The medical specialists that treat patients with infertility are known professionally as Reproductive Endocrinologists. Training in Reproductive Endocrinology requires a medical school degree. The physician must then complete a four-year residency in Obstetrics and Gynecology (OB/GYN), during which she or he receives broad training in general Obstetrics and Gynecology. The final course of training is a two or three-year fellowship in Reproductive Endocrinology. Fellowship training focuses on the diagnosis and treatment of infertility and related disorders. This training includes experience in microsurgery, laparoscopic and hysteroscopic surgery, in vitro fertilization-embryo transfer, sonography, and ovulation induction. In addition, the physician spends a significant amount of time performing clinical and/or laboratory research.
Upon completion of a Fellowship in Reproductive Endocrinology, specialists seek Board certification. Board certification is a multi-step process. To become Board certified in Reproductive Endocrinology, the physician must first obtain Board certification in Obstetrics and Gynecology. This requires successful completion of both a written and an oral examination. Board certification in Reproductive Endocrinology requires successful completion of additional written and oral examinations. The entire certification process takes several years to complete. Only those physicians who have successfully completed a Fellowship in Reproductive Endocrinology can become Board certified as an infertility specialist.
It is often quite difficult for a patient to determine whether or not their physician is an infertility specialist. Some physicians have gained skills through experience outside fellowship training, and some physicians successfully complete Fellowship training and do not obtain Board certification. However, Board certification is the only objective criteria by which patients can measure a physician's qualifications.
Assisted Reproductive Technologies (ART) include in vitro fertilization-embryo transfer (IVF-ET), gamete intrafallopian transfer (GIFT), zygote intrafallopian transfer (ZIFT), tubal embryo transfer (TET), and frozen embryo transfer (FET). Although ART has helped many people overcome their infertility, they are not the answer for every infertile couple. Most of the time we use ART only when less complex and less expensive methods of treatment have failed. However, in certain circumstances (such as advanced age or severe male factor) we may recommend ART as first-line therapy.
In vitro fertilization, GIFT, ZIFT, and TET are very similar procedures although there are a few significant differences. During IVF-ET, ZIFT, and TET, the oocytes and sperm are combined in a culture dish in the laboratory. Fertilization and very early embryo development occur outside the body, rather than in the fallopian tube. Once early embryo development is recognized, the embryos are transferred either into the uterus (IVF-ET) or the fallopian tube (ZIFT, TET). Since we have seen no significant difference in success rates, we usually perform IVF-ET because it is less expensive and doesn't require laparoscopy and general anesthesia. In addition, IVF-ET is the only procedure available for women with damaged fallopian tubes.
GIFT differs from the other procedures in that sperm and oocytes are transferred into the fallopian tubes immediately after oocyte retrieval. Fertilization thus occurs in the body, rather than in the laboratory. GIFT originally was thought to represent a breakthrough in infertility therapy. National ART statistics suggest that success rates are higher with GIFT than IVF-ET. However, many investigators have concluded that GIFT does not increase the likelihood of conception compared to other ART procedures, and that the statistics reflect differences in laboratory expertise or in the kinds of patients treated with GIFT versus IVF-ET. In addition, GIFT does not allow for confirmation of successful fertilization if the procedure does not produce a pregnancy. Your physician will discuss each of these procedures with you so that the most appropriate procedure for your individual situation will be used.
Couples who are considering ART should realize that it is an intensely emotional, physically arduous, and expensive procedure. Most couples find it difficult to consider the chances for success realistically without dampening the drive that allows them to undertake these procedures. Above all, couples should explore plans for the future, whether or not their attempts at ART are successful.
Every patient should have completed a basic infertility evaluation. Because of the physical, emotional, and financial demands of ART, these procedures generally are used in patients who have tried less complex and less expensive methods of correcting their infertility. The majority of patients in ART programs suffer from tubal factor, male factor, or unexplained infertility. ART candidates who will be using their own eggs must be under 45 years of age and must have
- No evidence of premature menopause
- At least one accessible ovary, and
- A normal uterus
Menopause and ovarian function are irrelevant for candidates using donor eggs. Donor egg recipients must be under 50 years of age and have a normal uterus. All ART candidates should be in good health and have no medical conditions that would pose a serious health risk to themselves or the child they would carry.
Participation in an ART program can be stressful and emotional. We encourage couples considering or pursuing ART therapy to attend group support sessions such as those offered by RESOLVE, a national infertility support group which has an active local chapter in San Antonio. We can also refer you to private counselors for individualized care.
One of the first questions that most people ask is "What is the chance for success?" The initial hope of achieving a pregnancy by ART is often dampened by the answer to this question. In 1998 in our program, liveborn infants occurred in approximately 25% of cases in which women had embryos derived from their own eggs transferred to the uterus. The 1998 nationwide "take home baby rate," was 25%. We believe that the delivery rate or "take home baby rate" is the only real measure of success. Patients should be aware, however, that some clinics define "success" as any positive pregnancy test, or any pregnancy, even if miscarried or ectopic. These "successes" are irrelevant to patients desiring a baby.
Success varies with many factors. One very important factor is the age of the woman. Over age 37, ART success rates decline dramatically. Another factor that affects ART success is the number of embryos that are transferred. According to 1998 national statistics, about 8% of cycles in which one embryo was transferred resulted in a live birth; with two embryos, the success rate increased to 26%. The success rate peaks with the transfer of three to four embryos.
Presently, the collection of oocytes, fertilization, and early embryo growth, are accomplished with a high degree of efficiency. The major hurdles to success are implantation after embryo transfer and early pregnancy loss. The rate of early pregnancy loss is slightly higher with ART compared to spontaneous conception. The risk of early pregnancy loss increases with age of the female partner. There is, however, no evidence that the risk of birth defects or chromosome abnormalities (such as Down's syndrome) is any different with ART. Pregnancy complications tend to be higher with ART pregnancies, primarily because of the much higher rate of multiple pregnancy. Twins occur in about 32% of ART pregnancies versus 1-2% of spontaneous pregnancies. The risk of more than a twin pregnancy about 6%.
To put these figures into perspective, studies have shown that the rate of successful pregnancy in couples with proven fertility in the past is approximately 20% per cycle. Therefore, although a figure of 25% may sound low, it is equal to or greater than the chance that a fertile couple will conceive in any given cycle.
We advise that patients plan at the onset to make several ART attempts. Programs that have the highest pregnancy rates average between three and four attempts per patient. There is no absolute restriction on the number of times that a couple can attempt ART. Although cumulative pregnancy rates increase through a total of six attempts, the success rate for any given cycle remains constant. A rest period between attempts is recommended usually an interval of at least one normal menstrual cycle. Couples who have achieved an ART pregnancy in the past have an increased likelihood of ART-related conception in the future.
Before starting ART therapy, we perform certain tests to ensure that conditions for successful pregnancy are optimal.
You should have a complete physical exam, including breast exam and Pap smear within one year of treatment. You should also start taking prenatal vitamins containing folic acid, which has been shown to reduce the risk of birth defects of the spine. Women over 35 should consider having a mammogram prior to ART therapy.
We confirm the womans blood type, and screen for antibodies that could affect the health of a fetus. We also perform a test for syphilis (a venereal disease that can affect the fetus). Documentation of immunity to rubella (German measles) may also require a blood test. Rubella during pregnancy can cause serious harm to the fetus. We require blood tests for hepatitis and HIV (AIDS) for both the patient and her partner. We may recommend a blood test for FSH (a hormone that regulates ovarian function). This must be performed on the second, third or fourth day of the menstrual cycle. This test can reveal abnormalities in ovarian function that can affect the success of ART therapy, especially in women over 35 years of age.
A semen analysis should be performed within one year of ART. Changes in sperm quality may occur over time, which could affect the success of ART therapy. In some cases, we may recommend additional semen testing. For example, we may test for the presence of anti-sperm antibodies. Sperm antibodies are proteins in the semen that can impair sperm function. These antibodies can also be found in the womans bloodstream. Sperm antibodies can impair fertilization, even in vitro. If we detect anti-sperm antibodies, we may prescribe special therapy before or during the ART procedure.
