When Is It Time To Turn To ART (Assisted Reproductive Technology)?

By V. Sahakian, MD

Published on August 17, 2006

Roughly 10-15% of couples of reproductive age suffer from infertility. The traditional definition of infertility is the failure to conceive after 12 months of trying. Although in the majority of cases this definition is acceptable, it should not be applied to every couple. For instance, a 40-year-old woman does not have the luxury of time to attempt to conceive for a year before asking for help. A six-month wait is more reasonable in this instance.

As complicated as the physiology of reproduction is perceived to be, in the majority of couples the diagnosis of infertility is relatively easy to reach.

Two of the most common mistakes that couples suffering from infertility (and even some physicians) make are holding off on treating the underlying cause and performing futile, ineffective treatments that only waste time, energy and money. It is therefore crucial that the patient is aware of the precise diagnosis behind her/his infertility and understands the approach taken by her/his physician to treat the condition.

In what follows, I will describe the most common causes of infertility for which the most appropriate treatment is assisted reproductive technology (ART). ART comprises several advanced treatments, including in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) and/or assisted hatching.

The Sperm Factor:

The male is responsible for up to 50% of cases of infertility. Ideally therefore, the initial screening evaluation of the male should be performed early in the infertility analysis. A careful semen analysis is the most important test to start the investigation of the infertile couple.

There are three important variables that one looks at when evaluating the sperm:

• Count: the number of sperm present in the ejaculate.
• Motility: The ability and percentage of the sperm moving in a forward direction.
• Morphology: The shape of the sperm head and tail.

Any major abnormalities involving any of these variables could result in lowering the chances of conception. Unfortunately, the cause of most sperm abnormalities can be neither determined nor treated successfully with simple therapy. On the other hand, advances in reproductive treatments, such as in vitro fertilization (IVF) and specifically intracytoplasmic sperm injection (ICSI) have revolutionized the treatment of male factor infertility. Today, the prospect of a successful outcome in couples suffering from this type of infertility is excellent.

The traditional treatment of intrauterine insemination (IUI) is NOT the best way to treat male factor infertility. There is a false impression that "washing sperm" for IUI improves the quality of the sperm. All it does is separate the portion of the sperm that is of "better quality." The number of "good sperm" not only does not increase but it might actually decrease during the washing process.

There is, however, a place for IUI treatments. Indications that may be cause for IUI include abnormal cervical mucus, problems with erection or intercourse, and problems with timing of intercourse (IUI can also be used in combination with fertility hormone treatment for better timing).

Two final examples of people who would benefit most from IVF with ICSI are those with poor sperm penetration and people who are found to have sperm antibodies.

Take Home Message: If your problem is male factor infertility, DO NOT waste time doing artificial inseminations…go straight to IVF with ICSI!

The Age Factor:

It is impossible to review infertility and avoid consideration of the effects of age on fertility or egg quality. Many women are delaying childbearing into their late 30s and 40s, which has resulted in a significant increase in infertility due to the "age factor." There is no doubt whatsoever that fecundity declines with age in women. Many studies, including IVF success rates, demonstrate a marked drop in pregnancy rates as women get into their late thirties. It has been shown, for instance, that the chance of a 20-year-old woman conceiving after one month of exposure is around 30%. At 30 years this rate drops to 20% per month and at 40 it is 10% per month. At 45, there is less than 2-3% chance that a woman will conceive on her own after trying for one cycle. Concomitantly, the miscarriage rate increases from 10% at the age of 20 to more than 40% at age 45.

The main reason for these phenomena lies in the fact that since women are born with a set number of eggs, the quality of these eggs deteriorates with time. It is imperative that women in their late thirties and older seek treatment at the first signs of infertility because the deteriorating quality of a woman's eggs translates into lower pregnancy rates. A direct corollary to this is the increased risk of chromosomal anomalies in infants born to older women. This is why it is recommended that women who plan on having a baby after the age of 35 have an amniocentesis performed 16-17 weeks into the pregnancy to rule out the possibility that the fetus is chromosomally abnormal.

The best treatment for age factor-related infertility is NOT fertility pills (such as Clomid) or artificial insemination. The notion that such treatment somehow increases the odds of conceiving has never been proven! Most normally ovulating women will still release only one egg even after taking fertility hormones. ART, on the other hand, will increase the odds of conception for several reasons:

(a) During an IVF cycle, multiple eggs are produced, retrieved and fertilized. Multiple embryos are obtained and more than one embryo is transferred. Unlike in natural cycles, where usually one egg and one embryo is produced, during an IVF cycle multiple embryos can be transferred, thus compensating through sheer quantity for the decline in egg quality. Since the odds of achieving a pregnancy are dependent on "egg quality," the transfer of more than one embryo will increase the odds of conception.

(b) Another reason IVF increases the odds of conception is the fact that during an IVF cycle egg and sperm "meet," albeit in a petri dish. In addition, ICSI often is performed to assure fertilization.

(c) As a woman ages, there is some evidence to suggest that the "egg shell," or the zona pellucida, hardens, making it difficult for sperm to penetrate the egg and fertilize it and more difficult for the embryo to "hatch" prior to implantation. Therefore, in older women, a technique called assisted hatching is routinely performed to improve the chances of implantation.

The age at which patients should decide that resorting to ART procedures is their best option is difficult to determine. In general, women over the age of 37-38 should approach the treatment of infertility aggressively and should not procrastinate by doing conventional treatments for more than 3-4 months.

Take Home Message: If your problem is purely an age factor related infertility, DO NOT spend more then 3-4 months trying conventional treatments such as artificial insemination!

The Egg Factor:

Somewhat related to age factor infertility is infertility related to a decline in "egg quality." This can be due to an age-related decline or to genetic or unknown causes.

