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IVF
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IVF or In Vitro Fertilisation involves retrieving eggs from the female and fertilising them in the laboratory by placing them with the sperms. This means that the sperm must have the capacity to fertilise the egg on its own in IVF. In contrast, ICSI involves injecting a single sperm in the egg, and is therefore used in extreme cases when the sperm have no motility of their own.
Pre cycle Preparation
Before you begin IVF you will go through a screening process to assess your reproductive health. This process may take 2-3 weeks. During your telephone consultation or office visit, you will meet your physician, who will take a detailed history and explain the process of in vitro fertilization and embryo transfer. Your doctor will order various tests and arrange a visit or telephone consult with the nurse coordinator and financial counselor. Testing might include:
Evaluating the Female
Cycle day 3 blood tests
A blood sample is drawn on the third day of your menstrual cycle (cycle day 3) to test your pituitary gland, ovaries, blood type, and certain infectious diseases (such as hepatitis and HIV). The results of these tests will help us plan your stimulation protocol and general medical care. Your doctor may select other screening tests according to your medical and fertility history. Please ask if the reason for any test is unclear to you.
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Mid-Cycle Ultrasound
An ultrasound is performed near the time of ovulation to measure the endometrium, which is the inside lining of the uterus, the location of early embryo development. The uterus, cervical canal, and ovaries are also studied. Critical measurements include the thickness and pattern of the endometrial lining, the curvature of the cervical canal, and the position of the uterus. A catheter may be passed through the cervix to measure the depth of the uterus, a uterine measurement or mock embryo transfer. A brief physical exam may also be performed if this is the first time you meet your doctor.
Hysterosalpingogram (HSG), Hysteroscopy or Hysterosonogram:
Hysterosalpingogram is a test done in the radiology department of the hospital to test your fallopian tubes and the uterus. This test is a frequently performed fertility test, but is not required prior to IVF. A small amount of fluid is injected into the uterus and tubes and an X-ray picture is taken. The picture outlines the uterine cavity and fallopian tubes and provides important information about the inside of your uterus.
Hysteroscopy is an examination of the interior of the uterus performed using a narrow hysteroscope, a long thin telescope with a light and lens. Small lesions like polyps and fibroids could prevent attachment of an embryo and act like an intrauterine device (IUD) inside your uterus. These can be removed through the hysteroscope. Hysterosonogram (Saline Sonogram):
A hysterosonogram is another test which can be performed to evaluate the uterine cavity for polyps or fibroids. A small amount of fluid (sterile saline) is injected through a catheter placed through the cervix and into the uterine cavity while a vaginal ultrasound is performed at the same time. This provides important information about the inside of your uterus without surgery or exposure to x-rays. Evaluating the Male
Semen analysis
A semen analysis provides a measure of semen volume, sperm concentration or number, sperm motility and sperm morphology. Although we accept evidence of normal sperm counts from outside laboratories, if there is any history of sperm abnormalities, we may request a semen analysis be performed in our laboratory before the planned IVF cycle. If persistent abnormalities are detected, a more detailed evaluation including additional tests and/or an exam by a urologist may be suggested. Fortunately, with the availability of ICSI (Intracytoplasmic sperm injection) we now have a very effective method of producing pregnancies even when sperm function is very poor.
Other tests
Other tests include routine and hormonal blood tests to look for any cause for abnormal semen reports.
Ovulation Induction
Ovulation induction is the stimulation of the ovaries to produce multiple follicles, each containing an egg. In the month prior to ovulation induction, oral contraceptives are given as a gentle means of preventing ovarian cysts, which are fluid sacs in the ovary. Such cysts, which were common prior to use of oral contraceptives, delayed the start of the cycle and interfered with normal ovarian function. Cysts are rare when oral contraceptives are used.
A few days before finishing the oral contraceptives, Lupron or Synarel is started. These are medications that turn off your normal menstrual cycles and prevent premature ovulation. Lupron and Synarel are very similar, but Lupron is taken by subcutaneous injection, and Synarel by nasal spray.
Lupron and Synarel may cause mild side effects -- hot flushes, mild headaches, and vaginal spotting a week to 10 days after beginning the medication; these symptoms are normal, and are signs that the medication is working. Please be certain that you are not pregnant prior to starting Lupron/Synarel, since these drugs can interfere with the normal hormones that support early pregnancy. (Note that Lupron/Synarel is discontinued well before you become pregnant).