We recommend evaluating the anatomy of the uterus prior to ART. We may suggest an x-ray procedure (hysterosalpingogram, HSG), ultrasound procedure (sonohysterogram, SHG), or hysteroscopy. An HSG is performed by injecting a special liquid (X-ray contrast) through the cervix into the uterus. The liquid is visible on x-ray films and outlines the anatomy of the uterus and tubes. This is performed in a radiology suite and requires no anesthesia. An SHG is performed by injecting sterile saline into the uterus during transvaginal sonography. This procedure is performed in the office without anesthesia. Hysteroscopy involves insertion of a small telescope and light source through the cervix into the uterus to look for abnormalities. We may also perform this procedure in the office using local anesthesia.
Prior to IVF/ET, we also perform a uterine measurement. The purpose of this procedure is to determine the length and curvature of the uterine cavity. This enables us to guide the embryo transfer catheter into the proper position during the actual embryo transfer. Uterine measurement is similar to a pelvic exam or intrauterine insemination. Your physician will place a speculum in the vagina, and insert a thin, flexible plastic catheter through the cervix into the uterus. You may experience a small amount of cramping when the catheter goes through the cervix and again when the tip of the catheter touches the top of the uterine cavity. This cramping, which is similar to a mild menstrual cramp, should resolve within 30-60 seconds.
Every cycle of ART involves multiple steps, and each occurs at a specific time during a six-week period. The procedure begins around the time of ovulation in the month preceding the ART cycle. We present an approximate timetable and overview below.
Cycle Preceding ART Cycle
- Initiation of oral contraceptives
- Initiation of Lupron® or other GnRH analog therapy
- Baseline pelvic ultrasound
- Ovarian stimulation with gonadotropins (e.g., Gonal-F®, Fertinex®)
- Monitoring of follicle development with ultrasound and serum hormone levels
- hCG administration
- Transvaginal oocyte retrieval
- Embryo transfer
- Progesterone supplements
- Hormonal studies and pregnancy test
- Follow-up consultation
Step 1 Initiation of Oral Contraceptives
We prescribe oral contraceptives in the cycle prior to the ART cycle. This ensures that GnRH analog therapy will start at the proper time. There is also evidence that oral contraceptives help prevent ovarian cysts, which sometime develop during GnRH analog therapy. You will usually begin a pack of oral contraceptives on the Sunday after your normal period begins. Alternatively, we may prescribe Provera for patients who ovulate irregularly or not at all.
Step 2 - GnRH Analog Administration
You will usually begin treatment with a GnRH analog on the sixteenth day of oral contraceptive pills or the sixth day of Provera pills, although this may vary. You do not need a pregnancy test before you start the GnRH analog.
We will usually instruct you to reduce the dosage of GnRH analog by one-half on the day you begin ovarian stimulation. You will use the GnRH analog until the day of hCG (human chorionic gonadotropin) administration.
We sometimes treat patients with a different dosage or schedule of GnRH analog. Your physician will advise you if these changes apply to you.
Step 3 - Baseline Pelvic Ultrasound
Most patients begin a menstrual period 4-10 days after starting GnRH analog therapy. Around the time of your expected period, we will perform an ultrasound to examine the ovaries. If we detect a cyst, we may withhold further therapy until the cysts resolve spontaneously (usually in about a week). Occasionally, we recommend cyst aspiration (drainage). This is a procedure in which your doctor inserts a fine needle connected to a syringe, guided by ultrasound, into the cyst. We may also perform a serum estradiol measurement to confirm ovarian suppression.
In general, we start ovarian stimulation after menstrual bleeding begins if the baseline ultrasound shows no cysts. We use several similar medications to stimulate follicle (egg) development. Pergonal®, Humegon® and Repronex® are injected intramuscularly (into a large muscle under the skin). Fertinex®, Gonal-F® and Follistim® are injected just under the skin using a smaller needle.
Step 5 - Monitoring of Follicle Development
We monitor follicle development with a combination of vaginal ultrasound and hormone measurements (blood tests). We must perform these tests frequently during the ART cycle to ensure that you take the proper dosage of medication. We usually see patients every other day for an ultrasound and an estradiol level. This allows us to adjust the dose of medication in an effort to improve follicular development. When the largest follicle reaches 12-13 mm, we usually schedule daily visits for ultrasound exams and serum estradiol tests. The amount of medication we prescribe each afternoon depends upon the results of the blood tests and ultrasound exams. Typically, the lab results from the blood samples are not available until after 2:00 p.m. Patients must be available in the afternoon so that we can confirm the dosage of medication for that day.
Human chorionic gonadotropin (hCG) is a hormonal drug which stimulates the final maturation of the oocytes. Determining the proper day for hCG administration is critical. If it is administered too early, few, if any, oocytes will be mature. If it is administered too late, the eggs within the follicles may be too mature (atretic), and will not fertilize. Optimal oocyte maturity occurs when we administer the hCG at the time two follicles measure at least 16 mm and serum estradiol is greater than 500 pg/mL. The drug is given as a single intramuscular injection. The time of the injection is based on the time at which we schedule the egg retrieval.
Step 7 - Transvaginal Oocyte Retrieval
Oocyte retrieval is performed about 35 hours after hCG has been administered. All retrievals are performed in a dedicate procedure room adjacent to our Embryology laboratory. An anesthesiologist usually administers intravenous medications (sedatives and pain relievers) in order to minimize the discomfort that may occur during the procedure. Side effects from these medications are much less common than with general anesthesia. Most patients sleep through the procedure but breathe without assistance. We will discuss anesthetic options with you prior to your retrieval.
Once you are comfortable and relaxed, your physician will place the ultrasound transducer into the vagina. A guide attached to the transducer leads the needle through the wall of the vagina and into each follicle in the ovaries. Your physician will collect the oocytes and follicular fluid into a syringe for transport to the Embryology lab. The laboratory staff will examine the oocytes microscopically.
After the retrieval, we will take you to a recovery room. You will be observed for 1-2 hours while the intravenous medications wear off. When you are fully awake, your vital signs are stable, and you have urinated, you will be released to go home. You may have some vaginal spotting and lower abdominal discomfort for several days following this procedure. Generally, patients feel completely recovered within 1-2 days. You should notify us immediately if you develop severe pain, heavy bleeding, or fever after the retrieval.
The number of oocytes we retrieve is related to the number of ovaries present, their accessibility, and the number of follicles that develop in response to stimulation. Ultrasound provides only an approximation of the number of oocytes that one can expect to recover. On the average, 8-15 oocytes are retrieved per patient. More than 95% of retrievals result in the recovery of at least one oocyte.
Step 8 - Insemination of Oocytes
The Embryology laboratory staff examines the fluid aspirated from follicles for the presence of oocytes. We routinely aspirate all mature follicles in order to obtain as many oocytes as possible. Not every follicle contains an oocyte, and rarely, a follicle may contain more than one.
It is important to determine the maturity of the oocytes in order to time the insemination properly. The oocyte can only be fertilized during a short interval of about 12-24 hours. If the oocyte is either immature or postmature (too old), it may not be capable of fertilization or normal development. If immature oocytes are obtained at retrieval, they can often mature in the laboratory prior to insemination. Normal pregnancies have occurred with such oocytes.
Semen is usually collected at home by masturbation the morning of the retrieval. The staff will instruct you regarding time of collection and transportation to the office. On rare occasions, a second semen sample may be requested by the laboratory staff. You should notify the staff beforehand if you are planning to leave town or will otherwise be unavailable after the first collection. We recognize the pressure that semen collection may generate under these circumstances. In many cases, some flexibility in the timing and even in the method of collection is possible. We may also suggest semen cryopreservation (freezing) before oocyte retrieval.
The laboratory staff prepares the semen specimen for insemination using techniques designed to separate the sperm from other material present in the ejaculate. As a result of this process, we select the most active sperm to inseminate the oocyte. We usually place about 10,000 sperm in a culture dish with each oocyte. The dish is placed into an incubator, which maintains a specific temperature, pH, level of humidity, and concentration of carbon dioxide. After 12-20 hours, the laboratory staff may detect evidence of fertilization under the microscope. In our laboratory, approximately 70% of oocytes fertilize. This figure may be much lower for patients with severe male factor. It is extremely uncommon for couples without male factor infertility to experience complete lack of fertilization in IVF-ET.