One screening test that infertility patients should perform checks for the "ovarian reserve." This involves a simple blood test for two hormones, FSH and Estradiol, and is done on the second or third day of the menstrual cycle. The results of these tests sometimes indicate a problem with egg production. Typically, the FSH should be less than 10 IU/L (international units per liter) and the Estradiol less than 50 pg/ml (picograms per milliliter). The interpretation of the results is also important. For instance, if a woman's FSH is greater than 10 IU/L, this could indicate that the ovaries may not respond adequately to fertility hormones or that the "quality" of the eggs produced would not be adequate to yield a pregnancy.

In general, if this hormone screening is abnormal, the patient has to be aggressive by resorting to IVF. Even with such treatment, however, pregnancy rates are significantly lower in these patients. The main reason why IVF is the best treatment option in women with elevated FSH levels is the fact that more than one embryo (if available) is transferred, thus increasing the odds that one embryo will be genetically healthy enough to implant. In addition, during the IVF process, assisted hatching can be performed to improve the chances of implantation. The latter is performed because it is believed that women who have elevated FSH levels also produce eggs with harder or thicker shells.

In some patients, the FSH is so elevated that it is not cost-effective to attempt an IVF cycle. In these cases, it is wise to proceed straight to egg donation.

It is also important to remember that these tests (FSH/Estradiol) sometimes erroneously indicate a problem; the only way to ascertain the validity of the result is to attempt a treatment cycle by taking fertility hormones, checking to see whether the ovaries respond adequately.

Take Home Message: If your problem is abnormal FSH and/or Estradiol levels, consider resorting to IVF at once. Your window of opportunity might be limited!

The Tubal Factor:

In order for a pregnancy to occur, egg and sperm have to "meet." This is accomplished through healthy Fallopian tubes, whose job is to pick up the ovulated egg from the surface of the ovary and transport it into the tubal cavity, where it will await the arrival of sperm. The sperm reaches the egg in the distal segment of the tube, where fertilization occurs. The tube is also responsible for the subsequent transport of the fertilized egg or embryo during the next 3-4 days to the uterine cavity where implantation takes place. It is therefore obvious how imperative it is to have healthy Fallopian tubes.

There are three common circumstances under which the tubes can be damaged.

(a) Congenital (or inherited) abnormalities: This is extremely rare and easy to diagnose since the tubes are typically absent.

(b) Infections: Usually caused by sexually transmitted diseases such as Chlamydia or Gonorrhea. These infections are notorious for damaging the tubes and causing infertility. Many patients are not even aware that they have the infection until it is too late.

(c) Surgeries: Any surgery performed in the lower abdomen or pelvis can cause scarring around the tubes and ovaries that can affect normal anatomy, and therefore fertility. Such surgeries include appendectomy, ovarian cyst surgery, fibroid surgery, bladder or bowel surgeries and others.

In some patients, only one tube is affected and pregnancy is therefore still possible. Every patient suffering from infertility should have a test to check for tubal blockage, called a Hysterosalpingogram or HSG. This test involves sending dye through the cervix and following the spill of the dye through the tubes via x-ray pictures.

If an abnormality is noted, a laparoscopy to check the tubes may be necessary. The severity of tubal damage is what determines what should be done next. If the damage is serious, surgical correction with subsequent conservative management (i.e. attempting to conceive naturally for a period of time) may be the best course of action.

Some women benefit from reconstructive tubal surgery and sometimes it is worth giving such treatment a chance as long as the age factor is favorable.

There are two instances in which surgery may be an option:

• If the tubal damage is minimal to mild.
• If the patient's age is favorable, i.e. probably under 35.

The reasoning behind this recommendation is the simple fact that it might take several months following reconstructive surgery to conceive and in case of failure to do so, the patient should still be in an age bracket where her chances of conceiving with IVF is still reasonable.

As a general rule, it is reasonable to attempt to conceive for a period of 6 months following successful surgical treatment of tubal disease; thereafter, the patient should resort to in vitro fertilization. Since IVF treatment bypasses the tubes altogether, the condition of the tubes is not as important.

It is also important to realize that artificial insemination to treat tubal disease makes no sense since it does not treat the underlying disease. The same is true for ovulation-inducing hormone treatment. Such therapy is a waste of time and money.

Take Home Message: If you suffer from infertility secondary to tubal disease, IVF is still your best option unless you're young and the damage is not extensive, in which case reconstructive surgery might be worthwhile!

Other Factors:

Finally, there are other instances when resorting to advanced infertility treatment such as in vitro fertilization is the most appropriate therapy:

• Endometriosis: As long as the tubes are not blocked, it is reasonable to attempt fertility hormone therapy with artificial insemination for 4-6 months.
• Unexplained infertility: The above is also true for couples who still cannot conceive even after infertility testing comes back negative. These couples can also benefit from the combined approach of fertility hormone therapy with artificial insemination (a 4-6 month treatment). The typical approach for a couple with unexplained infertility is oral fertility hormone therapy (Clomid, Serophene) with or without artificial intrauterine inseminations. Unfortunately, in many of these cases doctors use this treatment for many months despite failures to conceive. It is therefore important for every couple undergoing such treatment to discuss their long-term plan with their physician and to limit such therapy to no more then 4-6 months. Most studies have indicated that pregnancy rates drop significantly if a pregnancy is not achieved after 6 months of conventional treatment.

Similarly, women suffering from ovulatory dysfunction such as Polycyctic Ovarian Syndrome (PCO) should resort to IVF after failing conventional treatment for 4-6 months. In many of these cases, the hormonal imbalance associated with PCO disease can be overcome by doing IVF.

Take Home Message: Couples suffering from mild endometriosis or unexplained infertility may benefit from conventional infertility treatment for 4-6 months. In case of failure, however, IVF should be the next step!