Chapter 25a
Test Tube Babies - IVF & GIFT

from the book How to Have a Baby: Overcoming Infertility
by Dr. Aniruddha Malpani, MD and Dr. Anjali Malpani, MD.

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The birth of Louise Brown through in vitro fertilization (IVF) in 1978 was a major milestone in infertility treatment. It dramatically changed the treatment options for infertile couples, and techniques for assisted reproduction have evolved rapidly since then. In a short span of 20 years, IVF has become the cornerstone of reproductive medicine, and IVF clinics today routinely perform techniques which were thought to belong to the realm of science fiction a generation ago !

This chapter will help you understand assisted reproductive technologies (ART) such as IVF and Gamete Intra-fallopian Transfer (GIFT) that are now standard medical treatments for infertility. A few years ago, these techniques were used as methods of last resort, when everything else which had been tried had failed. Today, specialists will often resort to these techniques first, since they offer such excellent results, rather than waste the patient’s time and money with the traditional ineffective options. Today, thanks to IVF technology, there is practically no infertile couple who cannot be offered treatment. However, as with all technology, you need to understand exactly how it works, and when it should be used.

IVF

IVF is the basic assisted reproduction technique , in which fertilization occurs in vitro ( literally, in glass) . The man's sperm and the woman's egg are combined in a laboratory dish, and after fertilization, the resulting embryo is then transferred to the woman's uterus. The five basic steps in an IVF treatment cycle are superovulation (stimulating the development of more than one egg in a cycle), egg retrieval, fertilization, embryo culture, and embryo transfer.

IVF is a treatment option for couples with various types of infertility, since it allows the doctor to perform in the laboratory what is not happening in the bedroom – we no longer have to leave everything up to chance! Initially, IVF was only used when the woman had blocked, damaged, or absent fallopian tubes (tubal factor infertility). Today, IVF is used to circumvent infertility caused by practically any problem, including endometriosis; immunological problems; unexplained infertility; and male factor infertility. It is a final common pathway, since it allows the doctor to bypass nature’s hurdles, and overcome its inefficiency, so that we can give Nature a helping hand !

Tests prior to IVF

In order to perform IVF, only 3 things are required – eggs, sperms and a uterus, and before starting the IVF cycle, the doctor will check these.

First, a sperm survival test is carried out . This is a "trial" sperm wash, using exactly the same method as will be actually used in IVF, to assess whether an adequate numbers of sperms can be recovered in order to do IVF. This test will also help the laboratory to decide which method of sperm processing should be used during IVF.

A blood FSH level will provide an idea of the "ovarian reserve", and provide information on whether or not the woman will produce enough eggs after superovulation . For older women, some clinics do a clomiphene citrate challenge test . If the level is very high, this suggests early ovarian failure , and it may be a better idea to consider donor eggs.

Many clinics may do a hysteroscopy, in order to assess that the uterine cavity is totally normal. They may also do a "dummy" embryo transfer to make sure there are no technical problems with this procedure. Some clinics also do a cervical swab test, to rule out the presence of infection in the cervix.

If a woman has blocked fallopian tubes with large hydrosalpinges, some clinics will remove these prior to the IVF cycle, because they feel that the presence of a hydrosalpinx decreases pregnancy rates after IVF.

For men who have difficulty in producing a semen sample " on demand", the clinic may also freeze and store the sample prior to treatment, as a backup. This can help to prevent the tragedy of having to abort an entire treatment cycle because the man could not produce a semen sample when needed.

Blood tests which may be done include tests for immunity to rubella ; and tests for Hepatitis B, and AIDS. Most doctors will also advise patients to start taking folic acid, as part of prepregnancy care, as this helps to reduce the risk of certain birth defects.

Patients who stand a very poor chance of success with IVF include the following :

• Older women, whose ovaries are failing. However, there is no upper age limit at which IVF should not be done,- and in fact, for older women, it might represent their only chance of success. It's not really the age of the woman which is the limiting factor - it's the quality of her eggs.
   
• Men whose sperm count is very low. Most clinics will consider doing IVF only for men with at least 3 million motile sperm in the ejaculate. If the sperm counts are lower than this, then ICSI ( or microinjection ) is a better option.
   
• Women with a damaged uterus ( for example, because of healed tuberculosis ) because the chance of successful implantation of the embryo in the uterus becomes very poor.
   
• It is also not advisable to go in for IVF treatment without trying simpler treatment options first. IVF is a complex procedure involving considerable personal and financial commitment, so other treatments are usually recommended first.

