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Dr. Ng Soon Chye , Adjunct Professor

Articles

Assisted Reproductive Technologies

By Ng Soon Chye, MBBS, M.Med(O&G), MD, FRCOG, FAMS

Adjunct Professor, Dept Obstetrics & Gynaecology, NUS; Duke-NUS GMS; NTU

Permission granted to eMediHub to have the article reproduced in their website.

Copyright: O&G Partners Fertility Centre, 2004 & 2009

Introduction:

Infertility is a complex problem and our staff are fully aware of the terrific ups and downs that patients undergoing treatment suffer. Please feel free to bring up and clarify any medical, emotional social or ethical issues that you may have and we will try our best to resolve them. In any event, you can be assured of our utmost efforts to ensure a successful outcome.


Assisted Reproductive Techniques or ART means the use of techniques to bring the egg and sperm together (fertilisation) outside of the woman’s body, in a laboratory. It removes the need for the sperm to swim through the cervix and fallopian tube to meet the egg. ART requires sophisticated laboratory facilities and highly trained staff as compared to simpler techniques that involve deposition of the sperm at the entrance of the cervix such as artificial insemination using the husband's sperm into the cavity of the uterus (also called Intra-Uterine Insemination or IUI). This is not considered an ART procedure and by the time a couple comes for ART, such simpler methods would usually have been attempted and been unsuccessful.


ART has revolutionized the management of infertility. In most instances, ART involves recovering the eggs from the ovaries and fertilising them with sperm outside the body, in the laboratory (often giving rise to the misleading concept of a “test-tube baby”). The developing embryos are then replaced back into the womb. ART is usually not offered as a treatment unless other simpler methods fail, or the cause of infertility is so severe that simpler methods will not be suitable.


ART used to be called In-Vitro Fertilisation (IVF), which is the medical term for the technique. It was originally designed to help women with damaged tubes, as the eggs and sperm were prevented from meeting as the tubes were blocked. The introduction of new advances have allowed its use in a wide range of infertile conditions including male infertility. ART is a complex, time consuming, and stressful procedure; and your work/domestic schedule during the period of treatment should be as light as possible. Before starting the programme, the nurses and doctors will explain the steps involved and you will have to sign a consent form.


Indications:


Generally, ART may be used in the following situations:

  1. When there is damage or blockage of the fallopian tubes such that sperm are unable to meet the egg in the woman’s body.
  2. When the husband’s sperm count is reduced or the sperm are abnormal.
  3. For some women who have problems with cervical mucus which may impair sperm activity and survival.
  4. For some women with endometriosis.
  5. For women not able to release an egg (ovulation) on her own who have not conceived despite fertility drugs and/or IUI.
  6. For unexplained infertility of long duration.

Your doctor would be the best person to decide whether you need ART. At NUH, we would recommend ART only if simpler treatment procedures have not worked.

The aims of ART treatment are to:

  1. stimulate the woman’s ovaries to produce an optimum number of eggs (usually 1-150)
  2. monitor egg maturation using ultrasound scans
  3. retrieve these eggs when they are mature
  4. fertilise the eggs with the husband's washed sperm in the laboratory
  5. replace the embryos into the womb at the appropriate time
  6. support the implantation and development of the embryo with medication
  7. freezing of extra embryos

A) Stimulation

Under normal circumstances, most women produce only one egg each month. The chances of pregnancy are increased if more than one egg is fertilised and replaced. To increase the number of eggs, hormone injections (Buserelin and Gonal F) are administered daily to stimulate the production of more eggs. The most commonly used regime involves daily injections of Buserelin, usually commencing 21 days after your period starts (called the “down-regulation” regime). This hormone is first given to control your cycle by preventing your own hormones from disturbing egg production during the programme. Women may come to hospital every day for their injections, but as the needles used are very small, most women find it easier to learn how to give the injections themselves at home, or get their husbands to do it. This has the advantage that it saves you from coming to the hospital every day. After two weeks of these injections, your response is monitored by a blood test and ultrasound scan. If these show you have responded to the Buserelin hormone injections and the scan shows no abnormalities, a second hormone is added, called Gonal F. This is designed to stimulate the ovaries to produce many eggs. The exact dose of the Gonal F injections may be varied according to your response, but the nurse and doctors will decide and let you know of any changes.


B) Monitoring


Scans and blood tests are repeated once every few days in order to assess the growth of the developing eggs. All of these scans are done through the vagina using a small, long probe and the bladder should be empty of urine during the procedure. After your first scan at the end of your 2 weeks of buserelin injections, subsequent scans are done every few days after starting the Gonal F injections in order to monitor the growth of areas within the ovaries called follicles, which contain the developing eggs. These are seen as dark circles on the ultrasound scan. For most patients, vaginal scanning is not uncomfortable and the examination takes only a few minutes.