The nurse coordinator assigns a date for a vaginal ultrasound and blood test around the time the period starts. Using vaginal ultrasound, the ovaries are examined for ovarian cysts. Cysts often disappear on their own, but a cyst may be aspirated (removing the fluid) to help it collapse faster. The blood test measures estrogen, a hormone produced by the ovary. Most women are ready to start stimulation immediately, but if the estrogen level is elevated or a cyst is present on the ovaries, you may need another 5 to 14 days of Lupron/Synarel treatment before proceeding.
Occasionally, the male will be asked to give a backup sperm sample early in the cycle. This will be frozen and stored, to be available as an emergency backup. Let us know if obtaining a sperm sample on the day of egg retrieval might be difficult.
In a typical stimulation protocol, daily or twice daily injections of human gonadotropins, Humegon, Pergonal, Repronex, Gonal-F, or Follistim are started after the menstrual period. These medications are concentrated forms of the natural hormones which stimulate ovulation in a normal menstrual cycle. These medications are very similar, but Humegon and Pergonal and Repronex contain two hormones, luteinizing hormone (LH), and follicle stimulating hormone (FSH), while Gonal-F and Follistim contain pure FSH. Although these are different medications, there are only small differences in the way the body responds to them, so we will refer to all of them as gonadotropins in this web site.
The day gonadotropins begin is stimulation day 1, or "stim day 1" regardless of when it occurs after the period. The Lupron dose may be reduced when stimulation starts
The follicles are egg-containing areas inside the ovary. There are hundreds of thousands of follicles in each ovary, but during any one stimulation cycle only a few will accumulate fluid and grow large enough to appear on an ultrasound exam. Only the large follicles hold mature eggs.
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The eggs are about a tenth of a millimeter in diameter, just under a size that is visible to the naked eye, so the actual egg cannot be seen on ultrasound. The follicle is about two hundred times bigger than the egg, and can be seen clearly when it is large enough. Each follicle usually contains one egg surrounded by granulosa cells. Granulosa cells surround the egg, produce the follicular fluid, produce estrogen, and support the egg in its development. In the normal menstrual cycle, only one follicle matures, reaching about an inch in diameter. Occasionally a follicle may not contain an egg, and even more rarely there may be two or more eggs per follicle.
Gonadotropins cause several follicles to enlarge at once.
The number can vary from one or two to 30 in some women. The dose of gonadotropin is based on a prediction of how the ovaries will respond, and usually varies from one to eight ampules per day. Women who are very sensitive to the medication need only a small amount of gonadotropins, while those who are resistant require more.
When ultrasound examination and estrogen levels suggest that the follicles are large enough and the eggs are mature, you will stop Lupron/Synarel and gonadotropins and take one dose of human chorionic gonadotropin (hCG). hCG prepares the eggs for ovulation and fertilization. Egg retrieval is performed at about 36 hours after hCG, since ovulation normally begins about 40 hours after the hCG injection. The timing of hCG is critical, so it must be taken at the exact time you are instructed to give it.
Oocyte Retrieval
From midnight before the egg retrieval you should not have anything to eat or drink, including coffee or water. If you are taking medications for any other reason, talk with your doctor or nurse about taking the medication on the day of the egg retrieval. During the egg retrieval you may be given antibiotics or other medications, so make sure your doctor knows about any allergies or medical problems you have.
The egg retrieval is performed thirty-six hours after hCG injection. You are given sedation by an anesthesiologist through an intravenous catheter, a small tube in an arm vein. You are not completely asleep, but in a sort of twilight state; you remember very little of the retrieval. After you are sedated, the vagina is washed with a salt water solution. A needle is placed under ultrasound guidance into the ovary and fluid and eggs from the follicles in your ovaries are collected into a test tube and sent to the IVF lab. The whole procedure takes about 30 minutes, and discomfort is generally minimal. On average eggs will be retrieved from over two thirds of the follicles.
Complications after egg retrieval are rare. Since your doctor can see the needle on the ultrasound and uses the ultrasound to guide the procedure, the chance of a serious problem is small. Unusual problems include internal bleeding, vaginal bleeding, or infection.
Recovery after the egg retrieval is quite rapid. Some pelvic heaviness, soreness, or cramping are common. Spotting is normal, but should be less than a normal menstrual period. Usually the discomfort responds to a heating pad and rest, but pain medication is available. Most women are able to go home within two hours of the procedure. Make sure someone is available to take you home, since you cannot drive a car after sedation or anesthesia.
