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 that 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 that 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 that 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, sperm 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 number of sperm 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 FSH 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 pre-pregnancy 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 for older women, it might represent their only chance of success. It's not really the age of the woman that 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 vary. 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) analogue.

Today, most IVF programs use GnRH analogues in combination with gonadotropins during ovulation enhancement. Treatment with the analogues prevents the release of FSH and LH from the pituitary gland during treatment ("down regulation") and thereby prevents premature ovulation. This, therefore, gives the doctor much more control over the superovulation phase. GnRH analogues 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 down regulated, 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 recovers 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 analogues, 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 hyper stimulation 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

Egg collection is accomplished today by ultrasound-guided aspiration. This is a minor surgical procedure that can be done even under intravenous sedation. The ultrasound probe is inserted through the vagina. The probe emits high-frequency sound waves that are translated into images of the pelvic organs and displayed on a monitor, so that the mature follicles can be seen as black bubbles on the screen. The doctor guides a needle through the vagina are into each mature follicle. The follicular fluid containing the egg is then sucked out through the needle into a test tube, and all the follicles are aspirated, one by one. This is a very precise procedure, which requires considerable skill, and takes about 10-40 minutes to perform, depending upon the number of eggs. On an average, we retrieve about 4-16 eggs for each patient. If there are few eggs, many doctors will flush each follicle to ensure that each egg is retrieved.

The older method of performing egg retrieval involved a laparoscopy, and the eggs and follicular fluid were aspirated under direct vision. However, this method is rarely used today, because the vaginal-ultrasound - guided method is much quicker, easier and safer.

Insemination, Fertilization, and Embryo Culture

The aspirated follicular fluid is then immediately carried into the laboratory (which is adjoining the operation theatre) where it is examined by the embryologist under a stereozoom microscope, in order to identify the egg. Each egg is surrounded by sticky cumulus cells, and is called an oocyte-cumulus complex. These are washed in medium, graded for their maturity and then transferred into the CO2 incubator. The maturity of an egg determines when the sperm will be added to it (insemination). Insemination can be done immediately upon harvest, but is usually done after 2-6 hours.

On the day the eggs are harvested, the husband provides a semen sample. The sperm are separated from the seminal plasma in a process known as washing the sperm. The washed sperm are used to inseminate the eggs. Some men may have considerable difficulty producing a semen sample at the appropriate time, because of the tremendous stress they are under, and the " pressure to perform". For these men, using a previously stored frozen sample can be helpful. Viagra (sildenafil citrate) can also be used to help them to get an erection, as can using a vibrator.

A defined number of sperm (usually 100,000 sperm/ ml) is placed with each egg in a separate dish containing IVF culture medium. The dishes are placed in a CO2 incubator with a controlled temperature that is the same as the woman's body - 37 C. The conditions in the incubator and the ingredients in the culture medium are designed to mimic the conditions in the fallopian tube, so that the embryos can grow happily in vitro. The culture medium, which has to be very pure, contains various ingredients such as protein, salts, buffer and antibiotics that allow optimal growth of the embryo - think of it as "chicken soup for the less embryo"!

About 18 hours after insemination, the embryologist checks to see how many eggs have fertilized. This is called a pronuclear check, and normally fertilized embryos at this time are single cell, with 2 pronuclei. The pronucleus appears as a clear bubble within the embryo, and the male pronucleus represents the genetic contribution of the husband, while the female pronucleus represents the contribution of the wife. When these fuse, a new life, with a unique genetic composition is formed. Abnormally fertilized embryos (for example, those with three pronuclei), or those which have failed to fertilize, are discarded, or used for research.

There is quite a lot of suspense and anxiety till you find out from the lab how many embryos have fertilized. This is a biologic variable, which we still cannot control. Sometimes, even though the eggs and sperm may look excellent, there may be a total failure of fertilization. This can be a major blow, because it means that there are no embryos to transfer. Poor fertilization rates may be because of poor lab conditions, a sperm problem, or an egg problem. If only one patient has poor fertilization on a particular day, in a good lab, then it's usually the sperm that are held to be responsible.

The normally fertilized embryos are left in culture, where they continue to divide, and their quality graded after another 24 hours. Good quality embryos divide rapidly; and healthy embryos have 2-4 cells, of equal size, with clear cytoplasm and few fragments. The IVF lab is the heart of the IVF clinic today, and an IVF clinic is only as good as its lab! Unfortunately, most patients have no idea of what happens in the lab, and they rarely get a chance to talk with the embryologist, the skilled biologist who works in the IVF lab. The embryologist is the unsung hero of IVF treatment who does all the important work behind the scenes. The dramatic improvements in pregnancy rates with IVF today are because of the important contributions embryologists have made to finding the best ways of growing and culturing embryos in vitro.

Many patients are worried that their eggs, sperm or embryos may get mixed up with someone else's. While this can happen, the probability of it happening in a well-run laboratory is very low, because good labs have quality control mechanisms to prevent such mix-ups from occurring.

After 48 - 72 hours, when embryos usually consist of two to eight cells each, they are ready to be placed into the woman's uterus. This procedure is known as embryo transfer.

Embryo Transfer

Embryo transfer is most often done on an outpatient basis. No anesthesia is used, although some women may wish to have a mild sedative. The patient lies on a table or bed, usually with her feet in stirrups. Using a vaginal speculum, the doctor exposes the cervix. One or more embryos suspended in a drop of culture medium are drawn into a transfer catheter, a long, thin sterile tube with a syringe on one end. Gently, the doctor guides the tip of the loaded catheter through the cervix and deposits the fluid containing the embryos into the uterine cavity. The procedure should be done with great care and usually takes between 10 and 20 minutes. Some doctors perform the transfer under ultrasound guidance to ensure proper placement of the embryos in the uterine cavity. Most doctors advise a few hours of bed rest after the transfer.

Most clinics today transfer 2-3 good quality embryos on Day 2 or Day 3. Embryos are graded according to their appearance and rate of cell division and good quality embryos are those that have 4-8 cells, of equal size, with clear cytoplasm, and with few fragments. You should ask the doctor to show you your embryos under the microscope. Sometimes, only embryos of poor quality are available for transfer. While the chance of getting pregnant when only poor quality embryos are transferred is low, you can be reassured that if a pregnancy results, the child will be normal!