The blood tests that are done check for levels of certain hormones (oestradiol and LH) produced by the ovary and the brain. These tests give us a good idea of the health of the developing eggs and help to determine the best time to retrieve them from the ovaries. The dose of the Gonal F injected may have to be adjusted so as to allow optimum growth and ensure that the eggs obtained at the end of the procedure are at their best.

Modifications may sometimes be made to this basic regime to ensure the eggs continue to grow well. When the blood tests and ultrasound scans indicate that the follicles and eggs are ready, a special injection (called hCG or Profasi) is given at night to trigger the process of final egg maturation. Egg recovery is performed 36 hours after the hCG injection and it is very important that this injection is given at a precise time as instructed by the Nurses and Doctors, so please DO NOT forget!

CAUTION: As the injections you are going to have as part of the programme may potentially affect an existing pregnancy please use condoms in the month before starting the ART cycle.


C) Egg collection


If all goes well, egg collection usually takes place between 10 and 17 days after starting the Gonal F injections. You will be admitted to the Day Surgery Ward of the hospital in the morning and have the procedure done under sedation or a general anaesthetic. The procedure is generally pain free and the eggs are retrieved from the follicles through a fine needle inserted through the vagina under ultrasound guidance. There will not be any scars on your body and bleeding is minimal. Generally most patients go home the same day, a few hours after the procedure with some antibiotics to minimise any chance of infection. The nurse will also give you some progesterone pessaries (cyclogest) to insert into the vagina every night. This is a hormone designed to ensure the womb is ready for implantation of the embryo.


On the same morning that the woman goes for the egg collection, the husband has to produce a semen sample by masturbation. To ensure that the specimens are of the best quality he should have abstained from sexual intercourse for 3 to 5 days before the day of collection. Antibiotic tablets would also be prescribed to him to lessen the chance of any bacterial contamination for 2 weeks prior to this. Please remember to collect the sterile specimen bottles the day before the egg collection from the nurse in the Clinic before you go home. The time when the specimen is expected on the day of the egg collection would be made known to you later and confirmed by the nurses. Some husbands have difficulties producing the sperm specimens without their wives' help. These difficulties should be made known to our staff well before starting the programme so that special arrangements can be made. It is important that the specimen be kept warm at all times and to reach the laboratory as soon as possible in these cases. Occasionally a second specimen might be required and you would be informed of this usually well in advance.


D) Fertilisation


After the sperm sample is sent to the laboratory, it is prepared, washed and the most active and motile sperm used to inseminate the egg. This can be done either by mixing the egg with a known amount of sperm or by selecting the healthiest sperm and injecting it directly into the egg gently (a process called intra-cytoplasmic sperm injection or ICSI). This is recommended usually if the sperm count is low or of poor quality. The next day the eggs are examined under the microscope for the earliest signs of fertilisation. Not all the eggs may fertilise and in some cases fertilisation does not occur at all. Special tests can then be performed to understand the reasons for this in the hope of preventing it the next time.

E) Embryo monitoring

The cells in the fertilised eggs divide every day and are inspected each morning by the Embryologist, who will monitor and change the solutions bathing the embryos on a daily basis to ensure the best conditions to help them grow. The nurse will update you on a daily basis by telephone to keep you informed of the progress of your embryos. The healthiest embryos will be chosen to be replaced back into the womb. Once the embryos are ready for replacement you will be notified by the nurse. In NUH, the laboratory where the embryos are grown is situated within the Day Surgery Operating Theatre as the laboratory and its environment have to be very clean. It is a restricted place and only authorised personnel are allowed in. This is important because eggs, sperm and embryos are being handled and nurtured in the ART laboratory.



WHAT HAPPENS IN THE ART LABORATORY?


Oocyte Retrieval Day (Day 0)


On this day, the embryologist has the important task of preparing the couple’s eggs and sperm so that fertilisation can take place. Insemination is carried out by either placing each egg into a droplet of washed sperm suspension (IVF) or by injecting each egg with a single sperm (ICSI). After this, the eggs and sperm are left undisturbed in the incubator which is set at body temperature (37oC), a gas environment of 5% CO2 and 100% humidity, which are the exact conditions found in the fallopian tubes and womb of women.


Day 1


Fertilisation is being determined 16 to 20 hours after insemination. The fertilised eggs are carefully separated and transferred to new droplets of culture medium. They are then returned to the incubator where they are kept until the next morning.