The male will collect a sperm sample by masturbation the day of the egg retrieval. He should abstain from ejaculation for 2 days (48 hours) to 5 days before giving the sample. Occasionally a second sample on the day of the egg retrieval is required.
At egg retrieval, some of the cells in your ovary which produce progesterone are removed along with your eggs. Progesterone, a natural hormone, prepares the lining of the uterus for the embryos. Some women may not produce enough progesterone to maintain the early pregnancy, so a progesterone supplement may be taken. This continues daily for the next two weeks (and through early pregnancy) by injection, or vaginally by suppository or gel.
Don't plan on doing any work on the day of the egg retrieval. Avoid heavy lifting and vigorous exertion. Walking is fine, just don't overdo it. Avoid tub baths, hot tubs, Jacuzzis, swimming, or immersing yourself in water from the time of the egg retrieval until after your pregnancy test. Take showers rather than baths. Avoid medication except that which your doctor or nurse has asked you to take. Refrain from intercourse for one week after the transfer. Don't use douches, spermicides, or vaginal creams in this time period or throughout the luteal phase. You should not consume alcohol or caffeine during this time.
Keep in mind that we may want to contact you most days during the time from hCG to embryo transfer. Both male and female partners should be available every day for telephone calls and consultations in the rare event that an additional sperm sample is needed, or a change in plans is required. |
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Insemination & Fertilization |
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Some of the most important events in your cycle now occur behind the scenes, in the laboratory. The eggs mature for several hours before sperm are added, usually in the afternoon of your egg retrieval. The addition of sperm to the culture media is called insemination. Insemination is followed several hours later by fertilization, when the sperm enters the egg.
The stages that follow are very important to the future embryo. After fertilization, the sperm loses its tail and its head enlarges, so that, at this stage, the egg looks like a cell with two nuclei, called pro-nuclei. The pro-nuclei, which hold the genetic material of the sperm and the egg, are called pro-nuclei because they have not yet fused to form a single true nucleus. You may hear this stage referred to as the two pro-nuclear or 2PN stage. Identification of the 2PN stage is very important to determine if fertilization has occurred.
The 2PN stage can't always be identified. The pro-nuclei join or fuse within a few hours, producing a fertilized egg, or embryo. When this happens, the early embryo looks just like an unfertilized egg. Keep in mind that the embryos are kept in the dark and only observed for brief time periods, so the 2PN stage might not be seen for some of your embryos, and it may be difficult to tell how many embryos have fertilized.
After the pro-nuclei fuse, the embryo can begin cleaving, or dividing, first into two cells, then into four. Cleavage to four cells generally takes 36 to 48 hours or more after the egg retrieval. Embryo transfer typically occurs at 72 hours, three days after egg retrieval. Transfer can also occur at 5-6 days after egg retrieval, when the embryo develops to the blastocyst stage.
Problems can occur with fertilization and cleavage. Occasionally sperm are unable to penetrate the egg in the first 24 hours, and a fertilization failure occurs. Most eggs can fertilize only the first day, and a re-insemination the second day doesn't produce more embryos. When multiple sperm penetrate an egg, polyspermy occurs. Although polyspermic embryos are abnormal and cannot be transferred, polyspermy is sometimes a good sign, since pregnancy rates with the remaining embryos appear to be slightly higher when this occurs. Sometimes embryos do not divide or stop dividing at an early stage, and a cleavage arrest occurs. These embryos may resume division in the uterus, and can be transferred. Fragmentation or breakage of some of the cells in the embryo is also quite common; severe fragmentation will reduce pregnancy rates, but milder fragmentation is not a serious problem. Fragmented embryos are not thought to produce a greater risk for abnormal babies.
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Embryo Development |
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Ultrasound picture of Ovary: Injections of Lupron, Metrodin, Pergonal or Humegon allow the ovaries to develop many follicles as seen in this ultrasound immediately prior to egg retrieval.
Fertilized oocyte (2PN embryo): Immediately after fertilization, the egg contains two pronuclei. Each contains the chromosomal material from one of the genetic parents.
Four cell embryo: Each of the cells is called a blastomere. The embryo is surrounded by a protein matrix "shell" called the zona pellucida.
Eight cell embryo: On the third day after the egg retrieval eight cell embryos can be transfered to the uterus. On average, 10-15% of embryos such as this will implant after being transfered.