How many embryos to transfer is one of the most difficult decisions facing an IVF patient today. The more the embryos transferred, the greater the chances of getting pregnant. Since the purpose of an IVF cycle is to achieve a pregnancy, then why not transfer as many as possible? However, the price you pay for transferring more embryos is that the risk of a multiple pregnancy increases as well. In some countries, such as the UK, doctors are allowed to replace a maximum of only 3 embryos, to reduce the risk of high-order multiple births. Some clinics in Scandinavia have now started transferring only one embryo in young women, in order to reduce the risk of a multiple pregnancy. In USA and India, there are no laws, and some clinics will transfer 4 embryos for young patients, and up to 6 for older women - and this number is quite arbitrary. Doctors have tried to develop an embryo score (based on the number of embryos and their quality) in order to predict the chances of a pregnancy after embryo transfer, but this is still not precise. Since there is no easy answer as to how many embryos to transfer, many clinics will allow patients to decide for themselves. This is always a difficult decision, and you need to carefully weigh the pros and cons before making up your mind. There is no right or wrong number - and you need to take the path of least regret. Transferring more embryos increases the chances of getting pregnant; it also increases the risk of a multiple pregnancy. However, a high-order pregnancy is a complication for which the doctor can perform a selective fetal reduction, in order to reduce this to twins. Not getting pregnant may be a worse outcome for some patients! If embryo-freezing facilities are available, then supernumerary embryos can be stored, and this needs to be factored in as well.

The embryo transfer completes the medical treatment in the IVF cycle and most clinics provide "luteal phase support" after the transfer, usually with estrogen tablets and progesterone suppositories, to increase the chances of implantation. However, this period is often the hardest part of an IVF cycle for the patient, because of the agony and suspense of waiting to find out if a pregnancy has occurred. This can be determined by a blood test, which measures the level of the hormone, HCG (human chorionic gonadotropin) only 10 to 14 days after the transfer. For many patients, these 14 days are often the longest days of their life!

It is normal to blame yourself for something you may or may not have done during this time if you do not conceive. Therefore, try not to do anything for which you will blame yourself if you do not get pregnant. In general the following guidelines are offered:

No tub baths or swimming for 48 hours after embryo transfer.
No douching or tampons.
No intercourse or orgasms until the fetal heartbeat is seen on ultrasound, or the pregnancy test is negative.
Do not undertake excessive physical activity such as jogging, aerobics, or tennis.
Do not take any non-prescription medications or other prescribed medications without the approval of your doctor.
No heavy lifting.
You may return to "work" after 24 hours of bed rest (getting up for bathroom and meals only) and one to two days of light activity.
You may have some vaginal spotting or bleeding prior to your blood test. However, you must have the blood test done, even if you think your period has started. There are no symptoms or signs that will be able to tell you whether or not you are pregnant.

Many doctors used to advise "strict bed rest" after an embryo transfer. However, remember that your physical activity does not affect your chances of getting pregnant. Resting when you are well can be very emotionally taxing, and we encourage patients to lead as normal a life as possible. Many patients are worried that if they cough or sneeze, the embryo will "fall out". However, remember that this is physically impossible, and that if the embryo is going to implant, it will, no matter how much you exert.

Thus, there are numerous stages to every IVF treatment cycle, each of which must be reached and completed before moving on to the next stage:

more than one egg should develop;
eggs should mature;
ovulation should not occur before the eggs can be collected;
eggs must be retrieved during the "pick-up";
sperm must fertilize at least one egg;
fertilized eggs must divide and grow healthily, and all this so that...
the embryos might get implanted in the uterus.
Think of it as a series of hurdles, all of which have to be cleared, in order to win the race!

The enigma of embryo implantation - why doesn't every embryo become a baby?

While modern technology is very good at making embryos in the laboratory, we still cannot control the implantation process. We do not know which embryo will become a baby - and this can be very frustrating, for both patients and doctors! Many patients who do not get pregnant after an embryo transfer start believing that their bodies are defective, and that they have "rejected" the embryo. They feel that if they failed to become pregnant even after the doctor transferred 3-4 good quality embryos, that they are flawed. However, you need to remember that embryo implantation is a very complex process, which consists of a series of phases in which the embryo has to appose and attach itself to the maternal endometrium and invade into it. First, the embryo has to undergo further development, till it reaches the blastocyst stage, when it hatches from its shell, known as the zona. The hatched blastocyst then needs to implant in the endometrium, and the three phases of implantation are known as apposition, adhesion and invasion, and occur during the period of time known as the implantation window. Apposition, or orientation of the embryo (which is at the blastocyst stage at this time) within the cavity of the uterus, starts when the cavity has become minimal due to the suction of endometrial fluid by pynopods (small protrusions found on the surface membrane of the cells lining the uterus). Adhesion of the blastocyst is a progressive phenomenon that ties the embryo to the endometrium and is the primary event-initiating invasion. Many molecules, such as cytokines, growth factors and cell adhesion proteins called integrins play an important role in this complex process during which the blastocyst and maternal endometrium must undergo an exquisite dialogue.

Invasion is a self-controlled proteolytic process that allows the embryonic trophoblast to penetrate deep into the maternal decidua and to invade the endometrial spiral arteries by producing chemicals called proteinases. How implantation is regulated and brought about remains an enigma, but we need to remember that the implantation process is surprisingly inefficient in humans - Nature is not always very competent! After IVF, it's only about 10%, which means that only 10% of embryos implant successfully to become a baby. The responsibility for this low efficiency has to be shared between the embryo the endometrium, as well as a defective embryo-endometrium dialogue. We still cannot successfully predict which patient will get pregnant after embryo transfer. We now know that one of the major reasons for failure of the embryo to implant is a genetically abnormal embryo. Basic research on implantation is of great interest today, because embryonic implantation is the major limiting factor in allowing pregnancy after ART, but we still need to learn a lot about this "black hole" in our knowledge, before we can learn to control it! Some clinics attribute failure of the embryos to implant to immunological problems - and even offer "treatment" for this, but there is no proof to support this theory.

Many patients blame themselves when they don't get pregnant after an embryo transfer. They feel that the fact that the embryo did not implant means either that their body is defective; or that it "rejected" the embryo; or that they did not rest enough. However, please do remember that embryo implantation is a complex process, which you cannot influence by your diet or physical activity, so there is no need for you to blame yourself if the embryos do not implant.