The embryo transfer procedure is usually performed three days after the oocyte retrieval. This procedure is nearly identical to the uterine measurement. Your physician will pass the same type of catheter gently through the cervix into the uterus. After waiting for 1-2 minutes to allow any mild cramping to resolve, your doctor will deposit the embryos into the uterine cavity along with an extremely small amount of fluid. You will require no anesthesia for the embryo transfer. You will be discharged after resting for 20 minutes.
Several studies have indicated that maximal IVF-ET pregnancy rates occur in most cases with the transfer of three to four embryos. Therefore, we usually transfer a maximum of four embryos. The transfer of five or more embryos may increase the likelihood of a multiple pregnancy, which increases the pregnancy risks for the woman and the fetuses. For those cases in which more than four embryos develop, we offer embryo cryopreservation. This allows us to store excess embryos for transfer at a later date.
We will administer progesterone daily beginning on the day of embryo transfer. Ordinarily, specialized cells in the follicle will produce progesterone following ovulation. During oocyte retrieval, some of these cells may be removed along with the oocyte. Supplemental progesterone helps prepare the uterine lining for implantation.
This daily medication will continue until your pregnancy test. If the test is positive, you may be advised to continue to take progesterone for several more weeks. This medication historically has been administered as an intramuscular injection, but vaginal administration (suppositories, capsules or Crinone® gel) is now the standard form of treatment.
Step 11 - Hormonal Studies and Pregnancy Test
We will usually perform a serum pregnancy test 12-14 days after the embryo transfer. If the test is positive, we will also measure serum progesterone. On occasion, we may repeat tests every two or three days. If the test is negative, we will instruct you to stop the progesterone.
Step 12 - Follow-up Consultation
If the pregnancy test is positive, we will perform a vaginal sonogram about three weeks later. At this point, we are able to identify the number of embryos and can often see a heart beat. The risk of pregnancy loss is low after this developmental milestone. If the ART cycle is unsuccessful, you should schedule a consultation with your physician to review the procedure and discuss future treatment options.
The first ever IVF-ET baby, Louise Brown, was born in 1978, and was conceived without the benefit of any fertility drugs. In the years that followed her birth, the experience of most clinics was that the success of IVF-ET was improved by administering injectable fertility drugs to the woman. Thus, the use of injectable fertility drugs became the routine in IVF-ET. One disadvantage of injectable drugs is that they substantially increase the cost of IVF-ET. Not only are the injectable drugs themselves expensive; their use necessitates more office visits and testing in the days preceding oocyte retrieval, and more work for the IVF-ET laboratory personnel after retrieval to care for the resultant greatly increased number of oocytes. In order to give some chance of pregnancy to infertile couples who simply cannot afford conventional IVF-ET with injectable drugs, some clinics have continued to offer IVF-ET without injectable drugs, which significantly decreases the total costs of the procedure.
There are two slightly different ways in which IVF-ET can be performed without the use of injectable gonadotropins. One is "minimal stimulation IVF-ET," in which the woman takes the relatively inexpensive oral fertility drug clomiphene citrate (Serophene® or Clomid®) early in her cycle. This is the method our Program uses. The other way is to take no fertility stimulants whatsoever, and simply aim to retrieve the oocyte produced in the woman's natural cycle. The maximum "take home baby" rate (chance of having an actual living child) of minimal stimulation IVF-ET is generally believed to be 10-15%. In the U.S.A. in 1994, the most recent year for which figures are available, the "take home baby" rate of natural cycle IVF-ET in women less than 40 years old was 4.5% per cycle started, and 10% per oocyte retrieval procedure. The particularly low success rate of natural cycle IVF-ET may reflect a selection bias. That is, physicians may recommend natural cycle IVF-ET to patients who have previously demonstrated poor responsiveness to fertility drugs (thinking the fertility drugs will be of no benefit to them), thereby effectively selecting patients for natural cycle (IVF-ET) who have a particularly poor chance of becoming pregnant. Even if this is the case, it is unreasonable to expect any more than a 10-15% take home baby rate from minimal stimulation IVF-ET with current technology and methods.
The process of minimal stimulation IVF-ET begins with treatment with birth control pills in the cycle before stimulation. We will perform a baseline ultrasound around the time of your expected period after the pills. If that ultrasound is normal, you will take clomiphene citrate (50 mg), two tablets by mouth daily, cycle days three through seven. The next ultrasound will be performed on cycle day eight. Several more ultrasounds will be performed in subsequent days, the exact number and frequency depending on the rate of growth of the oocyte-containing structures (follicles). Usually, no blood work is needed for monitoring for couples undergoing minimal stimulation IVF-ET. On the date that the ultrasound indicates that the largest follicle has an average diameter of 18-20 mm, human chorionic gonadotropin (hCG) 10,000 units intramuscularly will be injected in the evening. Oocyte retrieval will be performed 35 hours after the hCG injection.
The basic techniques of oocyte retrieval, insemination, embryo culture, embryo transfer, progesterone supplementation after embryo transfer, and pregnancy testing after embryo transfer are very similar or identical to those used in conventional IVF-ET and are discussed elsewhere. Because patients undergoing minimal stimulation or natural cycle IVF-ET have only very few or one follicle(s), it may be possible to perform the oocyte retrieval procedure without the services of the anesthesiologist. Your physician can provide some medications for pain relief during the procedure, and most patients do well with this approach. You should discuss this matter with your physician before making a final decision.
Advances in microscopic equipment and knowledge about oocytes, sperm and embryos have lead to the development of new techniques in ART. Micromanipulation refers to the microscopic treatment of individual oocytes, sperm, or embryos in an effort to improve fertilization and/or pregnancy rates. These techniques require specialized equipment and personnel. The most common micromanipulation techniques used currently are intracytoplasmic sperm injection (ICSI), which is used to assist fertilization in cases of severe male factor infertility, and assisted hatching which is used in some cases in an effort to facilitate implantation of the embryos.
Intracytoplasmic Sperm Injection (ICSI)
The ICSI technique has been developed over the past 10 years to treat cases of severe male factor infertility. Candidates for ICSI may include patients with severe reductions in sperm number or motility, regardless of cause and patients with a history of failure of fertilization in conventional in vitro fertilization-embryo transfer (IVF-ET). The ICSI technique may also be used to achieve fertilization using surgically extracted sperm from patients with anatomic or surgical conditions (such as vasectomy) which prevent sperm from entering the ejaculate. In all these cases, donor sperm or ICSI may provide the only options for conception.
The ICSI technique attempts to achieve fertilization by the direct injection of a single sperm into the cytoplasm (interior) of the egg. This is accomplished in the following manner: Mature eggs are freed of surrounding cells by a combination of enzyme treatment and microdissection. Using special micromanipulation equipment, the eggs are individually injected with a single sperm. Injected eggs are returned to the laboratory incubator and are treated thereafter as in conventional IVF-ET.
The mechanical placement of a sperm into the egg bypasses all the normal processes of sperm-egg interaction that occur naturally as well as in conventional IVFET. These processes normally lead to the selection of the single fertilizing sperm based on its ability to pass through the many layers of cells surrounding the egg, to contact and bind to the egg coating (zona), to penetrate this coating, to contact and merge with the egg cell membrane and ultimately to be drawn into the egg where the genetic material in the sperm joins that of the egg. These interactions help assure that a normal sperm is selected by the egg for fertilization. Even when conventional IVF-ET is performed, the egg is exposed to tens of thousands of sperm from which to choose. In sperm injection, it is the laboratory that chooses. We rely on the size, shape, and motility of sperm to choose the ones for injection. While these characteristics are useful, they do not guarantee that the sperm selected for injection is normal.
The potential consequences of injecting a normal appearing sperm that is in fact abnormal include the development of a genetically abnormal embryo. Previous experience suggests that most abnormal conceptions do not implant or develop in the uterus. The incidence of congenital abnormalities (birth defects) following ICSI appears to be no higher than that of the general population. This observation is based on the experience of several thousand babies born worldwide following ICSI. Despite this reassurance, it is prudent to regard ICSI as an experimental technique not without risk since long term follow-up of offspring (regarding, for example their fertility is unavailable.) Recent evidence suggests that some forms of severe male factor infertility are genetic and may be passed on to children through the ICSI procedure. In addition, you must realize that within the normal human population a certain percentage (approximately 4%) of children are born with physical or mental defects, and that the occurrence of such defects is beyond the control of physicians.
