Assisted Conception

This is the most used assisted conception technique worldwide. IVF literally means fertilisation "in-glass", hence the origin of the name "test tube baby". For IVF, eggs are collected from the ovaries and then put together with sperm to fertilise in a laboratory dish before being transferred into the uterus (womb).

Ovarian stimulation protocol

IVF involves taking daily fertility drugs (hMG or recombinant FSH or recombinant FSH/LH with or without GnRH agonist or antagonist) to stimulate the ovaries to produce a high number of oocytes (eggs). The recruitment and development of follicles, which contain the eggs, is tracked by regular transvaginal ultrasound scans and sometimes blood tests. When at least three follicles are mature (greater than 17mm in diameter) a hormone injection (hCG) is given to ripen the eggs. Egg collection is performed generally under ultrasound guidance, and very seldom using laparoscopy 34-36 hours later. The egg collection procedure takes about 20 minutes.

The ovarian stimulation protocol is individualised to maximise the chances of success while reducing the risks, complications and possibly the costs of treatment.

Natural cycle

Sometimes it is possible to proceed to IVF without using any drugs for ovarian stimulation. In most cases only one or two eggs are collected but immature eggs can be matured in vitro before being fertilised. In most cases only one healthy embryo is available for transfer. Usually there are not enough embryos to be stored. Some people argue that using "natural cycle IVF" the endometrium (lining of the womb) may be more receptive to the implanting embryos.

What is IVF?

Once collected the eggs are placed in a laboratory dish, mixed with the sperm, which in most cases has been produced on the same day, and left overnight to fertilise. Following fertilisation, one or two embryos are transferred into the uterus through the cervix using a fine and thin tube called catheter. The healthy embryos can be transferred two to five days after fertilisation. Embryo transfer may be done under ultrasound guidance. Any good quality suitable remaining embryos may be frozen for future use.

Who are the candidates for IVF?

a) women whose fallopian tubes are blocked, damaged or absent
b) men whose sperm is moderately abnormal (count and/or motility)
c) couples in which previous IUI treatment cycles have failed
d) couples who are known to be at risk of genetic disease or who have already had a child with a serious genetic disease and require preimplantation genetic diagnosis (PGD)
e) women with a history of severe pelvic endometriosis with altered pelvic anatomy because of scarring and adhesions
f) women who have hormone imbalance and require high doses of fertility drugs

The success rate of IVF measured as live birth rate can be as high as 40% per
cycle with fresh embryos and up to 25% with frozen embryos.

Risks and complications of IVF

Failure of treatment -- this can result from cycle cancellation because of no response or over-response to stimulation drugs, failure to collect eggs, failure to fertilize eggs, failure of the embryos to develop normally and failure of implantation.

Failure of treatment can result in emotional strain, psychological stress and depression, and some couples may require psychological counseling.

Risks associated with egg collection -- discomfort, bleeding, infection and injury to organs (bladder and bowel).

Multiple pregnancy -- more than one fetus grows at any one time in the uterus (womb) after the transfer of two or more embryos. This is the single greatest complication of IVF treatment. Although the prospect of twin or triplets may seem attractive to some couples, high order of multiple pregnancies are associated with increased risks of maternal and fetal complications throughout pregnancy. In addition, multiple pregnancies place enormous strains for the parents including financial difficulties, emotional distress and physical exhaustion.

Ovarian hyperstimulation syndrome (OHSS) -- potentially a very serious condition which result from over-stimulation of the ovaries following treatment with fertility drugs. Several follicles develop in each of the ovaries and fluid collects in the abdomen. In severe cases (1-2%) fluid may fill the entire abdominal cavity and the chest. Admission to the hospital may be required and IVF treatment abandoned in that cycle.

Ectopic pregnancy -- when an embryo develops and implants outside the womb, generally into the fallopian tube. Women undergoing IVF treatment because of problems with their tubes have a greater risk of having an ectopic pregnancy. This can be a serious condition and admission to the hospital may be required.

This is a more sophisticated technique as compared to conventional IVF. Up to the point of egg collection, ICSI and IVF do not differ.

