In Vitro Fertilization (IVF)

By Steven T. Dodge, M.D.
California North Bay Fertility Medical Associates
Santa Rosa, CA, USA

In vitro fertilization (IVF) is the most potent fertility treatment available. Although complex and therefore expensive, if current trends continue it will soon become the most cost-effective treatment we have for all but the simplest of problems. What follows below is a brief review of the history and nature of IVF, including its indications, risks and success rates.

Robert Edwards, a Ph.D. physiologist, and Patrick Steptoe, a gynecologist, pioneered IVF in Great Britain during the 1970's. Edwards had spent the 1960's working with bits of human ovaries removed at surgery and had achieved the first fertilization of a human egg outside the body in 1967. During these same years Steptoe was helping to develop the new surgical technique of laparoscopy. By 1971 the two men had met and began to collaborate. Initially they retrieved eggs from the ovaries of volunteers by laparoscopy and focused on improving the timing of egg retrieval and in vitro culture conditions. By the mid seventies they felt ready to attempt pregnancy. Their initial pregnancy was unfortunately a tubal pregnancy (ectopic) in 1976. Then came true success and the first IVF baby, Louise Brown, was born in July 1978.

Steptoe and Edwards' original group of patients had undergone "natural IVF," meaning they were not given fertility drugs. Instead they were monitored closely and when ovulation appeared imminent, even if it was 3 o'clock in the morning, a laparoscopy was done and an attempt made to aspirate the single mature egg. As you might suspect they didn't always obtain the egg. Two Australian groups were only two years behind in achieving IVF pregnancies but they chose a different route. They stimulated their patients with fertility drugs in hopes of recovering more than one egg. As their initial success rates, about 5% per attempt, were higher than that of Steptoe and Edwards, all subsequent new IVF programs also used "stimulated IVF". Eventually even Steptoe and Edwards adopted this approach as well.

The 1980's saw continued improvement in embryology culturing techniques, refinements in fertility drug protocols and the ability to retrieve eggs with a vaginal ultrasound probe instead of laparoscopy. As a result IVF success rates began to climb slowly but steadily, reaching at the end of the decade 20-25% per attempt for women under the age of 40.

The 1990's have seen numerous general refinements, such as improvements in treatment protocols for women 40 and older and the development of ICSI (Intracytoplasmic perm Injection), a revolutionary treatment for severe male factor problems. With ICSI a single sperm can be injected into an egg and thereby achieve fertilization. For women 35 and older a technique called assisted hatching and the ability to grow embryos longer (3 to 5 days before transfer) helped improve the odds. Also, the process of egg donation (IVF using eggs donated by a younger woman) was perfected which produced high pregnancy rates in previously hopeless situations.

Treatment Process

A single attempt to achieve a pregnancy with IVF is called a cycle and includes several steps. The first is hormonal control of the woman's menstrual cycle, next comes stimulation of her ovaries with fertility drugs followed by close monitoring of the growth of the ovarian follicles, then egg retrieval and, lastly, transfer of a number of fertilized eggs (embryos) into her uterus.

1. Menstrual Cycle Control: The first step here is the use of birth control pills ("BCPs"), a seemingly odd thing for a fertility program to prescribe. The pills are started on the day a period starts or on the very next day and continued for 10-35 days until Lupron, a medicine that keeps the pituitary gland at rest, can be started. The length of time on BCPs is determined by when the period starts in relation to the week that is scheduled for the egg retrieval and embryo transfer. Since that is the busiest week of the entire IVF process it is important to select it with care.

2. Stimulation of Follicular Development: Once the Lupron is started and the BCPs finished a menstrual period will begin. A few days later we do a vaginal ultrasound exam in the office to make sure the pituitary gland has been successfully suppressed and that the ovaries and endometrium are ready for stimulation. Usually the ultrasound indicates normal baseline results and we can begin the next step, the use of the fertility drugs. The brand names of these preparations of FSH (Follicle Stimulating Hormone) are rather numerous: Follistim, Gonal-F, Repronex, Humagon, Metrodin, Fertinex and Pergonal. Most commonly a combination of two of these medications are used in the form of a daily injection for 7-10 days. It has long been our custom to teach a spouse, relative, friend or neighbor to give injections so frequent trips to our office are not needed.