Apart from the possible genetic consequences of selecting an abnormal sperm for injection, the physical trauma to the egg resulting from sperm injection can lead to degeneration of the egg, decreased fertilization rate, poor or arrested embryo development following fertilization, and reduced chance of a successful pregnancy outcome.
The benefit of ICSI is that it provides a way to treat extreme cases of male factor infertility which otherwise would remain untreatable. Experience shows that fertilization in vitro requires a minimum number of motile, normal shaped sperm. The chance for fertilization in vitro becomes very low when this minimum number of sperm is not available. Theoretically, only a few sperm are necessary to undertake ICSI. To date, however, the successful outcome of sperm injection is neither predictable nor consistent for all patients. The alternatives to ICSI for treatment of severe male factor infertility are limited. Sometimes all the eggs can be placed in one culture dish with all the available sperm. This is known as clutch insemination, which differs from conventional IVF-ET in which each egg is inseminated with a separate batch of sperm. A minimum number of actively moving, normal shaped sperm is still required for fertilization to occur with clutch insemination. Another option is donor sperm. Use of donor sperm normalizes the success of conventional IVF-ET in couples with severe male factor infertility. In cases where male factor is the only diagnosis, pregnancies with donor sperm can be achieved through timed insemination, a treatment far less expensive and complicated than IVF-ET.
There is no guarantee that these inseminations will result in fertilization or a pregnancy. The likelihood of conception can be decreased by coexisting female fertility problems. In general, the results of intracytoplasmic sperm injection decline with increasing age of the female partner. This probably reflects the progressive decline in oocyte quality with age of the patient and the egg's inability to survive the invasiveness of sperm injection.
A separate consent form and additional charge is required for ICSI.
Normally, embryos are transferred to the uterus three days after retrieval. Usually the embryos consist of eight cells at this stage. After transfer, the embryo must continue to develop to the blastocyst stage (a hollow ball of about 100 cells) before implantation can occur. This development takes several days. Immediately before implantation, the blastocyst must "hatch" from the zona coating which originally enveloped the oocyte. To assist the hatching process, we sometimes micro manipulate the embryos immediately before embryo transfer. This involves either making a slit in the zona using a fine glass needle or dissolving part of the zona coating with an acid solution. This must be performed under the microscope by trained personnel using special micro tools. There is a small risk of damage to the embryos from the procedure. It is not clear which patients are the best candidates for assisted hatching, but we may consider it for patients with repeated unexplained treatment failures or for women 40 years of age or older. An additional charge is required for assisted hatching.
Embryo cryopreservation is another important part of successful ART programs. Cryopreservation affords patients several advantages. Couples can cryopreserve embryos in excess of the ones that are usually transferred during an ART cycle. These embryos provide a second or even third opportunity for pregnancy without undergoing another ovarian stimulation and retrieval.
Those embryos that meet developmental criteria for appearance and rate of growth can be frozen at any of several stages in their development. The freezing process is computer controlled and employs special solutions to protect the fertilized eggs from damage. Frozen embryos are stored at 196°C (or approximately 400°F) below zero. Prior to ART, you and your partner must sign a consent form indicating what we should do with any additional embryos. Current choices are disposal or cryopreservation for your future use. We will store your embryos for a maximum of three years. During that time you must keep us informed of your current address at least annually. Social, ethical, and legal principles related to various aspects of ART have not yet been established. For this reason, you should discuss the implications of cryopreservation with your physician and with an attorney before proceeding with ART. Issues to consider include the disposition of embryos in the event of divorce or the death of either you or your partner. Our current policy is to dispose of cryopreserved material if both of the original partners to the agreement die.
As with cryopreserved semen, many embryos do not survive cryopreservation and thawing. Those that do may function less well than do fresh embryos, that is, they may implant and produce ongoing pregnancies at a somewhat lower rate than fresh embryos. Despite this we have established a very successful frozen embryo transfer (FET) program. In 1995, the nationwide "take home baby rate" per frozen embryo transfer procedure was 15%. Our success rate has been above the national average in recent years.
We will usually transfer up to four embryos during this procedure. Embryos can be transferred successfully during either a natural cycle or an artificial cycle in which you take estrogen and progesterone. There is no consensus regarding which approach is "best."
Each cycle of FET, like that of the other ART procedures, involves multiple steps, occurring at a specific time during a four-week period. An approximate timetable and overview are presented below. If you have been pregnant, or if it has been more than one year since your last embryo transfer, a repeat uterine measurement should be performed before FET. If you have never had an endometrial biopsy to evaluate the development of the lining of the uterus, we may recommend this prior to FET.
- Monitoring follicular development
- Monitoring for LH surge
- Documentation of ovulation
- Embryo transfer
- Hormonal supplements
- Pregnancy test
- Follow-up consultation
Monitoring of follicle development is often performed during an FET cycle by using transvaginal sonography. To determine the day on which you should begin monitoring, subtract seventeen days from the length of your menstrual cycle. For example, if it is 30 days from the first day of one menstrual cycle to the first day of the next, you should have your first ultrasound on cycle day 13 (30-17=13). You will have other ultrasounds as your dominant follicle nears maturity. These ultrasounds will continue until we have documented ovulation.
As the growing follicle nears maturity, the level of the hormone LH in the blood and urine rises dramatically. This is known as the LH surge. For the purpose of frozen embryo transfer, we define the day of the LH surge as the day a doubling of the LH level in blood is detected or day the urine LH test turns positive. It is important that the LH be monitored on a daily basis, as the frozen embryo transfer will be timed from the date of the LH surge. The timing of the embryo transfer will depend upon the stage at which your embryos were frozen. Embryos frozen at a more advanced stage of development (blastocysts) will be transferred later than embryos frozen at an earlier stage of development.
In addition to monitoring your LH, your physician may also confirm ovulation with ultrasonography through the time of ovulation. If ovulation does not occur, as evidenced by failure of the dominant follicle to collapse on ultrasound, then the frozen embryo transfer may be canceled. Alternatively, hormonal supplementation may be provided during the remainder of the transfer cycle.
Embryos are thawed on the morning of the scheduled frozen embryo transfer. In our laboratory, approximately 60-70% of embryos survive cryopreservation and thawing. We usually transfer 3-4 embryos during each FET cycle. However, this number is flexible, and your physician will discuss this issue with you.
The actual embryo transfer itself is identical to the embryo transfer following in vitro fertilization-embryo transfer. A small plastic catheter is passed gently through the cervix into the uterus. After waiting 1-2 minutes to allow any mild cramping to resolve, the embryos are deposited in the cavity along with a very small amount of fluid. No anesthesia is required for the embryo transfer. You will be discharged after resting for 20 minutes.
Patients undergoing FET may not require hormonal supplementation when we document normal follicular development and ovulation. Unlike the initial IVF-ET procedure during which the progesterone-producing granulosa cells are aspirated, those cells remain functional within the corpus luteum during your FET cycle. Progesterone supplementation may be administered to patients with ovulatory dysfunction or luteal phase inadequacy. In these cases, progesterone injections or suppositories begin following the embryo transfer and continue until the pregnancy test is performed.
We will usually perform a serum pregnancy test 12-14 days following the embryo transfer. If the test is positive, we may measure the serum progesterone level and recommend that you continue taking progesterone for several additional weeks. If the pregnancy test is negative, progesterone is discontinued and a period begins in a few days.
If the pregnancy test is positive, we will perform a vaginal sonogram about three weeks later. At his point, we are able to identify the number of embryos and can often see a heart beat in the developing embryo. The risk of pregnancy loss is low after this developmental milestone. If the FET procedure is unsuccessful, you should schedule a consultation with your physician to review the procedure and discuss future treatment options.