Maximizing Chances for Success

Women:

Avoid all medications. If you are taking other prescription medications check with your doctor prior to beginning your treatment cycle.

No smoking or alcohol use. Studies show both can result in lower pregnancy rates and a greater risk of miscarriage. Why put yourself through this if you are not doing everything YOU can to insure your success.

No more than two caffeinated beverages per day.
Avoid change in diet or weight loss or fad diets during IVF cycle. A healthy well balanced diet works best.

Refrain from intercourse three to four days prior to egg retrieval and following embryo replacement until the pregnancy test has been done.

Normal exercise may continue unless enlargement of your ovaries produces discomfort.

Avoid hot tubs or saunas.

Men:

Fever greater than 100.4o one to two months prior to IVF treatment may adversely affect sperm quality. Be sure to let your doctor know. If you are sick, please take your temperature and report any febrile illnesses.

Sitting in hot tubs and saunas is not recommended. Even a single episode in a hot tub can adversely affect sperm function. Please refrain from this for at least three months prior to treatment.

Drugs, alcohol, and cigarette smoking should be avoided for three months prior to treatment and at all times during the ongoing IVF treatment cycle to get the best results.

Abstain from intercourse for at least three days, but not more than seven days prior to collection of semen for egg collection and during treatment.

The Cost of IVF

The cost of a single IVF treatment cycle varies widely, from approximately Rs 30,000 to more than Rs 75,000 depending on the program and the items included in the fee. It is important to get an itemized listing from the selected program of what costs are included in the treatment cycle. Try to find your "total" medical cost - how much you will have to spend out of your own pocket for the entire treatment. Some clinics such as ours, offer a complete treatment package, which covers all the medical expenses of an IVF cycle. Many clinics do not include the cost of certain procedures (such as ultrasound scans) and these can then add up to quite a bit! Other expenses to be aware of include time missed from work and travel and lodging expenses. The number of treatment cycles needed to achieve pregnancy will, of course, determine the final cost.

Embryo Freezing

Since most IVF programs superovulate patients to grow many eggs, there are often many embryos. Since the risk of multiple pregnancies increases with the number of embryos transferred (and in fact the law in the UK prohibits the transfer of more than 3 embryos to reduce this risk), many patients are left with "spare" or supernumerary embryos. These can be discarded; or used for research. It is now also possible to freeze these embryos and store them in liquid nitrogen. These stored embryos can then be used later for the same patient - so that she can have another embryo transfer cycle done without having to go through superovulation and egg collection all over again. Moreover, since this embryo transfer is done in a "natural" cycle (when she is not taking any hormone injections) some doctors believe the receptivity of the uterus to the embryos is better. For women with irregular menstrual cycles, frozen embryo transfer can also be done in a "simulated natural cycle", in which the endometrium is primed to maximize its receptivity to the embryos by using exogenous estrogens and progesterone. Since pregnancy rates with good-quality frozen-thawed embryos are as good as with fresh embryos, we encourage all our patients to freeze and store their supernumerary embryos, rather than discard them. Freezing is very cost-effective, since transferring frozen-thawed embryos is much less expensive than starting a new cycle, so that it serves as a useful "insurance policy" in case pregnancy does not occur. However, since it is worthwhile freezing only good quality embryos, the option of freezing is a "bonus" which is available to only about 30% of all IVF patients. About half of all embryos frozen survive the freezing thaw process. It is reassuring to know that the risk of defects is not increased as a result of freezing. These frozen embryos can be stored for as long as is needed - even for many years. When they are in liquid nitrogen, at a temperature of -196º C, they are in a state of suspended animation, and all metabolic activity at this low temperature stops, so that a frozen embryo is like Sleeping Beauty!

Once stored, embryos can be used by the couple during a later treatment cycle, donated to another couple or removed from storage. These options should only be undertaken after considerable discussion.

Egg freezing

While we still cannot freeze unfertilized human oocytes efficiently, a new technique called vitrification (which uses ultra-rapid cooling together with an increased concentration of cryoprotectants) may allow us to offer this option to our patients, in the future, allowing the facility of egg storage and egg banking.
Analyzing a Failed IVF Cycle

If you don't get pregnant after your IVF attempt, you are likely to be very disappointed and disheartened. However, remember that this is not the end of the road - it's just the beginning! At the end of the IVF cycle, you need to sit down with your doctor and analyze what you learnt from it. Was the ovarian response good? Was the endometrium receptive? Did fertilization occur? Why didn't pregnancy occur (though this is usually a question we still cannot answer!)? Can you repeat the same treatment, or do you need to make changes before going in for your next attempt? When can you go in for your next IVF cycle? And even if you do not get pregnant, at least the fact that you attempted IVF should give you peace of mind that you tried your best, using the latest technology medical science has to offer.

The Second Time Around - the Next IVF Cycle

Most doctors would advise you to wait for a month before starting a new cycle. While it is medically possible to do the next cycle immediately, most patients need a break to marshal their emotional strength before starting again. Your doctor may need to modify your treatment, depending upon an assessment of your previous cycle. For example, if the ovarian response was poor, the doctor may advise you to increase the dose of drugs used for superovulation. If fertilization did not occur, you may need to go in for microinjection (ICSI). If the quality of the embryos was poor, you may be advised to consider a ZIFT rather than IVF. When an IVF cycle fails, many patients want to do "something new" or "something different" in the next cycle. However, do remember that the commonest reason for a failed IVF cycle is the failure of the embryos to implant - and since this is still an area of profound ignorance, there is little we can do to increase the probability of successful implantation occurring the next time. Rather than look upon the cycle as a "failure", it's better to treat it as having provided valuable information - for example, evidence that the sperm can fertilize the egg, which proves that they are normal! For patients who have had an embryo transfer, the odds are stacked in their favor that they will get pregnant sooner or later. Nevertheless, there is a lot of pressure to try the "newest or latest advance" the next time - which is why many clinics now offer expensive techniques such as immunologic testing and even immunotherapy - but these are still in the realm of "scientific witchcraft" and have not been proven to be helpful. In fact, if the IVF cycle was satisfactory, the doctor will often advise you to repeat exactly the same treatment again - and all that it may take to achieve your IVF success is time and another attempt. When an IVF cycles fails, there is a lot of pressure on both patient and doctor. Many patients will change the doctor because they do not conceive - but this is not usually a good idea, unless you are unhappy with your medical care. Doing a second IVF cycle in the same clinic is usually better than changing doctors, because your doctor can now tailor his treatment based on his observations during your earlier treatment cycle. Interestingly, we often find that couples going through a second IVF cycle are much more relaxed and in control. This may be because they are aware of all the medical and procedural minutiae, and are better prepared for these; and also because they have had a chance to establish a personal relationship with the medical team. Also, since they have already faced failure the first time around, many of them are much better able to cope with the stress of IVF, since they are prepared for the worst. With today's IVF technology, we can confidently reassure any patient that we can help them to get pregnant, provided they have inexhaustible resources of time, money and energy!
GIFT