3. Monitoring the Cycle: Usually we check for follicle growth after 5-7 days of the fertility drug injections. This involves a blood test to measure estradiol and a vaginal ultrasound to count and measure the follicles. Few women have follicles big enough to discontinue the medications at this point. Most must continue the injections and return for another blood test and ultrasound in 1-3 days.

Eventually the lead follicles reach a critical size and we can stop the fertility drugs. Now we must give an injection of HCG (Human Chorionic Gonadotropin) which will serve the same function as a natural cycle's LH surge. That includes final growth of the follicles, maturation of the eggs within the follicles and weakening of the follicle wall in preparation for ovulation. The biggest follicles will begin rupturing and releasing their eggs 39-40 hours after the HCG injection.

4. Egg Retrieval: The egg retrieval (ER) is scheduled to take place 36 hours after the HCG injection and is a procedure done in our office under light anesthesia (actually intravenous sedation) administered by an anesthesiologist. A needle guided by ultrasound is used to pass through the top wall of the vagina and into the fluid filled egg sacs ("follicles") in the ovary. This may sound complex but is actually quite easy and causes no pain, thanks to the anesthesia. It takes about 15 minutes to gather the eggs and the patient is ready to go home 60-90 minutes later. The fluid we remove from the follicles is given immediately to our embryologists who use their microscopes to find the otherwise invisible eggs.

5. Embryo Transfer: The eggs are usually inseminated a few hours after retrieval with sperm from the husband. This is done by our embryologists who are also responsible for culturing the fertilized eggs (now called embryos) until the time of transfer to the wife's uterus. The embryo transfer is usually done 3 days after the egg retrieval when the embryos are at the 4-10-cell stage. In selected cases transfer is done at the 5-day point when the embryos are "blastocysts." The transfer is a very simple procedure and is nearly always completely painless. It is very much like a routine pelvic exam and involves the passage of a very small plastic catheter through the cervix. A tiny drop (20-30 microliters) of culture media with the microscopic embryos suspended within is deposited in the upper reaches of the uterus.

6. Embryo Freezing (Cryopreservation): Embryos that are not transferred can be frozen in liquid nitrogen provided they are of good quality. Once frozen they can remain potentially viable for many years, perhaps even a decade. And as amazing as it may seem babies produced by frozen embryo transfer are just as healthy and have exactly the same chance of having birth defects as do babies conceived naturally.

Indications for IVF

1. Tubal Factor: IVF was developed specifically for women whose fallopian tubes had been injured by prior surgery or infection. Surgical repair of damaged tubes is rarely successful except in certain cases of tubal sterilization. For women with significant damage to the ends (fimbria) of their tubes, one IVF attempt offers a better chance of a viable pregnancy than surgery ever will and at a lower overall cost.

2. Male Factor: IVF is clearly the best treatment modality ever developed for low sperm count problems. ICSI, where a single sperm is placed inside each mature egg, has improved dramatically since 1990 and now offers hope even when extremely few sperm are obtained, either from semen or from needle aspiration of the testicular sperm ducts (PESAÑPercutaneous epididymal sperm aspiration).

3. Endometriosis: While not usually the first line of treatment for this problem, IVF works well for endometriosis. It is the therapy of choice for severe cases or when lesser treatments have failed or for women at or approaching age 40.

4. Unexplained Infertility: The results of IVF indicate that the unexplained infertility diagnosis is actually made up of four subgroups of problems. The smallest group (about 1%) has an implantation problem where a fertilized egg is just unable to imbed in the uterine lining. Another small subgroup (5-10%) has a fertilization problem such that even though sperm and eggs look normal, the sperm are unable to penetrate the eggs. This leaves the vast majority (90%) of unexplained couples where the problem is either poor egg quality or the failure of the egg to escape from the follicle at midcycle.

Risks of IVF

The track record of safety for IVF over the years has been very good. Nonetheless it is not devoid of risk and the main potential problems are listed below.