Hatched Embryo: Prior to implantation, the embryo, now at the blastocyst stage, must hatch out of the zona pellucida. Only then can it attach to the mother's endometrial lining.
Embryo Transfer:
Three or five days following the Egg Retrieval the patient will have the Embryo Transfer (ET). During this time the fertilized eggs (embryos) have been allowed to grow and divide in the incubator. The patient would have also been started on Progesterone suppositories or Crinone to prepare the uterine lining for implantation.
The day before ET the patient will be contacted and given a specific time to come to the clinic the next day for ET.
On the day of the embryo transfer, if you like, bring some relaxing music and a Walkman with headphones. Try to think about things that relax you. Bring a picture from your last vacation, a small pillow from home, or a special pair of socks to keep your feet warm. Don't drink coffee or soft drinks before the transfer. If you have a cold, cough, or allergies, let us know; you may need a cough or allergy suppressant. We request that you arrive at the center with your bladder at least half full as this will enable us to better visualize your uterus with the abdominal ultrasound.
About 15 minutes before the transfer, the physician will meet with the couple and discuss the number and quality of the embryos available for transfer. A decision will be made by the couple and their physician as to the number of embryos that will be transferred and the number to be frozen or discarded depending on the quality of embryos. The embryos will be separated into a separate dish. Meanwhile the physician will prepare the patient for the ET. This procedure is very similar to an artificial insemination procedure except that embryos are transferred to the uterus instead of sperm. A speculum is inserted in the vagina; the cervix is washed and cleansed. The embryologist will then load the embryos into a transfer catheter and deliver the catheter to the physician who gently introduces the small flexible tube through the cervical canal into the uterine cavity where the embryos are released.
This is done without anesthesia, and feels about like a Pap smear. A sensation or twinge as the catheter passes through the cervix is common, but the actual embryo transfer normally cannot be felt. Most transfers are performed with the female on her back, the normal position for a pelvic exam. Ultrasound via a transducer placed on the lower abdomen is often used to guide the transfer catheter.
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Once the embryos have been released, the catheter is taken back to the laboratory, where the embryologist inspects it for any retained embryos and gives an "all-clear" signal. The transfer itself takes about 30 seconds; the whole procedure takes fifteen minutes. If there are any retained embryos, they are reloaded and a second transfer occurs immediately to insure that all embryos reach the uterine cavity. A second transfer does not decrease your chance for a successful pregnancy.
Risks of IVF
The main risk of gonadotropins is ovarian hyperstimulation syndrome (OHSS). Ovarian hyperstimulation occurs in a small percentage of patients when too many follicles develop in the ovary. The ovary then grows to a large size and leaks fluids, resulting in nausea and bloating, dehydration, and, if severe, fluid collection around the abdominal organs, or ascites. In very severe cases, fluid collects around other organs, such as the lungs and heart, and blood clots and strokes can occur. If the ovary enlarges too much, rupture of the ovary and abdominal bleeding can occur. In rare cases, hospitalization and removal of abdominal fluid may be required to regulate fluid balance. In years past, fatalities have been reported, but are extremely rare.
Fortunately, serious cases of ovarian hyperstimulation are quite rare, and your doctor can predict and prevent hyperstimulation by monitoring the ovaries with ultrasound and blood estrogen levels. Removal of the granulosa cells during egg retrieval reduces the risk of hyperstimulation, so the risk with in vitro fertilization is lower than with gonadotropin use for simple ovulation induction. If the risk is very high, a cycle may be canceled. Although this is a rare event, it provides complete safety, in that hyperstimulation almost never occurs after a canceled cycle. If a cycle proceeds to egg retrieval, embryos may be frozen and saved for a later cycle, after the risk of hyperstimulation has subsided
Multiple pregnancy is a risk when several embryos are transferred. Since several eggs will be retrieved from the ovaries and inseminated, multiple embryos are likely to develop. If multiple embryos are transferred into the uterus, twins, triplets, or even quadruplets or more could occur, perhaps requiring a selective reduction. Higher multiples are rare. In IVF, the risk of multiple pregnancy depends on the number and quality of embryos replaced; your doctor will estimate the risk of multiples for you. Some patients are not willing to accept any risk of multiple pregnancies and therefore elect to transfer fewer embryos, freezing the remainder for use in a later frozen transfer cycle. Your doctor will discuss this with you before the transfer.
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