For patients with irregular cycles or ovulation disorders, and for patients who need to plan their therapy around time constraints, we can create an artificial menstrual cycle for FET. This involves treatment with an oral estrogen medication and progesterone (usually administered vaginally). This treatment is well established. Pregnancy rates are equivalent when compared to natural cycle FET. We sometimes recommend a trial (practice) cycle before the actual FET cycle so we can perform an endometrial biopsy to ensure that the medication dosages produce the proper development of the uterine lining. In addition, if you have been pregnant, we recommend a repeat uterine measurement before FET. The steps involved in FET with hormone replacement include:
- Hormone therapy (Estrace® and progesterone)
- Embryo transfer
- Hormonal studies and pregnancy test
- Follow-up consultation
It is important that you start estrogen therapy on the first day of your period. A dose of estrogen is usually administered for 14 days, although shorter or longer cycles may be used, Estrace® is the most common form of estrogen we use. This is a pill containing 2 mg of estradiol, the same hormone produced by the ovaries. We will have you take one pill twice a day for about 14 days. After about 14 days of Estrace®, (your physician may vary the dose or duration of therapy) progesterone is added. This may be administered vaginally or as an intramuscular injection. Estrace® and progesterone are continued until the day of the pregnancy test (usually 12 days after embryo transfer). If the test is positive, these medications may be continued for several weeks.
Embryo transfer is usually performed on the third or fourth day of progesterone therapy. As with natural cycle FET, embryos are thawed on the morning of the scheduled frozen embryo transfer. In our laboratory, approximately 60-70% of embryos survive cryopreservation and thawing. We usually transfer 3-4 embryos during each FET cycle. However, this number is flexible, and we will discuss this issue with you.
The actual embryo transfer itself is identical to the embryo transfer following in vitro fertilization-embryo transfer. A small plastic catheter is passed gently through the cervix into the uterus. After waiting for 1-2 minutes to allow any mild cramping to resolve, the embryos are deposited into the cavity along with a small amount of fluid. You will be discharged after resting for 20 minutes. No anesthesia is required for the embryo transfer.
We will usually perform a serum pregnancy test 12-14 days after the embryo transfer. If the test is positive, we also measure serum progesterone. On occasion, we may repeat tests every two or three days. If the test is negative, progesterone is discontinued and a period usually begins in a few days. Near the end of that period, your physician may request a vaginal sonogram and/or serum progesterone level.
If the pregnancy test is positive, we will perform a vaginal sonogram about three weeks later. At this point, we are usually able to identify the number of embryos and can often see a heart beat. The risk of pregnancy loss is low after this developmental milestone. If the procedure is unsuccessful, you should schedule a consultation with your physician. We will review the procedure and discuss further treatment options.
In recent years, with the standardization of IVF-ET techniques and the development of ICSI (intracytoplasmic sperm injection) for severe sperm disorders, it has become clear that the single most important factor in predicting the success of IVF-ET is the age of the female partner. For patients under 30, success rates of 30-50% per oocyte retrieval can legitimately be expected; for patients over 40, realistic success rates are only 5% to at most 15%. Oocytes from younger women possess greater fertility potential, and this potential is utilized in donor oocyte therapy. In this therapy, oocytes from another woman (the donor) are fertilized with the patient's (the recipient) husband's sperm, and the resultant embryos are placed in the recipient's uterus. The oocytes are stimulated and retrieved from the donor using routine IVF-ET techniques. The donor may be know to and recruited by the recipient (non-anonymous donation), or instead may be unknown to the recipient, having been recruited by the IVF-ET program (anonymous donation). In cases where a young (less than 35 years old) donor is utilized, high success rates, comparable to those achieved in women of similar age using their own oocytes, can be expected.
Candidates for Donor Oocyte Therapy
There are three main indications for donor oocyte therapy. One is ovarian failure, which can be due to a wide variety of different causes, including radiation, chemotherapy, surgical removal of the ovaries, and a variety of disease states which cause or are associated with ovarian failure. Another indication is for women who carry some serious genetic disease who wish to diminish the chances that the disease will be passed on to their offspring. The third, and most common indication, is for women whose age is sufficiently advanced that their fertility potential is impaired significantly.
Laboratory Testing and Genetic Screening
Approximately one month before initiating every treatment cycle, the oocyte donor undergoes a very thorough battery of tests for sexually transmitted diseases. Obviously, by screening for sexually transmitted diseases, we seek to minimize the chances that such a disease will be passed from the donor to the recipient (and possible fetus) by the oocyte donation process. Despite these thorough precautions, there remains a very small risk of transmission of disease from donor to recipient. In addition to sexually transmitted disease testing, the donor's blood type will be determined. The donor's blood type may be a factor in making the match between donor and recipient (see below).
In addition, donors have a very thorough evaluation of their medical and family history. The donor is required to fill out a multi-page form detailing her family history. This form, and other aspects of the donor's genetic and medical history are reviewed thoroughly by the administrators of the oocyte donation program prior to acceptance of the donor in the program. Even with this intensive screening, there remains a small risk that a baby resulting from the oocyte donation process will suffer from a genetic disease. Overall, the risks that a baby conceived through the oocyte donation process will have some birth defect, trivial or catastrophic, genetic or non-genetic, are the same as they are for the human population as a whole, namely 3-5%.
Matching Donor and Recipient
We understand that choosing to receive donated oocytes carries with it a simultaneous giving up of hope for pregnancy with one's own oocytes, and this can be a feeling of great loss. There are probably many characteristics that you hope your oocyte donor will possess, and you probably hope that your oocyte donor will possess many of your characteristics. We will do what we can to select a donor who meets your most important expectations, but you must understand that we will always face certain limitations. One requirement of our anonymous donation program is that anonymity be maintained. In order to accomplish this, we are limited in the amount of information that we can give you about the donor. We cannot tell you much more than the donor's height and weight, hair color and eye color, race, blood type, age, ad duration of formal education. You have the right to be as specific as you like about the characteristics of the donor, but you need to understand that the more specific you are, the longer the entire process may be delayed. Obviously, if your criteria are extremely specific and detailed, we may never find a donor who meets your expectations. It is the impression of the director of the donor oocyte program that women who agree to donate their oocytes tend to be upbeat, energetic, resilient, and altruistic. If they did not have these personality characteristics, they probably would not be willing to undergo the discomfort and risks involved in oocyte donation in the first place. Thus, to at least a small extent, the process of oocyte donation tends to select for women with these favorable personality characteristics. Most of our donors are students in good standing in one of the schools of the UT Health Sciences Center.
The blood type of the recipient, donor, and recipient's husband are factors that can play some role in the matching process. Blood typing at its most basic level is defined by two separate typing systems. One is referred to as the ABO system. Four different types exist in this system, A, B, AB, and O. The other basic blood typing system is the Rh type. Only two Rh types are common, positive and negative. Thus, a routine blood type is described as one of the four ABO types and one of the two Rh types. The main element of the blood typing system which has the potential to affect the health of a pregnant woman's baby is the Rh type. Serious compromise of the baby's health can occur when an Rh negative woman is carrying an Rh positive fetus. With modern obstetrical treatment, such complications are uncommon, but they still exist. There are two ways an Rh negative woman can have an Rh positive baby. One is if the father of the baby is Rh positive and the baby inherited Rh positivity from the father. The other way this can happen is if an Rh negative woman receives an oocyte from a donor who is Rh positive, and the genetic makeup of the oocyte confers Rh positivity on the resulting fetus. Thus, practically speaking, the main situation in which the blood type of the egg donor can pose increased risk for the recipient is when both the recipient and her husband are Rh negative. In this circumstance, the use of an Rh positive egg donor would expose the recipient's fetus to a risk of Rh incompatibility that would not have existed had the woman used her own eggs or received eggs from an Rh negative donor.
Differences in ABO type between mother and fetus pose little risk to the health of the fetus. Therefore, use of an oocyte donor whose oocyte might produce a pregnancy which is different from the ABO type of the recipient and husband is not such a serious medical matter. Although ABO incompatibility is of negligible importance medially, we understand that to some recipient couples it may still be an important factor to match, so that genetically impossible differences in ABO type between parents and child are not revealed later in life.