1. Multiple Pregnancy: The risk of multiples is directly linked to the number of embryos transferred. Multiple pregnancy carries with it the problems of greater discomfort, higher risks of pregnancy induced hypertension, fetal growth and development problems and cesarean section delivery compared to singleton pregnancies. The biggest threat, however, is prematurity.

2. Ectopic Pregnancy: The world's first IVF pregnancy in 1976 ended up in the woman's fallopian tube instead of her uterus. Even though the embryos are placed in the uterus they are incapable of embedding in the endometrium immediately and may drift into a fallopian tube. In women with normal fallopian tubes 1-2% of all IVF pregnancies are ectopic. For those with damaged tubes the risk can be as high as 4-5%. This is still considerably below the 15-30% risk for ectopics in women with abnormal tubes who conceive naturally. We can usually diagnose most ectopic pregnancies very early, before any risk of rupture of the fallopian tube which allows a choice between two forms of treatment: laparoscopic surgery to remove the ectopic or an injection of methotrexate to dissolve it.

3. Ovarian Hyperstimulation: The fertility drugs used in IVF usually cause the ovaries to enlarge somewhat. Some women's ovaries are so sensitive to these medications they enlarge 4 or 5 times normal size and cause discomfort and fluid collection, a problem called the ovarian hyperstimulation syndrome. Severe hyperstimulation occurs in 1% of patients and requires a few days to a week of bed rest and occasionally even hospitalization.

4. Infection: There is a 0.1 percent (1 per 1,000) risk reported in the medical literature that a pelvic infection will occur after an egg retrieval. These infection have been mild in some cases and severe, even to the point of requiring major surgery, in others.

5. Cancer: A study in 1994 showed a possible increase in risk of ovarian cancer in women who took the fertility pill clomiphene (Clomid) for a long period of time (12 or more months). Clomid is not used in IVF and no studies to date have indicated any increased risk for IVF medications but perhaps studies in the future will. Counterbalancing this theoretical risk is the known benefit of pregnancy, which lowers the risks of cancer of the breast, ovary and uterus.

Success Rates

Everyone considering IVF clearly needs to know the success rates achieved by the program they plan to work with. And yet correctly estimating a particular couple's chances is quite difficult due to the many variables involved such as age, cause of the infertility, health of the woman's uterus and so on.

The woman's age often has the greatest influence on the chances of success. This is because of the decline in both the number and quality of eggs that occurs over time. The figures below indicate the success we have had with IVF in couples where the woman's uterus was normal. Uterine abnormalities can reduce the effectiveness of IVF and unfortunately so can cigarette smoking which damages or kills eggs. Blocked fallopian tubes swollen with fluid (hydrosalinx) can reduce IVF success rates by one-half, unless first removed surgically. Therefore in individual cases the averages below may not apply.

Woman's Age = Viable Pregnancy Rate:
< 35 = 40% per IVF Cycle
35-39 = 33% " " "
40-41 = 28% " " "
42-43 = 17% " " "
43-44 = 12% " " "
45 = 0% " " "

End Points (When to Stop)

One of the great difficulties with IVF is that is very hard to know when to stop. Throughout this discussion we have been talking about success in terms of percentages and probabilities. We can not with certainty predict who will ultimately succeed with IVF and who will not. A poor prognosis patient may conceive in her first IVF cycle and a supposedly good prognosis patient may still be unsuccessful after their third or fourth cycle.

Random chance (plain old luck) has a lot to do with how soon success will come. Clearly though there must be a point at which we can no longer blame bad luck for continued failure. We obviously don't know everything there is to know about fertility and there are almost certainly a host of rare problems that may prevent successful embryo implantation. Finding this break point between chance and pathology is enormously important and is therefore the focus of a great deal of current research. The best evidence we have currently is that the "point of diminishing returns" is reached after IVF cycle number three or four.

This applies to couples where IVF produces a reasonable number of good quality embryos for transfer. If, on the other hand, only unhealthy embryos result from the first IVF cycle then the chances of success are much lower than normally found and the couple may well consider stopping IVF at that point.