The Basic Steps of IVF

Superovulation or Ovulation Enhancement

During superovulation , drugs are used to induce the patient's ovaries to grow several mature eggs rather than the single egg that normally develops each month. This is done because the chances for pregnancy are better if more than one egg is fertilized and transferred to the uterus in a treatment cycle. Depending on the program and the patient, drug type and dosage varies. Most often, the drugs are given over a period of nine to twelve days. Drugs currently in use include : Human Menopausal Gonadotropin (HMG) , Follicle Stimulating Hormone (FSH) , Human Chorionic Gonadotropin (HCG ) and gonodotropin releasing hormone (GnRH) analog .

Today, most IVF programs using GnRH analogs in combination with gonadotropins during ovulation enhancement. Treatment with the analogs prevents the release of FSH and LH from the pituitary gland during treatment ( "downregulation") and thereby prevents premature ovulation. This therefore gives the doctor much more control over the superovulation phase. GnRH analogs can be used either in the form of a long protocol ( when they are started from Day 21 of the previous cycle) ; or as a short protocol ( when they are started from Day 1 of the cycle). Another option is to use the newer GnRH antagonists, which can selectively suppress the LH surge, and it is hoped that these may provide better control.

An ultrasound scan is done on Day 3, to confirm that there are no cysts in the ovary. A blood test for estradiol can also be done, to ensure that the ovaries are quiescent and downregulated, and the result should be less than 50 pg/ml. The HMG injections for superovulation are then started from Day 3. The dose of HMG used needs to be individualized for each patient. Our standard dose is 225 IU for patients less than 35; 300 IU for patients more than 35; and 150 IU for patients with PCOD.

Timing is crucial in an IVF treatment cycle, in order that the doctor recover mature eggs. To monitor egg production, the ovaries are scanned frequently with vaginal ultrasound, usually on a daily or alternate day basis from Day 10 onwards. Blood samples are also drawn in some clinics, to measure the serum levels of estrogen , and sometimes luteinizing hormone (LH). While some clinics do this on a daily basis, we feel this is very unkind to the patient, who often ends up feeling like a pincushion ! For most patients, the ultrasound scan provides enough information, and it is very rarely that we need to do blood tests for our patients – we try to be kind ! The dose of the HMG is adjusted, depending upon the ovarian response.

By interpreting the results of the ultrasound, we can determine the best time to harvest or remove the eggs. Follicles usually grow at a rate of 1-2 mm/day, and a mature follicle has a diameter of about 16-20 mm in size . Thus, if a patient has about 10 follicles on ultrasound, of which the largest is more than 18 mm, we know that the follicles are mature and the eggs are ready for retrieval. The endometrium should also be examined carefully on the vaginal scan, and this should be thick ( more than 7 mm, and have a triple texture). Some clinics also measure the blood estradiol level, to provide additional information, and each mature follicle produces about 200-300 pg/ml of estrogen . When the follicles are mature, we prescribe an injection of human chorionic gonadotropin (HCG) to trigger off ovulation. The use of HCG allows us to control when ovulation will take place – and this is 36 – 39 hours after the HCG injection. This precise control allows the IVF team to be prepared to harvest eggs just before that time. The HCG simulates the woman's natural LH surge, which normally triggers ovulation.

With older forms of superovulation regimes using clomiphene and HMG, the treatment cycle was cancelled in roughly one quarter of the IVF cycles. One of the reasons for this was that some of these women had a premature , spontaneously occurring LH surge with resulting premature spontaneous ovulation . When this happened, the follicles ruptured prior to egg collection, and the eggs were lost in the pelvic cavity, as a result of which they could not be retrieved. While spontaneous LH surges are very rare with the use of GnRH analogs, we still need to cancel cycles in about 10 % of patients.

The commonest reason for canceling a cycle today is a poor ovarian response. If patients grow less than three follicles, and if the estradiol level is low, the chances of a pregnancy are poor, and patients may decide to abandon the cycle. The problem of a poor ovarian response is commoner in older women and in women with elevated FSH levels, and these can be difficult patients to treat ! Patients who have a poor ovarian response during IVF treatment are often very upset, because this is not something they ( especially if they are young) are mentally prepared for. Most young women expect to grow a lot of eggs, and are shattered when they don’t do so. However, remember that this is not the end of the road – it simply means that the superovulation regime will need to be modified for the next treatment cycle. The doctor may need to increase the dose of HMG in order to grow more follicles, and this is often helpful for young women.

The other reason to cancel a cycle is when patients grow too many follicles ! These are usually patients with PCOD; and if there are more than 25 follicles, or if the level of the estradiol is more than 6000 pg/ml, many clinics will cancel the cycle, because the risk of ovarian hyperstimulation syndrome ( OHSS) is very high. An alternative option is to go ahead with egg collection, and freeze all the embryos. This allows the doctor to salvage the cycle; and if the embryos are not transferred, the risk of OHSS is reduced. The frozen embryos can then be transferred later, giving the patient a good chance of achieving a pregnancy.

Egg Retrieval

[continued on next page]

by Dr. Aniruddha Malpani, MD and Dr. Anjali Malpani, MD.

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