Ovarian stimulation protocol

Daily fertility drugs (hMG or recombinant FSH or recombinant FSH/LH with or without GnRH agonist or antagonist) are necessary to stimulate the ovaries to produce a high number of oocytes (eggs). The recruitment and development of follicles, which contain the eggs, is tracked by regular transvaginal ultrasound scans and sometimes blood tests. When at least three follicles are mature (greater than 17mm in diameter) a hormone injection (hCG) is given to ripen the eggs. Egg collection is performed generally under ultrasound guidance, and very seldom using laparoscopy 34-36 hours later. The egg collection procedure takes about 20 minutes.
The ovarian stimulation protocol is individualised to maximise the chances of success while reducing the risks, complications and possibly the costs of treatment.

Natural cycle

Sometimes it is possible to proceed to egg collection without using any drugs for ovarian stimulation. In most cases only one or two eggs are collected but immature eggs can be matured in vitro before being fertilised. In most cases only one healthy embryo is available for transfer. Usually there are not enough embryos to be stored. Some people argue that using "natural cycle" the endometrium (lining of the womb) may be more receptive to the implanting embryos.

What does ICSI involve?

This assisted conception technique involves injecting a single sperm directly into the centre (cytoplasm) of an egg, which when fertilised is transferred in to the uterus (womb) using conventional embryo-transfer methods. ICSI is carried out using a piece of equipment known as "micromanipulator".
In details, the ICSI injection process involves holding an egg by gentle suction with a microscopic tube and then picking up and injecting a sperm into the centre of this egg using a very thin glass pipette. The eggs are then left overnight in the incubator for fertilisation. The next day the embryologist assesses the eggs for fertilisation.

Who are the candidates for ICSI?

a) couples whose male partner has severe sperm abnormalities with low sperm count, reduced sperm motility, an high number of sperm with an abnormal appearance, or where there are antisperm antibodies, that cause sperm to stick together
b) couples who have had failed IVF treatment because of failed fertilization
c) couples whose male partner has no sperm in the ejaculate but sperm can be retrieved surgically from the testes using techniques like percutaneous sperm aspiration (PESA) or testicular sperm extraction (TESE)
d) women who use frozen eggs

Like IVF, the success rate of ICSI measured as live birth rate can be as high as 40% per cycle with fresh embryos and up to 25% with frozen embryos.

Risks and complications of ICSI

The risks associated with egg collection, the risk of ectopic pregnancy and the risk of ovarian hyperstimulation syndrome (OHSS) are the same as IVF. The risk of multiple pregnancy after ICSI is the same as IVF, but it has been reported an increased incidence of monozygotic twinning with ICSI. The risk of failure of treatment in terms of failed fertilization is lower with ICSI as compared to IVF.

Regarding any genetic risks, it has been reported that the risks of birth defects in children conceived after ICSI may be higher than natural conception. Studies in the literature suggest that the increased incidence may be attributed to parental characteristics, including the casue of subfertility and chromosomal abnormalities, rather than the use of assisted reproductive technology itself. There is a 1.4-2.0 fold increase in the rate of birth defects following assisted conception as compared to natural conception. Children born after ICSI have a higher rate of chromosomal abnormalities either inherited from paternal structural chromosomal abnormalities or de-novo. A proportion of men with severe sperm problems have a genetic basis for this, usually an abnormality of the Y chromosome. This is likely to be inherited by male offspring after ICSI. Children conceived by ICSI appear to have more congenital abnormalities, particularly urogenital defects, which can be surgically corrected. Overall the data in the literature are rather reassuring for the long-term consequences of children born after IVF/ICSI.

What is IUI?

This is a relatively simple fertility treatment that involves inserting prepared sperm into the uterus (womb) around the time of ovulation (release of an egg) using a very fine tube known as a catheter. IUI is usually the first line treatment for unexplained subfertility. It is necessary that the fallopian tubes are patent (healthy) and the sperm is normal before embarking upon IUI.

The majority of clinicians prefer to stimulate a woman's egg production by prescribing fertility drugs to be taken during the first part of the monthly cycle. The recruitment and development of follicles, which contain the eggs, is tracked by transvaginal ultrasound scans. When a follicle is mature (greater than 17mm in diameter) a hormone injection is given to ripen and release the egg. Insemination is carried out 34-36 hours later. On the day, the man's sperm is prepared so to select the best possible sample to be deposited through a sterile catheter into the cavity of the womb. This process takes only a couple of minutes.