Day 2 to Day 6


The couple’s embryos are taken out of the incubator and graded as good, fair or poor, using a microscope once every morning. Grading of the embryos is carried out very quickly and they are then returned to the incubator. The embryo culture medium is also changed according to the developmental stage of the embryos. This is again carried out very quickly but yet accurately and gently. A lot of respect and dignity is paid to the embryos by the embryologist.


The following is the developmental stage of the embryos on different days after fertilization:

Day 2 4-cell stage

Day 3 either 8-cell stage or compacting stage

Day 4 compacted stage (16 to 32 cells)

Day 5 either cavitating or early blastocyst stage (> 50 cells)

Day 6 either expanding or fully expanded blastocyst stage (>160 cells)


F) Embryo replacement


Embryo replacement (ER) is normally carried out when the embryos are between 3 and 6 days old. The exact time will depend on the quality of the embryos. As the embryologists have been nurturing the couple’s embryos right from Day 1, they are able to determine the most suitable day for replacement of the embryos back into the womb. The embryologist is also able to select the best quality embryos for transfer. Any excess embryos that are not replaced into the womb are cultured to the blastocyst stage (Day 5 or 6) and frozen for future embryo replacement. Only good healthy embryos are frozen.


Embryo replacement is a painless procedure and no anaesthetic or sedation is required. All we ask is that you try to have a full bladder during the procedure in order to ensure a smooth transfer. This is one of the most important parts of the programme. The embryos are placed gently back into the womb through the cervix using a very thin, soft plastic tube. This procedure will feel just like having a Pap smear.

Usually between 2 and 3 embryos are replaced: if you are young (less than 35 years of age) only two are replaced as the chances of multiple pregnancy is higher if more embryos are replaced. However, the average number replaced if the woman is over the age of 35 is 3 embryos. Occasionally, but only under special circumstances, four are replaced. These limits are determined by the Ministry of Health, Singapore. The chances of pregnancy increase with the number of embryos transferred but so does the incidence of multiple births, hence the need for the control. Your Doctor will decide what is the best for you. The period that the embryo is cultured in the laboratory may be adjusted to suit the different needs of each patient but in practice, the usual is 3 days. Occasionally we culture to 5 days.. With your permission, any extra embryos that are not replaced will be frozen for future use only if they are of sufficiently good quality.


After the replacement, you will be asked to rest in bed for a few hours after which you can go home. Whilst at home, you should not plan to do anything strenuous for the following few days so as not to disturb the embryos. Hormonal injections will also be given to you to support the anticipated pregnancy. Blood tests are performed 14-16 days after egg collection to confirm pregnancy. Some bleeding from the vagina can occur even though you are pregnant, so it is important to do this test even if you think you are having your period.

G) Hormone support after embryo transfer

This is necessary to increase the chance of the embryos attaching or implanting in the womb. Medication during this period (the luteal phase) must be individualised for you and usually consists of hormonal pessaries with or without injections. We will let you know the exact details when you are discharged from the hospital on the day of egg collection.

H) Pregnancy Test

A blood test is performed about two weeks after the embryo is transferred. This test indicates whether a pregnancy has resulted from the treatment. Sometimes some vaginal bleeding may occur even though you are pregnant so it is important to come for the pregnancy test. Injections and oral medication will be given to support the developing embryo if the pregnancy test is positive. An ultrasound scan is arranged for two weeks after the positive pregnancy test to confirm the presence and the number of embryos that have successfully implanted.

The 2 week waiting period before the blood test for pregnancy can be a trying and stressful period for both partners (especially the wife) and it is advisable that your schedule should be as light as possible. As multiple eggs have developed in the ovaries you may have a sensation of fullness in the lower abdomen. You may feel tired so ensure that you have a good diet and plenty of rest at night. Your doctors and nurses are trying their best to achieve the desired result for you. Do not hesitate to tell them any worries that you may have. Remember we are always available and more than happy to help.


It is important to realise that not every cycle results in a successful pregnancy. Failure in one cycle does not mean that you have a reduced chance of success in the next. Your doctor or nurse would be available to counsel and advise about subsequent treatment in case of an unsuccessful cycle.

I) Freezing of Extra Embryos

Extra embryos that are healthy will be frozen if you give us the instructions to do so. They can be kept frozen for 5 years, and extended for another 5 years; there is an annual storage fee. Using these embryos are much easier, as there is no need to stimulate the ovaries with injections, and no need for an operation to recover the eggs. Hence the cost is also much cheaper.


FREQUENTLY ASKED QUESTIONS


HOW MUCH IS IT GOING TO COST?


