In Vitro Fertilization

GENERAL INFORMATION

In Vitro Fertilization (IVF)

In vitro fertilization and embryo transfer (IVF-ET) is a procedure designed to enhance the likelihood of conception in couples for whom other fertility therapies have been unsuccessful or are not possible. It involves multiple steps resulting in the insemination and fertilization of oocytes (eggs) in the laboratory. The embryos created in this process are placed into the uterus for implantation. Each stage of the procedure has specific risks, which are outlined below.

Benefits of Therapy

IVF may provide a couple who has been otherwise unable to conceive with a chance to establish a pregnancy.

Risks of Therapy

Superovulation stimulates egg development

The "superovulation" techniques used in IVF are designed to stimulate the ovaries to produce several eggs (oocytes) rather than the usual single egg as in a natural cycle. Multiple eggs, and therefore multiple embryos, increase the number of embryos available for transfer and ultimately, the probability of conception.

The medications required to boost egg production may include, but not limited to the following: Lupron (a Gonadotropin Releasing Hormone-agonist), Follistim, Repronex or Gonal-F (FSH, or follicle stimulating hormone), Humegon (combination of FSH and LH or luteinizing hormone), and Pregnyl or Profasi (hCG, human chorionic gonadotropin). Each is administered by injection only. Lupron, Follistim, Repronex and Gonal-F are given subcutaneously (beneath the skin), and the others are intramuscular injections (into the muscle). Risks associated with injectable fertility medications include tenderness, infection, and hematoma, swelling or bruising at the injection site.

Risks associated with the medications include: allergic reactions, hyperstimulation of the ovaries (mild, moderate, or severe), failure of the ovary to respond, and cancellation of the treatment cycle.

There are situations that can occur during a stimulation that may result in cancellation of your IVF cycle and stopping treatment for a period of time. This occurs because the ovary produces either too many or too few eggs in response to drug stimulation protocol. Although we realize that this can be a big disappointment, at times it is necessary to discontinue administering the medications to avoid the possibility of complications and to afford you the best chance of success. If canceling the cycle becomes necessary, you will be told to stop your injections. No hCG injection will be given and no egg retrieval will occur. You will be asked to schedule an appointment with your physician to make decisions for future treatment cycles.

When ovulation induction medications are used in fertility therapy, the ovaries are coaxed to produce more than one egg to the point of maturity. Consequently, hormone levels of estrogen and progesterone reach much higher than normal values. When the estrogen level becomes mildly to moderately elevated, side effects that may be experienced include: fluid retention with slight, transient weight gain, nausea, diarrhea, pelvic discomfort due to enlarged, cystic ovaries, breast tenderness, mood swings, headache, and fatigue.

If the estrogen level rises excessively and hCG is administered to trigger final maturation of the eggs and ovulation, the following more serious complications may result from severe ovarian hyperstimulation syndrome:

	excessive fluid retention with fluid in the abdomen and/or chest cavity
	thrombosis of arteries and/or veins (formation of blood clots) which may lead to stroke, embolus, or potentially fatal complications
	excessively enlarged ovaries which have the possibility of rupturing or twisting (a surgical emergency)
	Any of these three problems may require prolonged hospitalization.

Because of the potential for these severe complications, it is important that we carefully monitor your response to these medications. This monitoring also allows your physician to determine when the eggs are ready for the next stage, oocyte (egg) retrieval. Monitoring includes frequent blood drawing for estradiol (estrogen) and possibly progesterone, LH and FSH levels. These blood tests will take place over approximately a 12 day period. Risks associated with blood drawing include:

	pain at the site of needle stick
	tenderness or infection of the skin
	bruising or scarring of the site of blood draw
	development of a blood clot in the vein (thrombosis, thrombophlebitis)

The second portion of the monitoring phase in IVF involves the use of intravaginal ultrasound to track follicular growth. The eggs develop inside fluid-filled cysts of the ovaries called follicles, which enlarge as the eggs mature. Ultrasound studies usually begin after an estrogen response has been measured and continue on a frequent basis until oocyte (egg) retrieval. The ultrasound studies are performed using a vaginal probe. Vaginal sonograms carry no appreciable risk but may cause slight discomfort, particularly as you near the point of ovulation.

Ovarian stimulation with the fertility medications causes multiple follicles to develop. This is desirable in IVF because as the number of eggs increases, the chance for success increases; multiple embryos can also increase the risk of multiple pregnancy. Approximately 20-25% of pregnancies with IVF will be multiple. Most of these will be twins but triplets, quadruplets or even greater multiple pregnancy can occur. A procedure called "selective reduction of pregnancy" has been performed in several medical centers across the country in selected cases of triplets or more. Selective reduction is not offered on site or by GRS staff. More information on this procedure is available upon request from other centers.

A possible association between the use of fertility drugs and an increased risk of developing ovarian cancer has been raised by some investigators. The exact risk, if any, is unknown at this time due to the problems associated with conducting such studies. The Food and Drug Administration, as well as other national agencies and medical organizations, do not advocate a change in prescribing these fertility drugs at this time.