Treatment of the Oocyte Donor
In general, stimulation of the oocyte donor's cycle is brought about using a similar regimen of drugs that a woman using her own oocytes for in vitro fertilization-embryo transfer is commonly given. Late in the cycle which precedes ovarian stimulation, the donor is started on daily treatment with one of two drugs, Lupron ® or Synarel®, generally the former. Daily injections of Lupron® will continue for a total of nearly three weeks. After the donor's period has started, daily intramuscular injections of a pharmaceutical gonadotropin preparation, such as Humagon®, will be added to the daily Lupron® injections. Generally, the donor will receive daily gonadotropin injections for a total of seven to twelve days. During the time that the donor is receiving the gonadotropin injections, she will have frequent vaginal ultrasound examinations and blood drawing for determination of estradiol (E2) level. When ultrasound and blood testing indicate that development of the follicles (follicles are the ovarian structures that contain the oocytes) is optimum, the donor receives an intramuscular injection of a different pharmaceutical called human chorionic gonadotropin (hCG). Two days after hCG injection, oocyte retrieval is performed. We will need a sperm specimen from the recipient's partner on the day of the retrieval, because the oocytes are inseminated on this day. Transfer of fertilized eggs (embryos) to the recipient's uterus is generally performed three days after the oocytes retrieval.
Treatment Regimen for Recipients
In general, we try to arrange for recipients to have a "fresh" as opposed to frozen embryo transfer. In order to do this, the recipient's cycle must be manipulated to synchronize her with the donor. A combination of two or three hormonal medications is used to modify the recipient's cycle.
Recipients who ovulate and have regular menstrual cycles and menstrual bleeding on their own will start with a medication which suppresses their own cycle. Either the drug Lupron® (which is given as a subcutaneous injection) or Synarel® (which is sniffed) can be used for this purpose. A few days before the recipient's period is expected to start, she is started on Lupron®. One to three days after her period starts the recipient will begin taking oral estrogen daily in addition to the Lupron®. The formulation of estrogen which works best for our purposes is Estrace® 2 mg. The recipient will take Lupron® and Estrace® 2 mg, _-1 tablet daily while waiting for the donor's cycle to come into synchrony with hers. When the donor's cycle has "caught up" with the recipient's, a simulated (artificial) 28 day menstrual cycle will be created in the recipient with the hormonal medications. To do this, the recipient takes an increased dose of Estrace® for 14 days. Sometimes we perform blood tests for hormone levels and/or an ultrasound on day 12 or 13 of the cycle to ensure an appropriate response. Lupron® treatment will continue throughout this time. On cycle day 15, that is, after the recipient has completed the fourteen days of Estrace®, progesterone treatment is begun. Progesterone is given either as a daily intramuscular injection of a preparation of progesterone in oil, or as twice daily doses of micronized progesterone, which is placed in the vagina. On the same day that progesterone treatment is begun, Lupron® is discontinued. The recipient will continue taking Estrace® and progesterone until the day her pregnancy test is performed. Fresh embryo transfer will be performed anywhere between cycle day 15 and 20, bet generally on cycle day 17 or 18. (Cycle day 17 or 18 is the third or fourth day of progesterone administration.) A sensitive blood pregnancy test will be performed on the 12th day after embryo transfer. If the recipient is pregnant, Estrace® and progesterone treatment will be continued for several more weeks.
Recipients who have complete ovarian failure and have no spontaneous menstrual cycles will not have to take Lupron®, but otherwise will take the same regimen of medications just described.
It is the policy of this program to have the recipient perform a practice or trial cycle of this hormonal regimen before a treatment cycle is actually performed. The main purpose of the trial cycle is to evaluate the recipient's response to the hormones by means of an endometrial biopsy. In our program, we do not match one of our anonymous donors to a recipient until the recipient has completed her practice cycle and the biopsy of the lining of the uterus in that cycle was found to show adequate development of the uterine lining. If the biopsy indicates that the lining is insufficiently developed, generally the recipient's regimen of hormonal treatment will be altered and the practice cycle and biopsy repeated. The other benefit of the trial cycle is to ensure that the recipient knows how to take the hormones, so that a mistake will not be made during the treatment cycle. Patients may not be required to use Lupron® or Synarel® in the trial cycle even when we plan to use it in the actual transfer cycle.
Gonadotropin releasing hormone (GnRH) is a hormone produced in the brain which indirectly stimulates ovarian function. Analogs of GnRH are synthetic forms of this hormone which do not directly induce follicle development or ovulation but which have become very important in ART therapy. There are several advantages to using GnRH analogs. First, they make ovarian stimulation easier to regulate, since the patient's own hormone production is suppressed. Second, patients who are treated with GnRH analogs tend to produce a greater proportion of mature oocytes than patients who do not receive them. Third, GnRH analogs markedly decrease the risk of cycle cancellation for most patients. Prior to their use, 20-30% of IVF-ET cycles were canceled because patients would have a premature LH surge with spontaneous ovulation. Using GnRH analogs, the risk of cycle cancellation is less than 5%. Fourth, ovarian function can be suspended with GnRH analogs for variable periods of time if necessary, which allows for flexibility in cycle scheduling.
The major disadvantage of GnRH analogs is that most patients require more medication for ovarian stimulation. This increases the cost of an ART cycle. For most patients, this disadvantage is far outweighed by the advantages. Occasionally, patients require adjustments in dosage of GnRH analogs, or may respond better to treatment without analogs. Your doctor can discuss these issues with you.
Mechanism of Action
Analogs of GnRH initially stimulate the pituitary gland to release all the stored gonadotropins (LH and FSH - the hormones that normally stimulate ovarian function). Over the course of a week to ten days, GnRH analogs suppress the production of any new LH and FSH. This effect appears to prevent the ovaries from receiving mixed signals - from the patient's own LH and FSH and from the medications that we administer to stimulate follicle development. The result for many patients is a more synchronized development of mature oocytes.
Dosage and Monitoring
The GnRH analog we use most commonly is leuprolide acetate (Lupron®). Lupron® must be injected to be active. In ART therapy, we use a formulation of Lupron® which can be injected just under the skin, in a manner similar to insulin injections for diabetes therapy.
The usual dosage of Lupron® is 0.1 or 0.2 cc daily as a single injection. Menstruation usually occurs four to ten days later. During the time of actual ovarian stimulation, the dosage of Lupron® is halved (e.g., 0.1 cc to 0.05 cc daily). Lupron® is usually administered until the day of hCG administration. Some patients, because of their history or condition, are treated with a different dosage or schedule of Lupron®. Your physician will advise you if these changes apply to you.
Another GnRH analog used in ART therapy is nafarelin acetate (Synarel®). Synarel® is administered as a nasal spray. The usual starting dose is two sprays twice a day. The timing of administration is identical to Lupron®. The dosage of Synarel® is usually halved (e.g., from two sprays twice a day to one spray twice a day) when ovarian stimulation is begun.
Adverse effects from GnRH analogs are uncommon. Occasionally, ovarian cysts may form during therapy. These usually resolve spontaneously. Rarely, cysts may grow so large as to cause abdominal bloating and pain. Even less common is ovarian torsion, in which the ovary twists and cuts off its own blood supply. Surgical removal of the ovary may be necessary in these very rare circumstances.
Other adverse effects of GnRH analogs include headaches, mood changes, and altered sleep. Hot flashes may occur during prolonged therapy. Allergic reactions are rare. A slight redness and discomfort may occur at the Lupron® injection site, and patients using Synarel® may experience nasal stuffiness.
To increase the likelihood of pregnancy through ART, multiple oocytes must be produced. This is accomplished through the administration of gonadotropins-hormonal medications which stimulate the ovaries. Stimulation can be achieved with a variety of drug regimens. Gonadotropin medications come in several forms. Repronex® and Humegon® are combinations of FSH and LH. They replace a woman's own LH and FSH which are normally produced by the pituitary gland. Fertinex®, Gonal-F® and Follistim® are preparations that contain only FSH. Gonal-F® and Follistim® are recombinant products which are made by genetically engineered cells. This process ensures uniform purity and potency. Because the dose of hormones we use in ART is greater than what the body normally produces, the ovaries typically develop more than one oocyte as occurs in a natural cycle.
Gonadotropins act directly on the ovary to stimulate the growth of follicles (the structures in ovaries which contain eggs). Granulosa cells within the follicles grow and develop which cause the follicles to enlarge and fill with follicular fluid. These developing follicles can be counted and measured using transvaginal ultrasound. As the follicles grow, they produce increasing amounts of estrogen, which can be measured with a laboratory blood test. Some physicians prefer one formulation or another. Your doctor can discuss this with you in more detail.