The cost depends on the type of ART programme that you undertake, the amount of drugs used, the class of ward that you choose to stay, the length of hospital stay, the procedures completed and whether microinjection techniques (ICSI) have been necessary. The total cost can range from about $12,000 for a younger woman around 35 years old, as she needs fewer Gonal F injections, to $15,000 for a more mature woman of 40 due to the need for more injections. This figure can vary from time to time as it depends on the individual’s response. There is another regime (short protocol, with GnRH antagonist); cost is similar to the standard regime. The frozen-thaw cycle costs much less, about $3,000 to $4,000.


DO I NEED TO STAY IN HOSPITAL?

You do not need to stay overnight in Hospital. The length of stay in the Day Surgery ward depends on the type of programme designed for you. You normally would stay just for the morning during the egg collection. It is done first thing in the morning and you would normally be well enough to go home at lunchtime. When it is time to have the embryo replacement, you have to come back to hospital in the morning but can go home in the afternoon.

HOW MANY TIMES CAN I DO ART?

In Singapore, the Ministry of Health (MOH) normally limits the number of ART attempts to 10 cycles if they are younger than 40. For those above the age of 40 when they enter the programme, a maximum of 5 cycles is permitted. The success rate of each attempt is the same and the more you try, the higher the chance of eventual pregnancy. Most couples undergo several cycles before a pregnancy is obtained. If you are over the age of 45 then we will need to seek approval from the Ministry to continue.

WHAT ARE MY CHANCES OF SUCCESS?

The chances of successful pregnancy will be affected by your age - the older you are, the lower the chances of success. For a woman less than 35 years of age, her chances of success will be approximately 40% for each cycle. As she gets older, the chances of success fall and by the age of 40 the chances of pregnancy fall to less than 15%. Poor semen or sperm quality will also lower the pregnancy rates.


Results collected from the USA, UK, France and Australia show a remarkably similar clinical pregnancy rate of about 28-36% for those cases where eggs were retrieved. In these cases, the number of deliveries was about 25%. We have managed to obtain better results in NUH over the years despite the fact that our patients are some of the most complicated.

The take-home baby rate is lower than the pregnancy rate because some pregnancies are complicated by miscarriage, ectopic pregnancy (where the pregnancy develops in the tube) or premature deliveries. However, once you get past this risk period of approximately the first 12 weeks, the chance of delivering a live baby is about 70%.

WHAT ARE THE POTENTIAL COMPLICATIONS OF ART?


1) Excessive response. The most important complication of the test tube baby programme is excessive response of the ovaries to the Gonal F hormone injections. This is called ovarian hyperstimulation syndrome (OHSS) and occurs in about 1% to 2% of the cases. Most cases are mild and we further minimise this problem by careful selection of the doses of drugs used and also close checking of follicle development through blood tests and ultrasound scanning and readjusting the dose as necessary. Most women going through the programme will experience some bloating and discomfort due to the ovaries enlarging. You only need worry when these symptoms get very severe, which will affect only 1-2 % of women. If this does happen you will need to come into hospital for a few days for monitoring and some blood tests.


2) Multiple births Since more than one embryo is usually replaced there is a slightly increased chance of multiple births. These are mainly twins (25-30%) but occasionally, triplets occur (5-6%).


3) Cancellation. Although all care is taken to ensure the success of your programme, sometimes it is necessary to cancel the cycle halfway. This could be due to many reasons including inadequate follicle development, premature ovulation, poor semen quality or abnormal fertilisation. Modification of egg stimulation regimes could prevent the recurrence of some of these problems in subsequent treatment cycles. Only about 10% to 15% of cases are cancelled prematurely. The majority go on to the stage of embryo replacement.

4) Miscarriage: The rate of spontaneous miscarriage is 20% to 25%. It is important to realise that pregnancies in normal couples without infertility have a slightly lower miscarriage rate. The rate of spontaneous miscarriage increases with age and is about 40% in women 40 years and greater of age.


5) Ectopic pregnancy. In about 5-10% of pregnancies the embryo develops outside its normal position in the womb. This condition is diagnosed by an ultrasound scan which would be arranged for you early in pregnancy. A pregnancy outside the womb cannot survive and an operation may be required to remove the pregnancy.


6) Genetic problems There is some evidence that congenital abnormalities are slightly increased in ART births but they are due more to the women’s age. We will always look out for these problems, with tests once pregnancy is established.


WHAT ARE THE SUCCESS RATES?


With ART treatment, the overall rates of pregnancy are age-dependent - the older the woman is, the lower the chances of pregnancy. At my current Fertility Centre (O&G Partners Fertility Centre at Gleneagles Hospital), the fertility rate is about 45% overall; this rate is higher for patients less than 30 years old, and lower with older patients. With frozen-thawed embryos, the pregnancy rate is about 40%.


Date Posted : 2009-07-20 14:54:09