Who are the candidates for IUI?

a) couples with unexplained (idiopathic) subfertility of less than 3 years duration
b) couples whose woman's cervical mucous is altered in amount and texture for the sperm to pass through
c) couples who have sex problems such as impotence, premature ejaculation, vaginismus, etc.
d) couples in whom the woman has minimal/mild endometriosis
e) women undergoing insemination with donor sperm

The success rate measured as live birth rate for IUI using fertility drugs (stimulated IUI) is around 18% per treatment cycle and 30-35% after 5 cycles (known as cumulative live birth rate). The cumulative live birth rate for donor insemination is 60-65% after 6 cycles.

It involves the use of fertility drugs to stimulate the development of one or two mature follicles in the ovaries of women who do not develop and release a mature egg every month on their own (oligo- or anovulation). Treatment has the potential to be successful if there are no other causes of infertility. Generally it should be recommended after all relevant infertility investigations have been carried out and irregular ovulation is the only problem. Pregnancy rates per month are around 15-20%, and depend on the age of the woman, the drug used, duration of infertility, other infertility factors. Ovulation induction should be offered for 6-9 months, as the chances that a pregnancy will occur are substantially lower after that.

The most common drugs used for ovulation induction are:
a) clomiphene citrate, which is an oral tablet taken either days 2-6 or 5-9 of the woman's menstrual cycle.
b) injectable gonadotrophins containing follicle stimulating hormone (FSH) and given by intramuscular injection and subcutaneous injections on a daily basis. The injections are started early in the menstrual cycle and are continued for approximately 7-12 days. An injection of human chorionic gonadotrophin (hCG) may be given to induce ovulation once a mature follicle (greater than 17mm in diameter) is seen on scan.

Ovulation induction is somewhat different from controlled ovarian hyperstimulation (COH) which involves the use of the same sort of drugs (administered in the same way) but it is aimed at stimulating the development of multiple mature follicles in order to increase pregnancy rates with IUI/IVF/ICSI treatments. COH helps to get multiple eggs and sperm together either in-vivo (intrauterine insemination) or in-vitro (in vitro fertilisation with or without intra-cytoplasmic sperm injection).

Regular ultrasound monitoring is essential when using injectable gonadotrophins as there are substantial risks associated with over-stimulation if the ovaries over respond to the drug.

A blastocyst is an embryo at an advanced stage of development (day 5 post fertilization). With blastocyst transfer, embryos are cultured in the laboratory incubator to the blastocyst stage before they are transferred to the uterus (womb). Potentially using these extra days in culture could help to select the embryos that may have a better potential to implant. It is considered a more natural type of transfer as compared to day 2 or 3 transfer. This is because the blastocyst is transferred to the uterus at almost the same time that it would have entered the uterus should the pregnancy have been spontaneous. Not all embryos will develop to produce blastocysts in the laboratory. Embryos can stop developing at the four-cell stage (day two) and progress no further.

The procedure for blastocyst transfer is identical to that for normal embryo transfer. According to the HFEA data in the UK, the live birth rate with fresh blastocyst transfer is 57.6% for women under 35 years, 50% for women between 35 and 37 years, 38% for women aged between 38 and 39 years, and 33.3% for women aged between 40 and 42 years.

Egg freezing can be used successfully for both social and medical reasons. It is becoming more relevant and in demand as many women are facing the real challenge of having successful, healthy pregnancies later in life. This technique offers women planning to have children after the age of 37 the opportunity to effectively slow down their biological clocks by storing their eggs during their reproductive prime. Further, women at risk of premature ovarian failure or those undergoing specific medical treatment that may affect their fertility, such as chemotherapy, radiotherapy or surgical removal of the ovaries, may benefit from egg freezing.