GIFT stands for gamete intrafallopian transfer. A gamete is a male or female sex cell -- a sperm, or an egg. During GIFT, sperm and eggs are mixed and injected into one or both fallopian tubes. After the gametes have been transferred, fertilization can take place in the fallopian tube as it does in natural, unassisted reproduction. Once fertilized, the embryo travels to the uterus by natural processes.

As in IVF, a GIFT treatment cycle begins with ovulation enhancement which is followed by egg harvest, usually by means of laparoscopy. But the similarity to IVF ends here. In IVF, an embryo is transferred. In GIFT, gametes are transferred.

Only patients who have at least one normal, healthy fallopian tube are candidates for GIFT. Such patients include women who have unexplained infertility or mild endometriosis and couples whose infertility results from male, cervical, or immunological factors. Some doctors recommend that couples with male factor infertility proceed with GIFT only if it has been proven that the man's sperm can fertilize the woman's egg either by in vitro fertilization or by past pregnancies.

The Basic Steps of GIFT

The basic steps of GIFT are ovulation enhancement, egg harvest, insemination, and gamete transfer. The eggs are usually harvested during laparoscopy. During this same laparoscopy procedure, which takes about an hour, eggs are mixed with sperm and the gametes are transferred.

Insemination

The harvested eggs are examined under the microscope and graded for maturity. The selected eggs are placed in individual dishes and combined with sperm (insemination). The sperm are prepared in advance in the same manner as for IVF. Some doctors prefer to wait for about 10 minutes before the transfer, since during this period the sperm adhere to the zona pellucida of each egg. Many programs load eggs and sperm individually into a catheter and inject them into one or both of the fallopian tubes.
Gamete Transfer

The sperm - egg mixture is loaded into a specially designed catheter. This is then directed into the fallopian tube(s) through their fimbrial opening while looking through the laparoscopy. Up to four eggs and sperm may be injected into one or both tubes. Gametes will be transferred only if the fallopian tubes appear healthy. If the surgeon determines that the tubes are unhealthy, IVF should be attempted instead. For this reason, GIFT should be undertaken only at facilities that have the capability to perform IVF also.

Pregnancy Rate

Specialists generally agree that pregnancy rates are higher for GIFT than for IVF - in fact, GIFT is about twice as successful as IVF. In part, this may be due to the type of patient accepted into GIFT programs. It may also be because the in vivo tubal environment is more "physiologic " for the gametes and embryo than the in vitro environment.

The advantages of this technique are:

The fallopian tube acts as the laboratory.
The embryo will reach the uterus at a later stage in its development, as with normal conception.
The procedure is considered morally acceptable to some religious groups that object to IVF, as conception occurs within the human body.
The endometrium will also be more receptive to the embryo because of the greater time the embryo takes to reach the uterus.
GIFT & IVF Compared

There are several differences between GIFT and IVF. The most important one is that GIFT requires at least one healthy fallopian tube, whereas IVF is appropriate treatment for women with tubal disease or even no fallopian tubes at all. At present, GIFT requires laparoscopy for transfer An IVF treatment cycle can be complete without laparoscopy. This is one of the reasons many IVF clinics no longer offer GIFT, even though it offers a higher pregnancy rate. Because they do not have easy access to an operation theatre. Ideally, you should opt for treatment in a clinic which offers all the procedures, so that the doctor can select the one that is best for you, depending upon your individual circumstances.

In the case of GIFT, fertilization occurs unobserved inside the body. Whereas in IVF, fertilization takes place in a laboratory dish and can be confirmed visually with a microscope. Visual confirmation of fertilization is especially important in cases of male factor or unexplained infertility. To obtain visual confirmation and still have the greater chance of pregnancy afforded by GIFT, one of the variations of GIFT described later (ZIFT, PROST or TET) may be used, to give the patient the benefit of combining the advantages of both the procedures.

Vaginal GIFT

A major disadvantage with conventional GIFT is that a surgical procedure, namely, laparoscopy, is needed to transfer the eggs and sperm into the fallopian tube. Recently, a non-surgical method has been described by Dr. Robert Jansen and Dr. John Anderson from Sydney IVF, Australia, in which the gametes can be transferred into the fallopian tubes through the vagina and cervix under ultrasound guidance. This requires a special set of catheters, which allow the doctor to enter the uterine ends of the fallopian tubes through the cervix. Once the catheters have been accurately positioned and ultrasound can help in this the gametes are injected into the tubes. Since this method does not involve surgery, the benefits to the patient are obvious - less expense, no hospitalization, no scar and no anesthesia. However, the technique does require much more technical expertise and is still being investigated more thoroughly. Also, the pregnancy rates with the method are less than with conventional laparoscopic GIFT.

The Cost of GIFT

The cost of a GIFT treatment cycle varies from one program to another, falling within the same basic range of Rs 30000 to Rs 70000 plus range, which is typical for IVF.

Variations of GIFT

Variations of GIFT include procedures with names like ZIFT, PROST, and TET - an alphabetic potpourri!

ZIFT, i.e. zygote intrafallopian transfer, is also called PROST, which stands for pronuclear stage transfer. When a sperm penetrates an egg, the sperm introduces its nuclear material into the egg. Approximately 14 hours after penetration, two distinct pronuclei, one from the sperm and one from the egg, are visible under the microscope. Pronuclei are taken as indicators that fertilization has occurred. The fertilized egg before cell division begins is also called a zygote. During ZIFT, eggs are removed by transvaginal aspiration and fertilized in a laboratory dish. The next day, when the fertilized eggs have reached the pronuclear stage, the embryos are transferred to the fallopian tubes during laparoscopy.