Dosage and Monitoring
Gonadotropins are packaged in vials containing 75 or 150 International Units (IU). In the first cycle of IVF-ET we routinely administer 300 IU of gonadotropins daily for three days. This dosage may vary depending on the patient's history. We then see patients in the office for regularly scheduled transvaginal ultrasound examinations and serum estradiol tests. The dose of gonadotropins is then determined by the result of the ultrasound and estradiol tests. Most women require between seven to ten days of gonadotropin therapy.
Humegon® and Repronex® require intramuscular injection, usually into the muscles of the buttocks. Fertinex®, Gonal-F® and Follistim® are administered subcutaneously, like an insulin or allergy shot.
Gonadotropin preparations are strong medications. Although rare, a potentially serious adverse effect of gonadotropins is ovarian hyperstimulation. Even after oocyte retrieval, the ovarian tissue may continue to grow in response to the prior gonadotropin stimulation. As the ovaries enlarge, discomfort and bloating may occur. Occasionally, an enlarged ovary may become twisted. This condition is referred to as ovarian torsion. When this occurs, surgery may be required to either remove the ovary or untwist it.
In addition to discomfort, women suffering from severe ovarian hyperstimulation may develop ascites (a collection of fluid in the abdomen or pelvis). This fluid enters the pelvis by leaking through blood vessels. Although rare, this condition can be severe enough to produce swelling of the abdomen and shortness of breath. Hospitalization is required in cases of severe ovarian hyperstimulation. Treatment for ovarian hyperstimulation usually consists of bed rest and intravenous fluids. On rare occasions it is necessary to drain fluid from a patient's abdomen. Hyperstimulation is more severe when pregnancy occurs, as the developing pregnancy produces the hormone hCG, which stimulates the ovaries to continue to grow. Hyperstimulation can remain a potential problem for to 2-3 months during the pregnancy.
There does not appear to be any increased risk of birth defects in offspring of women who take gonadotropins compared to conceptions in the general population. However, there is a greater risk of early miscarriage in patients taking gonadotropins. Approximately 20-25% of gonadotropin induced conceptions miscarry within the first trimester. Multiple pregnancy is another adverse effect of gonadotropins therapy. Approximately 25% of IVF-ET pregnancies are multiple. The risk of more than twins is about 5%.
Although not truly an "adverse effect," the cost of gonadotropins must be taken seriously. One ampule (amp) of 75 IU typically costs about $50 to $70. As these medications are commonly administered for seven to ten days, it is not unusual for the medication cost for a single cycle to cost $1000 to $2000. Some women have obtained gonadotropins in other countries. According to the FDA, it is illegal to import drugs from other countries for use in the United States. Some patients with poor response to stimulation have admitted to using imported gonadotropins.
In summary, gonadotropins are strong, effective medications for inducing follicle development. Their use must be monitored carefully, preferably with a combination of regular transvaginal ultrasound examinations and estradiol determinations. When administered and monitored carefully, the risk of adverse effects is acceptably low.
Human Chorionic Gonadotropin
Human chorionic gonadotropin (hCG) is an injectable medication that is administered to complete oocyte maturation. It can also be used in conjunction with clomiphene citrate, or in a natural cycle. The brand names for hCG are Profasi® and Pregnyl®. These medications come in 5,000 and 10,000 unit ampules. Typically a 10,000 unit ampule costs $35-$50.
Mechanism of Action
Human chorionic gonadotropin is structurally similar to the LH which is produced by a woman's pituitary gland. It acts on the ovary in a manner similar to a woman's own LH. Human chorionic gonadotropin, like LH stimulates the final maturation of the oocytes in the follicle. It also stimulates progesterone production from the ovary after egg retrieval. This progesterone is important to prepare the uterus for implantation of the embryo.
Dosage and Administration
Human chorionic gonadotropin can be administered several different ways. We commonly administer a single injection of 10,000 units. Once hCG is administered, ovulation usually occurs in approximately 36 to 40 hours. We therefore routinely schedule oocyte retrieval at 35 hours after hCG. This helps ensure maximal egg maturity, which is important for fertilization and embryo development. Occasionally, several doses of 2,500 units (usually every three days) are administered after egg retrieval to stimulate progesterone production.
It typically takes 8-10 days for single injection of 10,000 units of hCG to be cleared from the blood stream. As hCG is the same hormone that is produced by a developing pregnancy, patients should not have a blood or urine pregnancy test sooner than ten days following the hCG injection. If a pregnancy test is performed earlier, it may measure the hCG that was given by injection rather than measure hCG produced by a pregnancy.
When given by itself, there are few, if any adverse effects to hCG. However, when given in conjunction with gonadotropins, ovarian hyperstimulation can occur. In fact, hyperstimulation is extremely rare if hCG is not administered.
Clomiphene citrate (Clomid® and Serophene®) is an oral medication that is commonly administered to induce ovulation in women who do not ovulate regularly. We also use clomiphene citrate for minimal stimulation IVF-ET. Typically, each 50 mg pill costs approximately $5.00 to $8.00.
Mechanism of Action
Clomiphene acts within the brain to promote the production of the hormone, GnRH. As a result, the pituitary gland makes more FSH and LH, the hormones that stimulate ovarian function. In particular, the increased FSH stimulates more follicles in the ovaries to grow.
Dosage and Monitoring
For minimal stimulation IVF-ET, the usual dosage of clomiphene is 100 mg daily for five days, beginning on day three of the menstrual period. Follicle development in response to clomiphene is most accurately determined by ultrasound. Typically, you will take a cycle (pack) of oral contraceptive pills to regulate the start of your period before stimulation. We perform an ultrasound to examine the ovaries around the time you finish the oral contraceptives. The next ultrasound will be performed the day after the last clomiphene citrate dose. Additional ultrasounds will be performed (usually every other day or daily) until the day the largest follicle measures 18-20 mm in diameter. On that day hCG, 10,000 units will be injected intramuscularly in the evening. Oocyte retrieval will be performed 35 hours after the hCG injection. A urine ovulation predictor kit may be used in addition to ultrasound monitoring. These kits detect large amounts of LH in the urine. Once a follicle is mature, the pituitary releases a large amount of LH, called an LH surge. Most women will ovulate within 24 hours of detecting a urinary LH surge. When a spontaneous LH surge is detected in a minimal stimulation cycle, the cycle may be canceled as it is difficult to time the egg retrieval to obtain a mature egg prior to ovulation.
Severe adverse effects are uncommon with clomiphene citrate. First, as multiple follicles can sometime develop, multiple pregnancy may occur. This complication is uncommon in minimal stimulation IVF-ET. Another complication is ovarian cyst formation. While these cysts usually resolve spontaneously, they may cause bloating and abdominal discomfort. On rare occasions, these cysts may rupture causing abdominal pain. Approximately 10% of women who take clomiphene citrate experience hot flashes, which may disrupt sleep. A small percentage of patients (less than 5%) report some visual changes during clomiphene citrate therapy. Some patients describe blurred vision, while other patients describe seeing spots or flashes of light or after images. You should report any of these adverse effects to your physician.
There does not appear to be any increased risk of birth defects in offspring of women who take clomiphene citrate. In large studies, the risk of birth defects does not appear to be greater than that noted in the general population. Likewise, the risk of miscarriage in women taking clomiphene does not appear to be increased over that noted in the general population.
There has been recent concern about an association of the use of clomiphene with the subsequent development of ovarian cancer. At this time, information about this subject is very limited. While several studies have suggested an increased risk of ovarian cancer in women who have taken clomiphene citrate, these studies have been widely criticized for many reasons. If the risk of ovarian cancer in women taking clomiphene is increased at all, this increase appears small. The lifetime risk of ovarian cancer in all women is approximately 1 in 70. If the preliminary evidence turns out to be true, the increased rate of ovarian cancer in patients taking clomiphene may be as high as 3 to 4%. This increased risk of ovarian cancer in patients taking clomiphene seems to occur only in women who have taken clomiphene for greater than one year (12 cycles). The risk has not been observed in women who have a successful pregnancy from clomiphene therapy.
Q: Does ART damage the ovaries?
A: There is no evidence to suggest that laparoscopy and/or oocyte retrieval damage the ovaries. There is one report which suggests that infertile women who take fertility drugs and do not get pregnant have an increased risk of ovarian cancer. However, the study did not collect information on the type of drugs used, and the control (comparison) population may not have been selected accurately. The fertility drugs used in ART have been in use over 30 years, and other studies have suggested no increased risk.