The ovarian stimulation protocol is individualised to maximise the chances of success while reducing the risks, complications and possibly the costs of treatment. Daily fertility drugs (hMG or recombinant FSH or recombinant FSH/LH with or without GnRH agonist or antagonist) are necessary to stimulate the ovaries to produce a high number of oocytes (eggs). The recruitment and development of follicles, which contain the eggs, is tracked by regular transvaginal ultrasound scans and sometimes blood tests. When at least three follicles are mature (greater than 17mm in diameter) a hormone injection (hCG) is given to ripen the eggs. Egg collection is performed 34-36 hours later. The egg collection procedure takes about 20 minutes. Following egg collection, the eggs can be preserved using either the slow-freeze method or the vitrification method (also known as fast-freeze) before storing them in liquid nitrogen at -196 °C for future use. According to the HFEA eggs can be stored up to a period of 10 years which can be extended only in exceptional circumstances. Not all eggs survive the freezing/thawing process. Healthy viable eggs are then fertilised using ICSI.

Egg freezing is still experimental with a small number of births using this method in the UK. The live birth rate using frozen eggs is approximately 15%. Data in the literature show that there is no increase in birth defects or chromosomal abnormalities in children born from frozen eggs.

Egg sharing allows a woman to share her eggs (donor) with a woman who needs donated eggs (recipient) to have in vitro fertilisation (IVF) treatment. The egg sharer and recipient usually remain anonymous to each other at the time of treatment, but they may be already known to each other before coming for treatment. The physical characteristics of the women are looked at very carefully and every attempt is made to make the closest match possible. Approval by the recipient will always be required before proceeding to treatment.

The donor undergoes ovarian stimulation as for a conventional stimulated IVF cycle but agrees in advance to donate half of the eggs that she produces during the treatment cycle to a matched recipient. The benefit to the donor will be a much reduced cost of the IVF treatment, whereas the benefit to the recipient will be to use donated eggs to overcome the underlying fertility problem.

Women wishing to enter the egg sharing programme need to meet the following criteria:

• Younger than 35 years
• Body mass index between 20-30 kg/m2
• Non-smoker
• Have no history of viral infections
• Have no personal or family history of genetic diseases
• AMH between 15.8 and 28.7 pmol/l
• AFC greater than 10
• Referred for IVF because of tubal factor or male factor infertility

Genetic testing is done to ensure that healthy embryos are selected for transfer in the uterus (womb). Testing the embryos before transfer enables couples who carry a genetic disease to avoid the dilemma of whether to terminate the pregnancy if the created embryo is affected.

Pre-implantation genetic diagnosis (PGD)

This sophisticated technique checks embryo for the genes associated with serious genetic diseases such as haemophilia, Duchenne muscular dystrophy, cystic fibrosis and thalassaemia. Once the fertilised egg has undergone further divisions, one or two cells are taken and assessed for specific genetic errors. This allows couples who are at risk of producing a baby with a specific genetic problem to commence a pregnancy knowing that the embryo is unaffected by the condition.
It is recommended to a) women who have had terminations of pregnancy because the baby had a genetic disease, b) couples who already have a child with a genetic disease, and c) couples who we know to be at risk of certain genetic diseases.

Pre-implantation genetic screening (PGS)

This sophisticated technique screens embryos for aneuploidy (loss or gain in the number of chromosomes). Currently there is lack of data in the literature to recommend PGS as a routine procedure. However it may assist the following: a) women older than 37 years who are at a high risk of carrying a baby with chromosomal abnormalities, for example Down's syndrome, b) women with history of recurrent miscarriage (three or more consecutive early pregnancy losses), and c) couples who have had several failed IVF treatments.

Array Comparative Genomic Hybridisation (Array CGH)

This technique allows regions on every chromosome to be analysed for aneuploidies (number of chromosomes) compared with current techniques that are restricted to specific chromosomal defects. CGH is able to screen all 23 chromosomes. Array CGH has two main advantages over other methods of screening: the first is "gene chip" technology that tests DNA very quickly, so that embryos do not need to be frozen while they are checked. The second is that instead of removing cells from embryos, which can damage them, it relies on testing the eggs, which are the cause of 85 per cent of chromosomal defects. The reliability and accuracy of CGH has to be tested rigorously in properly designed trials before it can be concluded that this new technique offers a real benefit in higher take home baby rates.