Guide to ART
ART: A Step-by Step Guide
Every cycle of ART involves multiple steps, and each occurs at a specific time during an approximately 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. There are different treatment regimens available for ovarian stimulation. Your physician will individualize your treatment regimen based upon your age, medical history and what in their personal experience they believe will maximize your chances of success. The following are some of the protocols and medications you may use during your ART stimulation.
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®, Follistim®, Menopur®,Fertinex Bravelle®, Microdose HCG)
- Monitoring of follicle development with ultrasound and serum hormone levels
- GnRH antagonists (Cetrotide®or Ganirelix®) may be started if Lupron was not used
- 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 and your gonadotropins 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 may 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. Alternatively, you may use GnRH antagonists instead of GnRH agonists. The GnRH antagonists will be started after you have already taken several days of gonadotropin medications. 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.
Step 4 - Ovarian Stimulation
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 small 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. After starting and taking the medications for a few days, we usually will 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. Towards the end of the stimulation we may need to schedule daily visits for ultrasound exams and serum estradiol tests. The amount of medication we prescribe each day 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.
Step 6 - Final Oocyte Maturation/hCG Administration
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 16-20 mm and serum estradiol is greater than 500 pg/mL. The drug is given as a single intramuscular or subcutaneous injection depending upon the brand of chorionic gonadotropin utilized. 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 dedicated 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 or test tube 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 our center by masturbation the morning of the retrieval. The staff will instruct you regarding time of collection. 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 or inject an individual sperm into the egg if intracytoplasmic sperm injection (ICSI) is deemed necessary. 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.
Step 9 - Embryo Transfer
The embryo transfer procedure is usually performed three to five 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 excellent IVF-ET pregnancy rates occur in most cases with the transfer of one to two embryos, which also minimizes the risk of multiples. The transfer of 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 the number of embryos develop that are used for the “fresh transfer”, we offer embryo cryopreservation. This allows us to store excess embryos for transfer at a later date.
Step 10 - Progesterone Supplements
We will administer progesterone daily beginning the day after the retrieval or on the day of embryo transfer depending upon the individual physician’s protocol. 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 either an intramuscular injection, but vaginal administration (suppositories, capsules or Crinone® gel) may also be used. Depending upon the individual physician’s protocol you may also be treated with oral medications such as methylprednisolone and doxycycline after the oocyte retrieval and with estrogen supplementation to begin on the day of embryo transfer.
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 may 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 and supplemental medications.
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 heartbeat. 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.