Approximately 24 hours after a fertilized egg reaches the pronuclear stage, it divides for the first time and becomes a two = a cell embryo. This cell division is called cleavage. It is at this stage or later that TET, tubal embryo transfer is performed. The embryos are transferred to the fallopian tube during laparoscopy.

PROST, ZIFT, and TET differ from GIFT in that fertilization takes place in a laboratory dish instead of the fallopian tube. Moreover, they differ from IVF in that the fertilized egg is transferred to the fallopian tube instead of to the uterus. They offer the best of both IVF and GIFT, namely, documentation of fertilization in vitro and also higher pregnancy rates because of tubal transfer. However, the cost of ZIFT, PROST, or TET is usually greater than IVF or GIFT.

Success Rates - Making Sense of the Figures

The most important question most patients have about IVF is: What are my chances of getting pregnant?

This is a difficult question to answer, since there are so many variables involved. Chances of success depend upon:

The wife's age - chances decline with increasing age, precipitously so over the age of 40.
The reason for the IVF - chances of pregnancy decline when IVF is done for male factor infertility.
The quality of the IVF Clinic and its services.
The number of embryos/eggs transferred.
The superovulation regime used.
Of course, there are some variables about which nothing can be done, such as the wife's age. But other variables can be controlled to try to maximize chances of a pregnancy! The good news is that with improving IVF technology, pregnancy rates with IVF have increased dramatically.

Pregnancy rates are related directly to how many embryos are transferred. For example, when three good quality embryos are transferred, the chance of pregnancy is about 40% in that cycle. The number of embryos transferred needs also to be balanced against the risk of multiple pregnancies, which naturally increases with more embryos. With this in mind, the Fertility Society of Australia recommends that no more than three embryos be transferred during any treatment cycle. Studies done the world over show that the average pregnancy rate per cycle for IVF is about 30 % for most patients; and about 40% for GIFT. How can a patient interpret this figure? For example, let us consider a 30-year-old patient with irreparable tubal damage who goes through one IVF cycle. She can look at the pregnancy rate figure of 30 % in two ways. A success rate of 30 % means there is a 70 % chance she will not get pregnant. On the other hand, if she does not go in for any treatment, her chance of getting pregnant is zero. The IVF cycle has increased this to 30 % - no one can do any better than this today! Of course, for the couple that gets a baby, it's a 100% baby - and for the one who fails, it's 0%. For the individual patient, it's really not a question of statistics! Each IVF treatment cycle is a bit like taking a gamble - and you need to hope for the best and prepare for the worst!

IVF treatment should not be considered to be a single shot affair. Patients should plan (mentally at least!) to go through at least three to four cycles to give themselves a fair chance of getting pregnant. With four treatment cycles, the chance of getting pregnant (the cumulative conception rate) is about 70%. What this means is that even though the chance of getting pregnant in a single cycle may never be more than 40%, over a period of four treatment cycles, the chances increase to 70% because the success rate is cumulative. Thus, let us assume the pregnancy rate for IVF at a clinic is 30%. If 10 patients start an IVF cycle, three will get pregnant, leaving seven patients. If these seven do another IVF cycle, another 30% (2.1 patients - so let's say another two) will conceive. If the remaining five do another cycle, one more will get pregnant; and at the end of the fourth cycle, one more will conceive; so that of the 10 patients who started, seven will have got pregnant in four attempts. This is because the chances of getting pregnant in the next IVF cycle do not decrease just because a pregnancy has not occurred in the previous cycle, so the best bet would be to keep on trying. Theoretically, we could reassure every couple taking IVF treatment that they would get pregnant, provided they are willing to go through as many cycles as are required, till they hit the jackpot! Of course, one has to set a limit somewhere, and the decision when to stop is something that only the couple can make for themselves. After more than six failed IVF cycles, the chance for a pregnancy with IVF does decline.

Games IVF Clinics Play with Pregnancy Rates

Of course, some clinics have much better pregnancy rates than others. Nevertheless, many clinics will quote inflated rates and this can mislead patients! Unfortunately, in India there is no central registry or monitoring of IVF clinics, so that you pretty much have to trust what the doctor tells you. In many countries in the West, the law mandates that IVF clinics report their pregnancy rates to a central authority - thus ensuring that IVF clinics maintain high standards and quality control. This regulation can be very helpful for patients.

Different programs define success in various ways. To most couples, success means the birth of a baby, not just a pregnancy, so that what needs to be determined is the "take home baby rate." Some clinics quote pregnancy rates when describing their success rates - and these can be considerably higher than the live birth rate, depending upon how a pregnancy is defined. Thus, some programs define pregnancy when the pregnancy test is positive; others define pregnancy as a fetus seen on ultrasound.

So-called biochemical pregnancies are also fairly common after IVF. These are pregnancies confirmed by blood and urine tests but in which the embryo does not develop beyond the earliest stage. No gestational sac and fetus is seen on ultrasound examination. Counting biochemical pregnancies will, of course, inflate the pregnancy rate.

Other ways of juggling with pregnancy rates include: accepting only patients who have a good chance of getting pregnant, or selectively reporting pregnancy rates achieved in younger women (and excluding other patients from data analysis).

Most good program today express their pregnancy rate as the number of babies born per treatment cycle, and this is the figure you should be looking at.

Newer procedures

IVF technology is improving by leaps and bounds and many exciting advances have taken place recently.

Many of these are now available in India, and these include the following.

Assisted Fertilization

One of the major problems with IVF today is the low pregnancy rate after successful embryo transfer. The reason why such few embryos implant successfully (only one of 10 embryos will become a baby) is one of the things we really do not understand today. Dr. Jacques Cohen from New York believes this is because the surrounding shell of the embryo (called the zona pellucida) hardens when it is cultured in the laboratory. Some clinics therefore use "embryo surgery" (called zona drilling or assisted hatching) to "soften" the shell of the embryo, and they believe this helps in increasing pregnancy rates by improving implantation rates, since embryo hatching is facilitated. Hatching can be done using an acid (acid Tyrode's) or with a laser. However, assisted hatching has not been shown to be helpful when used on a routine basis for all patients, and most doctors feel that it should be utilized only when needed for example, for the small proportion of patients who have a thick zona or perhaps, for patients over 40 years of age, or those who have had repeated implantation failures. Unfortunately, many IVF vlinics perform assisted hatching indiscriminately, primarily in order to enhance their revenue.

