Pregnancy
Positive test in urine or serum (>50 IE/L), no earlier than 15 days after the puncture.
On-going pregnancy
Intact intra-uterine pregnancy, > 10 weeks after the puncture.
Confidence interval
Interval in which there is a 95% certainty.
The number of continuing pregnancies per cycle started has been chosen as the method of recording and comparing the IVF figures. This percentage tells us something about the care delivered by a centre – but is far from the whole story.
Firstly, this percentage is dependent on all sorts of other factors, such as the age of the woman, the length of time she has wanted a child and the number of previous treatments. These factors may vary from centre to centre. For example, if a centre primarily treats older women, that centre’s chances of a pregnancy will be lower.
Secondly, this percentage may vary from year to year for unpredictable causes. It therefore makes sense to look at the results over several years.Finally, other factors such as patient satisfaction, the percentage of complications and the percentage of multiple births are also important to the quality of care. If several embryos are transferred, for example, not only do the chances of a pregnancy increase, but so also do the chances of multiple births with all the associated risks.