Retrieving the oocytes (egg retrieval)

For IVF, collection of eggs is usually performed under transvaginal ultrasound guidance. To accomplish this, a needle is inserted (under IV sedation) through the vaginal wall into the ovaries using ultrasound to locate each follicle. The follicular fluid is drawn up into a test tube to obtain the eggs. Although patients are given pain medications intravenously and are carefully monitored by an anesthesiologist, some women may experience some discomfort during the procedure. Generally, the oocyte (egg) retrieval takes 30-45 minutes. Patients are usually discharged home within a couple of hours after the retrieval. Risks of oocyte (egg) retrieval include:

potential reactions from the drugs and procedures used in the administration of anesthesia are rare.

risks associated with the passage of the needle through the vagina into the ovaries, including infection, bleeding, inadvertent damage toadjacent structures including but not limited to: the bowel, bladder, blood vessels, ureter, uterus or ovary(ies), and adhesion formation (internal scarring) following the procedure. Although uncommon, significant bleeding or damage to bowel may occur, and surgery may be required to repair such damage. This is a very uncommon event. Rarely, infection may become severe enough to require hysterectomy and/or removal of one or both ovaries.

Collecting and preparing the sperm

A semen sample will be obtained from the partner by masturbation on the day of the oocyte (egg) retrieval. This is usually obtained while the retrieval is being performed. Abstinence from ejaculation for two to four days prior to providing this semen specimen is recommended. After he specimen is produced, the sperm will be prepared for inseminating the collected eggs in our laboratory. A second sample of fresh semen may be needed the day of or the day after egg retrieval to inseminate egg(s) that were not mature or did not initially fertilize. Because this can be a stressful time period for men, the man/partner may be unable to produce a specimen when needed. If a frozen specimen is not available and a fresh ejaculate can not be produced, any eggs collected will be discarded. Men who feel that they may have difficulty producing a semen specimen have the opportunity to have their specimens frozen by our laboratory ahead of time for use in this situation.

Insemination of eggs and embryos culture

Following egg retrieval, the follicular fluid is immediately transferred to the adjacent laboratory for identification of eggs, evaluation, and readied for insemination. In the process of collecting the follicular fluid, many eggs are usually obtained. It is strongly recommended that all of these eggs be inseminated to maximize the number of embryos available for subsequent transfer. Any objection(s) to policy should be stated in writing and attached to the IVF-ET consent form with the expectation that pregnancy success will be reduced. Otherwise, the prepared sperm will be added to each egg and they will be allowed to incubate overnight under controlled laboratory conditions. The next day, each egg is evaluated for evidence of fertilization. However, it is possible that no eggs fertilize. If this happens, the laboratory staff will re-inseminate the eggs or perform intracytoplasmic sperm injection (ICSI) in hopes of obtaining embryos for transfer. If fertilization still does not occur, the eggs will be discarded and the remainder of the procedure will be cancelled. In the case of severe male factor, the couple may be asked to consider the option of using anonymous donor sperm (obtained through a licensed sperm bank for use as a "backup" or secondary sperm source) if it is not possible to obtain sufficient sperm from the partner at the time of fertilization.

The eggs that have fertilized will be allowed to develop for one or more additional days under controlled laboratory conditions before they are placed inside the woman's uterus. Depending upon the couple's wishes, some fertilized eggs or embryos may be frozen and stored for future use.

After the embryos are transferred to the womb, the woman will continue progesterone supplementation that begins on the evening of your egg retrieval procedure. Progesterone can be taken as a combination of oral troches and rectal/vaginal suppositories or by injections. Administration of these medications after egg collection has been shown to create a more favorable uterine environment for the embryos, which therefore increases pregnancy rates. Side effects of progesterone include:

	vaginal dryness
	bloating, breast tenderness
	depression, mood swings
	delay of menses

Synthetic progesterone-like medications have been associated with certain birth defects. By using only natural progesterone, the risk of drug-induced birth defects are significantly reduced. It is important to note, however, that birth defects occur in approximately 3 % of spontaneously conceived pregnancies in the USA. Therefore, use of natural progesterone does not guarantee a child without a birth defect.

Transferring embryos to the uterus

Embryos are transferred to the uterus through a small tube, or catheter. This procedure is much like a pap smear and does not require any anesthesia and is usually painless. The embryos are placed in a small amount of fluid inside the catheter, which is passed through the cervix at the time of a speculum examination. The embryos are placed in a manner so they reach the top part of the uterus. The number of embryos transferred depends on individual circumstances of the couple and this decision will be made collectively by you, your physicians and the embryologist, two to four embryos may be transferred in one treatment cycle.

Embryo transfer can cause mild cramping. Although unlikely, during the embryo transfer the embryo(s) may be displaced through the cervix (causing loss of embryos) or into the fallopian tubes (causing possible tubal pregnancy). There is a small risk of bleeding or infection as a result of the transfer procedure.

After transfer, the woman may get dressed and leave after a brief rest. A pregnancy test will be done 12-14 days after the transfer regardless of whether you have had any uterine bleeding.