Embryo surgery has also been used for embryo biopsy, for preimplantation genetic diagnosis, in which single cells are removed from the developing embryo, to make sure the embryos are healthy and have no genetic disease. This is described in more detail in Chapter 26.

Embryo multiplication, by removing some of the cells from the embryo and allowing them to divide, can allow doctors to "multiply" the number of embryos formed in vitro. The new embryos can then be coated with a new shell (zona) and then transferred into the uterus. This could help to increase the chances of pregnancy in women who can produce only a small number of embryos.

Other scientists feel that the reason for the poor implantation is the poor quality of the embryo cultured in vitro. They have therefore tried to improve embryo quality in the laboratory by trying to provide it with more natural ("physiological") culture conditions. This is done by a method called co-culture in which the embryo is cultured along with "feeder cells" in the culture dish. These cells provide the embryo with the extra nourishment they need for better growth. Better pregnancy rates are claimed with co-cultured embryos as compared to embryos grown under traditional IVF conditions.

Cytoplasmic transfer

Some patients going through IVF grow lots of eggs, but persistently form poor embryos that fail to implant. In some of them, this may be because they have a problem in their cytoplasm (the area within the shell of the egg that lies outside of the nucleus) - either in their mitochondria or the cell-division apparatus. Dr Cohen hypothesized that it should be possible to correct this problem by replacing just the cytoplasm of the egg, instead of the whole egg, thus keeping the mother's own genetic contribution (the DNA contained in the nucleus) to the baby intact. This high-tech method is called cytoplasmic transfer, and uses cytoplasm donated from the healthy eggs of another woman.

Blastocyst transfer

The formulation of new laboratory culture media - the liquid in which the embryo is grown in vitro - has made it possible to "grow" embryos in vitro beyond the typical two to three day state of development, till they become blastocysts. A blastocyst is the final stage of the embryo's development before it hatches out of its shell (zona pellucida) and implants in the uterine wall. Initial studies suggest that transfer of the embryo on day 5, at the blastocyst stage, may yield higher pregnancy rates. There may be two possible reasons for this. Firstly, transfer of the blastocyst to the uterus may be more physiologically appropriate, since this mimics nature more closely, so that the implantation rate may be higher. Also, waiting till the blastocyst stage allows the doctor to select the "best" embryos, since unhealthy embryos are likely to die (arrest) before they reach this stage. Blastocyst transfer also significantly reduces the possibility of potentially dangerous high-order multiple births, such as triplets. Higher implantation rates allow doctors to transfer fewer blastocysts - perhaps only one - reducing or avoiding multiple births and their associated problems. Supernumerary blastocysts can also be successfully cryopreserved with resulting pregnancies after thawing.

While blastocyst transfer is a very promising advance for patients who grow lots of eggs (good ovarian responders), its utility for the difficult patient - the poor ovarian responder - is still debatable. This is because if there are few eggs, there is a very real risk that none of them may develop to the blastocyst stage. All of them may "arrest", so that there are no embryos available for transfer. Every patient needs to balance these risks and benefits, depending upon the clinic's experience and success rate.

Simplifying IVF

Some people might ask whether all this is relevant to Indian conditions. While these technologic refinements are very exciting, IVF clinics in India should also focus on simplifying IVF technology, so that it can be made more affordable for the average Indian couple. Advances that have occurred and have helped to simplify IVF and make it more easily available include the following.

Intravaginal culture: This is a technique for IVF, which provides the same rate of fertilization that conventional IVF does, at a fraction of the cost. In this method, which was first described by Dr. Ranoux of France in 1984, the eggs and sperm are placed in a sterile vial, which is then sealed and placed in the woman's vagina. Thus, the woman acts like her own incubator, since she keeps her eggs and embryos at body temperature. Since expensive laboratory equipment is not needed, this is much cheaper and as effective as conventional IVF!

Natural cycle IVF: Natural cycle IVF is much less expensive because it does away with the high expense of gonadotropin injections used for superovulation. In this method, the single egg which the woman grows in her unstimulated ovulatory cycle is used for IVF. While the pregnancy rate is lower, the expense (and the stress of IVF) is much less! Interestingly, "gentler" IVF is becoming increasingly popular in the West as well. Many doctors are very critical of the large amounts of hormones that are being used in traditional IVF in order to produce large quantities of eggs. Gentler ovarian stimulation (using only clomiphene or smaller doses of HMG) has also become popular once again, since it reduces the risks of complications, such as ovarian hyper stimulation and multiple pregnancies.

In Vitro Maturation: A new technique called "in vitro maturation" allows doctors to collect many immature eggs during a "natural cycle." These eggs are then matured in vitro, by adding special chemicals to the culture medium. ICSI (microinjection) can then be used to fertilize these eggs. This technique is very promises, because it allows the doctor to collect many eggs without having to superovulate the woman, thus helping to reduce the risks and costs of IVF. However, the pregnancy rates with IVM are still not as good as with conventional IVF.

Transport IVF: Transport IVF is a recent innovation pioneered in the Netherlands; and also by Dr. Kingsland of the UK. In this, the egg retrieval is performed by the gynecologist in his own clinic or hospital and the eggs (in the follicular fluid) are then transported to a central IVF laboratory by the husband in a portable incubator. Insemination, fertilization and embryo transfer take place in the central laboratory. This method allows gynecologists to take an active part in their patients' treatment; ensures high quality, since all laboratory procedures are performed in a central laboratory; and also minimizes patient inconvenience (since superovulation and egg retrieval are done by the local gynecologist, the number of visits the patient has to make to the IVF center are minimized.)

Donor Sperms, Eggs and Embryos

Couples with no sperm or eggs can undergo IVF with the use of donor sperm or eggs.

For IVF, cryopreserved donor sperm are processed in the same way as fresh sperm. In some cases of female infertility, fertilization may be attempted first with the husband's sperm, and if this fails, donor sperm may be used in a second attempt. Alternatively, if several eggs are aspirated, some may be inseminated with the partner's sperm and some with donor sperm.