Q: Why is the success rate with ART so low?
A: Studies of human reproduction indicate that for a couple with proven fertility, the likelihood of conception is only 20% per month. ART affords couples with infertility factors similar chances for conception.
Q: Were concerned about multiple births from ART. Should we just have one embryo transferred?
A: Any time more than one embryo is transferred, the chance for multiple pregnancy exists. In fact, about 25% of birth from ART are twins, a rate much greater than in the general population (1 in 80 pregnancies). Triplets and quadruplets have also been conceived through ART. However, the majority of ART pregnancies (70%) are singletons, and the chance of any pregnancy with ART increases with the number of embryos or oocytes transferred. Success rates appear to peak on average with transfer of three or four embryos. We will discuss the options and implications of transferring fewer than four embryos, but in general we will not recommend transferring just one. Although we do not directly offer it, selective reduction is available to couples who conceive multiple gestations. We can provide you with more information about this procedure.
Q: Is there an increased chance of birth defects if I become pregnant through ART?
A: No. The risk of congenital anomalies in children conceived through ART is the same as the risk in the general population. Chromosome abnormalities, such as Down syndrome also occur at a rate similar to the general population.
Q: I had my tubes tied (tubal ligation) several years ago. Would I be a candidate for IVF?
A: Although surgical reversal of tubal sterilization may be a better option, IVF-ET is still a consideration, especially in older women or in couples with male factor infertility. The success rate is greater for ligation reversal than for a single cycle of IVF-ET, although the results of IVF-ET are obtained more rapidly than ligation reversal. If ligation reversal has been attempted and has failed, IVF-ET represents the best option. Cost and other factors involved in surgical reversal must be considered when making this decision.
Q: Does insurance cover the procedure?
A: Unfortunately, most insurance plans do not cover ART procedures. Some programs cover portions of the therapy. Our staff would be happy to help you determine your level of coverage. We strongly recommend you do this prior to starting ART therapy.
Q: How many days does the entire procedure take?
A: The entire procedure takes approximately six weeks. However, we only need to see you intensively at the UT Medicine Fertility Center over a two-week period. These details are discussed in the "Step by Step" sections.
Q: Can we have intercourse while attempting ART?
A: Yes. We recommend that the man abstain from ejaculating for at least 48 hours preceding egg retrieval. This precaution assures that the semen sample for ART is of optimal quality. Near the time of egg retrieval, the ovaries can be enlarged and tender, which can make intercourse uncomfortable.
Q: What if I ovulate before the retrieval?
A: Virtually all cases of premature ovulation are now prevented by the use of GnRH analogs. In rare cases in which Lupron® or Synarel® are not used, we perform an ultrasound prior to retrieval to make sure the follicles are intact. In the uncommon case of ovulation, we will not perform retrieval because the quality of the remaining oocytes is affected adversely.
Q: Will scar tissue around my ovaries make it impossible to retrieve oocytes?
A: No, the oocyte can usually be retrieved by transvaginal aspiration even when the ovaries are covered with scar tissue. In rare cases, scarring pulls the ovaries out of the normal pelvic position. This condition can be identified before ART with ultrasound.
Q: How much activity is recommended after ET?
A: We recommend a fairly quiet 24 hours after ET. Thereafter, most patients resume their normal routines. Strenuous exercises, running, etc. should be avoided until a pregnancy test has been performed.
Q: After embryo transfer, how long must we wait until we have intercourse without risk to the embryo?
A: No one knows for sure. We recommend abstinence for a minimum of 48 hours after transfer.
A cost estimate for an ART cycle is difficult to provide because some costs vary considerably between patients. In particular, the number of ultrasounds and estradiol measurements, and the amount of stimulation medications can significantly change the total cost of the procedure. Because the ART procedures involve multiple steps, any patient who does not proceed to a further step is usually charged only for the cost of the completed procedures. Before initiating ART, you should discuss financial arrangements with our billing personnel.
Additional expenses to consider may include loss of wages from time missed at work, as well as, expenses incurred by travel and accommodations for our out-of-town patients. In addition, the medications employed in ART procedures (human menopausal gonadotropins, hCG an GnRH analogs) are very expensive. All of these factors must be considered in ascertaining the financial feasibility of participation in an ART program.
We are sensitive to the tremendous financial investment that couples make to participate in this program. We continuously strive to keep our costs manageable and we seek funded research protocols in which ART costs for the participants may be defrayed. In addition, through the efforts of our professional organizations, we are actively lobbying both at the state and national levels for insurance coverage for ART.
Corson, Stephen L., M.D. Conquering Infertility: A Guide for Couples. New York: Prentice Hall Press, 1990.
Franklin, Robert R., M.D. and Dorothy Kay Brockman. In Pursuit of Fertility: A Consultation With a Specialist. New York: Henry Holt & Co., 1990.
Nachtigall, Robert, M.D. and Elizabeth Mehran. Overcoming Infertility. New York: Doubleday, 1991.
Novotny, Pamela Patrick. What You Can Do About Infertility. New York: Dell Publishing, 1991.
Karow, William G., M.D., William C. Gentry, D.H.D., Christopher Hsuing, and Andrienne Pope, Ph.D. A Baby of Your Own: New Ways to Overcome Infertility. Dallas, Texas: Taylor Publishing Co., 1992.
Harkness, Carla. The Infertility Book: A Comprehensive Medical and Emotional Guide. San Francisco: Volcano Press, 1992.
Robin, Peggy. How to be a Successful Fertility Patient. New York: William Morrow and Co., Inc., 1993.
Becker, Gay. Healing the Infertility Family. New York: Bantam Books, 1990.
Hill, Susan. One Woman's Passionate Quest to Complete Her Family. New York: Viking Penguin, 1990.
Mullens, Anne. Missed Conceptions: Overcoming Infertility. Toronto, Canada: McGraw-Hill Ryerson, 1990.
Clapp, Diane, BSN, RN and Merle Bombardieri, LICSW. How Can I Help? A Handbook for Family and Friends of Couples Going Through Infertility. Fertility Counseling Associates, 33 Bedford St., Lexington, MA 02173, 1991.
McGuirk, James and Mary Elizabeth McGuirk. For Want of a Child: A Psychologist and His Wife Explore the Emotional Effects and Challenges of Infertility. New York: Continuum, 1991.
Salzer, Linda P. Surviving Infertility: A Compassionate Guide Through the Emotional Crisis of Infertility. New York: Harper Perennial, 1991.
Borysenko, Joan. Minding the Body, Mending the Mind. New York: Bantam Books, 1987.
Stephenson, Lynda Rutledge. Give Us a Child: Coping with the Personal Crisis of Infertility. New York: Harper and Row, 1987.
Baughan, Jill. A Hope Deferred: A Couple's Guide to Coping with Infertility. Oregon: Multnomah Press, 1989.
Assisted Reproductive Technologies
Centers for Disease Control and Prevention. 1995 Assisted Reproductive Technology Success Rates. U.S. Department of Health and Human Services, 1997.
Wisot, Arthur L., M.D. and David R. Meldrum, M.D. A Guide to In Vitro Fertilization and Other Assisted Reproductive Methods. New York: Parohs Books, 1990.
Silber, Sherman, J., M.D. How to Get Pregnant With the New Technology. New York: Warner Books, Inc., 1991.
Lauritzen, Paul. Pursuing Parenthood-Ethical Issues in Assisted Reproduction. Bloomington: Indiana University Press, 1993.
Partridge-Brown, Mary. In Vitro Fertilization Clinics - A North American Directory of Programs and Services. McFarland and Company, 1993.
Sher, Geoffrey, M.D., and Virginia Marriage. From Infertility to In Vitro Fertilization. New York: McGraw Hill, 1988.
Somerville, MA 02144-1731
(617) 623-0744 - Telephone Helpline
RESOLVE of South Texas
|The Endometriosis Association
P.O. Box 92187
Milwaukee, WI 53202
|The American Society for Reproductive Medicine
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Birmingham, AL 35216
|The North American Council on Adoptable Children
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|Centers for Disease Control and Prevention
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Atlanta, GA 30333