The transfer of several embryos increases the probability of success. If you do not make arrangements for embryo transfer at the time recommended, your chances for pregnancy could decrease. Multiple embryo transfer also increases the risk of multiple pregnancy. Approximately 20-25 % of pregnancies with IVF will be a multiple pregnancy. Most of these will be twins. Triplets, quadruplets or even greater multiple pregnancy can occur. Any multiple pregnancy carries an increase risk of miscarriage(s), premature labor and premature birth as well as an increased financial and emotional cost. Pregnancy-induced high blood pressure and diabetes are more common in women pregnant with more than one fetus. Prolonged hospitalization may be necessary for these pregnant women, and for the mother and babies after delivery. In the event of multiple pregnancies, the option of selective reduction will be reviewed with the couple. Tubal (ectopic) pregnancy is also possible, and a combination of normal pregnancy and ectopic pregnancy may occur. A tubal pregnancy is a condition that may require laparoscopy or major surgery for treatment. Like spontaneous (natural) conceptions, pregnancies that arise through IVF may result in miscarriage. In the event of a miscarriage, a dilatation and curettage (D&C) may be necessary.

Couples going through therapy must choose and formalize their choice in the appropriate GRS consent form one of the following options for handling of any remaining embryos:

Freezing (cryopreservation) of remaining embryos for use by the couple in future treatment cycles. This option requires an additional charge.

Anonymously donating the embryos for use by another infertile couple(s), if the donating couple and the donated embryos meet the screening criteria. You will not receive any money for this donation. Nor will GRS "sell" them. GRS reserves the right to cryopreserve (freeze) any donated embryos as well as the right to discard any donated embryos if a suitable woman cannot be identified to receive the embryos.

Allowing the embryos to develop in the laboratory until they perish, at which time they would be disposed of in a manner consistent with professional ethical standards and applicable legal requirements. This usually occurs within 10 days after egg collection.

Other issues

Any assisted reproduction process or technique can be psychologically stressful. Significant anxiety and disappointment may occur. We encourage you to consider short-term supportive counseling during this time and will provide you with a list of psychiatrists, psychologists, counselors and social workers who may help you through this difficult time.

A substantial time commitment is required by both partners to complete an entire course of IVF therapy. It will be necessary for couples to adjust their schedules to undergo the required testing and therapies associated with IVF-ET. It is the responsibility of the woman to report to our office as scheduled for repeated ultrasound examinations and blood tests over several days or weeks before and after the expected time of egg collection. It is the responsibility of the man to be available at the time identified by the physician to provide sperm.

Theoretical concerns & potential for success:

Unfortunately, neither conception nor successful outcome of pregnancy is guaranteed by the IVF-ET procedure. There are many reasons why pregnancy may not occur with the IVF-ET procedure. In fact, there are complex and largely unknown factors, which limit pregnancy rates following assisted reproductive techniques. Some of the known reasons for failure include, but are not limited to:

There may be a failure to recover an egg because:

	Follicles that contain mature eggs may not develop in the treatment cycle
	Ovulation has occurred before time of egg recovery
	One or more eggs cannot be recovered
	Pre-existing pelvic scarring and/or technical difficulties prevent safe egg recovery
	The eggs that are recovered may not be normal
	There may be insufficient semen to attempt fertilization of the recovered eggs because the man is unable to produce a semen specimen, because the specimen contains an insufficient number of sperm to attempt fertilization or because the laboratory is unable to adequately process the specimen provided, or because the option to use a donor sperm as a "back-up" was declined.
	Fertilization of the eggs to form embryos may fail even when the egg(s) and sperm are normal
	The embryos may not develop normally or may not develop at all. Embryos, which display any abnormal development, will not be transferred.
	Embryo transfer into the uterus may be difficult/impossible or implantation(s) may not occur after transfer, or the embryo(s) may not grow or develop normally after implantation.
	Any step in the IVF-ET process may be complicated by unforeseen events, such as hazardous or catastrophic weather, equipment failure, laboratory conditions, infection, human error and the like.
	In the event the couple should die before embryo transfer, the embryo(s) will be discarded unless other provisions are made in writing.

When pregnancy occurs following IVF, usually it will be a normal pregnancy. However, there is always a risk of abnormal pregnancy, miscarriage, blighted ovum, ectopic pregnancy or premature delivery. This is because the process of IVF-ET does not protect against such normal occurrences. Congenital abnormalities, genetic abnormalities, mental retardation or other birth defects which occur in approximately 3 % of spontaneously-conceived pregnancies may still occur in children born following assisted reproductive techniques. A large review of a subset of children born following assisted reproductive procedures found the incidence of developmental anomalies similar to a control group of children spontaneously conceived. Women with multiple pregnancies have a much higher risk of complicated pregnancies, including the following: toxemia, pre-eclampsia, miscarriage, premature labor and delivery, stillbirth, cerebral palsy in the babies, birth defects, and other complications.

Alternatives to IVF-ET:

Depending upon the individual and unique cause(s) of infertility for each couple, conception through alternative means other than IVF-ET may or may not exist. Possible success rates of these alternatives may vary depending upon the type and severity of the cause of the infertility. For some couples, it may even be possible to conceive spontaneously without a physician's help. You should discuss these alternative treatment methods with your physician before you proceed with IVF-ET therapy.

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