Donor eggs can be used in GIFT or IVF for women who have no eggs (ovarian failure) but who do have a healthy uterus.

A couple may also choose to use donor eggs if the woman has a genetic disease that could be passed on to a child. Donor eggs can also be used in some cases of long standing infertility when other procedures have failed - for example, women with many previous unsuccessful IVF cycles. The use of egg donation is now becoming increasingly commoner, as older women are seeking infertility treatment. Since the chance of a pregnancy in the older woman depends directly upon the quality of her eggs, many older women opt to use donor eggs from younger women - which increases their pregnancy rates dramatically. This also creates headline news, for example, when a menopausal woman has given birth with donor eggs. In rare cases, when both the man and woman are infertile, donor sperm and donor eggs have been used together.

Unfortunately, it is still not possible to freeze and store eggs on a routine basis - they are too fragile! This is why fresh eggs need to be used for donor egg treatments. These may come either from another infertile patient; or a volunteer egg donor; or a friend or relative, who offers to donate eggs.

Egg donation for IVF requires the egg donor to undergo ovulation induction and ovum aspiration. The donation of eggs carries more risk and causes greater inconvenience to the donor than does the donation of sperm.

The use of donor eggs requires that the cycles of the donor and the recipient be closely synchronized. This requires treatment of the recipient, so that her endometrium is primed and is receptive to the embryos at the time of transfer. For amenorrheic women with ovarian failure, this can be achieved by treating them with exogenous estrogens and progesterone. Other women who are cycling need to be down regulated with GnRH analogs before starting treatment with exogenous estrogens.

In the future, it is possible that scientists will discover ways to collect and store immature eggs. This may make "egg banks" a reality, and considerably simplify the technique of egg donation.

Couples with both a sperm and an egg problem can also use donor embryos. Since embryos can be stored, some infertile couples going through an IVF cycle, who have chosen to freeze their supernumerary embryos for themselves, are willing to donate their surplus frozen embryos to other infertile couples when they get pregnant. Since donor eggs are still so hard to come by, many couples may choose to resort to using donor embryos, since these are much more easily available. You can think of donor embryo treatment as very similar to adopting a baby with the difference that you are carrying the pregnancy and giving birth to the baby!

Some couples are worried that if they use donor eggs or donor embryos, their body will "reject " them, because these are genetically foreign. However, remember that all embryos are genetically foreign to the mother, because half the genetic material comes from the father! The uterus is an "immunologically privileged" site, and donor embryos have as good a chance of implanting as normal embryos.

Risks and Complications of IVF and GIFT

Many couples are still worried that babies born after IVF are abnormal or weak. You need to remember that in one sense there is nothing "artificial" about these babies they aren't synthetic babies, which are being manufactured in the laboratory! Remember that IVF is a form of assisted reproductive technology, where technology is being used to assist Nature to accomplish what it has failed to do for the infertile couple! Over a hundred thousand babies have now been born after IVF treatment, and the risk for birth defects is not increased after IVF treatment.

The most worrisome complication of IVF is that of ovarian hyper stimulation syndrome (OHSS), because of superovulation. The cause of "ovarian hyper stimulation syndrome" is that superovulated ovaries contain many follicles that are loaded with estrogen. After ovulation, a huge amount of estrogen-rich fluid is poured directly out of the enlarged and fragile ovaries into the abdominal cavity. This fluid also contains chemicals like kallikrein-kinin and VEGF (vascular endothelial growth factor), which then coat the lining of the abdominal cavity (called the peritoneum) and cause it to become very permeable (leaky). Fluid (serum) literally pours out of the bloodstream into the peritoneal cavity because of the "leakiness" of the abdominal cavity's lining. The ovaries balloon in size, the abdomen swells, and some women may get lightheaded with relatively low blood pressure, or dizzy because of the decreased blood volume. Many women going through IVF treatment will have mild degrees of ovarian hyper stimulation with a little bit of lower abdominal swelling, discomfort, and dizziness. This does not require hospitalization, just bed rest at home. It is only the rare, severe cases that require hospitalization. The occasional patient today who develops severe hyper stimulation must go into the hospital, have intravenous fluids for several days, and wait for her ovaries to reduce in size and for her body to readjust. Some patients may even need to be admitted into an intensive care unit for monitoring and observation, since this can be life threatening.

At one time this was a very dangerous condition only because it was not fully understood. We now know that by putting a small "paracentesis" catheter into the abdomen and draining all of this fluid, the patient is made much more comfortable, she can breathe more easily, and by getting rid of this estrogen irritation, fluid leakage into the abdomen slows down dramatically. Thus, even in the very rare cases of severe hyper stimulation syndrome, knowledgeable treatment makes the likelihood of any dangerous outcome very remote.

Interestingly, the worst cases of hyper stimulation syndrome occur when a woman becomes pregnant. This is because her placenta is making HCG and stimulating the ovaries to continue to pour out large amounts of estrogen-rich fluid. So although it is a very unpleasant side effect to endure, hyper stimulation syndrome often means good news.

If you grow too many follicles (more than 25), or if your estradiol level is very high, the doctor may be forced to cancel the IVF cycle, because of the high risk you run of developing ovarian hyper stimulation syndrome. Remember that hyper stimulation cannot occur unless ovulation takes place. Thus, if the doctor with holds the HIG injection, there is no risk of developing hyper stimulation. In some clinics, doctors can salvage this cycle by collecting all the eggs and freezing all the embryos. Since the embryos are not transferred, the risk of hyper stimulation is reduced; and the frozen embryos can then be transferred in a future cycle.

Complications can also occur during the egg harvest procedure. The removal of eggs through an aspirating needle entails a slight risk of bleeding, infection, and damage to the bowel, bladder or a blood vessel.

In all techniques of assisted reproductive technology, the chance of multiple pregnancy is increased when more than one embryo or egg is transferred. Although some would consider having twins to be a happy result, there are many problems associated with multiple pregnancies, and problems become progressively more severe and common with triplets and each additional fetus thereafter. Women carrying a multiple pregnancy may need to spend weeks or even months in bed or in the hospital. There may be enormous bills for the prolonged and intensive care for premature babies. There is also a greater risk of late miscarriages or premature delivery in multiple pregnancies.

A recent treatment option for women with multiple pregnancies is that of selective fetal reduction, in which one or more of the fetuses are selectively destroyed (usually by injecting a toxic chemical, potassium chloride, into its heart under ultrasound guidance). In most cases, the killed fetus is then reabsorbed by the body - and the other fetuses continue to grow. Of course, the risk of all the fetuses being lost because of a miscarriage (as a result of inadvertent trauma during the procedure) is also present, and is about 10% in experienced hands.

There is approximately a 54% chance of an ectopic pregnancy with IVF. This is not because of the procedure, but rather because women going through IVF already have damaged tubes, which predisposes them to having an ectopic.

IVF is physically demanding - and stressful! The effects of blood tests, anesthetic and operation are tough on your body. Hormone stimulation causes lethargy and fatigue, notwithstanding the sometimes extensive travelling required each day. Some people find treatment conflicts with their employment or other commitments.

A final risk is not physical, but psychological. The major risk for most patients is the risk of failure that even after spending all the time, money and energy required for a treatment cycle, they will not get pregnant. Couples undergoing IVF have described the experience as an emotional roller coaster. The treatments are lengthy, involved, and costly. These procedures often create high expectations but are more likely to fail than to succeed in a given cycle. The unsuccessful couples will feel frustrated in their quest for pregnancy. It is common to feel angry, isolated, and resentful towards both the spouse and the medical team. At times, this feeling of frustration leads to depression and feelings of low self-esteem. The support of friends and family members is very important at this time.

The danger of over treatment and under treatment

IVF techniques have now become well established, and most towns in India have one or more IVF clinics today. This is all for the best, because infertile couples no longer need to travel long distances for IVF treatment. However, because offering IVF has become a fashionable trend, there are now too many IVF clinics in competition with each other. Many of these clinics are poorly equipped, and the staff inadequately trained, with the result that pregnancy rates are poor. Many clinics have started, and then closed down in a few months, without being able to achieve even a single pregnancy dashing many patients hopes in the process. Unfortunately, this often means that all IVF clinics start getting a bad reputation. In order to protect yourself, it's a good idea to ask the clinic staff to actually show you the embryos under the microscope. Most good clinics do this routinely, and some even offer video records. Not only is this reassuring for the patient, it also helps them to "bond" with the embryos!

Another danger of too many IVF clinics is the risk of over treatment. In order to remain profitable, many clinics now offer IVF to infertile couples as a treatment of first choice (rather than reserving it for patients who truly need it). While this does help them to keep their financial bottom line healthy and to increase their pregnancy rates (since many of these patients are young couples, who never needed IVF in the first place!), it is an inappropriate use of limited medical resources. IVF treatment should be reserved only for patients who really need it. Paradoxically, while rich patients end up getting IVF even when they don't need it, poor patients are often deprived of this treatment even though they need it, because of the expense involved. Unfortunately, the Government still does not consider that providing infertility treatment should be a part of its family planning program. Hopefully, this will change in the future, and providing infertility services will be seen to be a part of comprehensive reproductive care services. This will provide many more infertile couples access to assisted reproductive technology.

Supporting each other

You may not be able to comfort each other enough at times of disappointment, especially when you are both upset. If you don't have a family or a friend who can provide support (without pressure), then the positive and sensitive assistance offered by a support group may be very suitable, either in the short term or longer. Yet other people may seek the more specialized assistance of a counselor, who is either attached to the clinic or based in the community.

Going through an IVF cycle can be very stressful, and you need to be prepared for the ups and downs. Many clinics have found that optimistic and well-prepared patients do have better pregnancy rates, and counseling and emotional support can be very helpful in improving your chances of getting pregnant!

Every time you start a cycle, you have to hope for the best and be prepared for the worst. It literally is like gambling - and hoping that you hit the jackpot! Many patients find the first cycle the most stressful - and find it much easier to do a second cycle, because they are more in control and understand much better what they are going through.

If you judge the outcome of an IVF cycle only on the basis of whether or not you get pregnant, then with the limitations of today's technology, you are more likely to be disappointed than otherwise. However, do remember that each cycle also provides you with valuable information, such as whether the sperm fertilize the egg or not, so that you can plan your future course of treatment. Going through an IVF cycle can also give you peace of mind that you tried your best!

Selecting an IVF Program

When selecting an IVF program, information is crucial. Important points for consideration include the qualifications and experience of personnel, types of patients being treated, support services available, cost, convenience, and rate of successful pregnancies. Older program have established live birth rates based on years of experience. Although new program won't have as much experience and may still be determining their live birth rates, their personnel may be equally qualified.

The range of services offered by an IVF program should be carefully considered. Not all programs are equipped to provide all services, such as tubal transfer, ZIFT, sperm donors, ICSI and cryopreservation of embryos. It is best to select a full-service clinic, which offers all the possible treatment options, so that the one that is best for you can be used.

The above considerations and answers to the following questions, which may be asked of the program, will help you make an informed decision when choosing an IVF program.

Cost and Convenience

1.How much does the entire procedure cost, including drugs per treatment cycle?

2. Do we pay in advance? How much?

3. What are the modes of payment?

4. How much do we pay if my treatment cycle is cancelled before egg recovery? Before embryo replacement?

5. What are the costs for embryo freezing, storage, and transfer?

6. How will the treatment schedule affect our commitments at work?

7. If I must have lodging, is there a low cost place for me to stay? Do you help arrange this?

8. If I do not get pregnant, when do I make my next appointment for further evaluation and counseling?

Details About the Program

1. How many doctors will be involved in my treatment?

2. To what degree can my own doctor participate in my treatment?

3. What types of counseling and support services are available?

4. Whom do I call day or night if I encounter a problem?

5. Do you freeze embryos (cryopreservation)?

6. Is donor sperm available in your program? Donor eggs?

7. Do you have an age limit?

Success of the Program

1. When did this program perform its first IVF procedure?

2. How many babies have been born from this program's IVF efforts?

3. In the past two years, how many treatment cycles have been initiated for IVF?

4. How many deliveries resulted in twins or other multiple births?

Credits: Dr. Aniruddha Malpani, MD and DR. Anjali Malpani,