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IVF and GIFT

INTRODUCTION

The birth of Louise Brown through in vitro fertilization (IVF) in 1978 dramatically increased public awareness of clinical alternatives for infertile couples. Today, new techniques for assisted reproduction are evolving rapidly.

This section will help couples understand assisted reproductive technologies such as IVF and gamete intrafallopian transfer (GIFT) that have become accepted medical treatments for infertility. For many couples who have exhausted traditional clinical and surgical treatments for infertility, these technologies may offer the best hope for pregnancy. Through these procedures, many couples with otherwise untreatable infertility have given birth to healthy babies.

IN VITRO FERTILIZATION (IVF)

“In vitro” literally means outside of the body. IVF is a method of assisted reproduction in which the man’s sperm and the woman’s egg are combined outside of the body in a laboratory dish. If fertilization occurs, the resulting embryo is transferred to the woman’s uterus, where it will hopefully implant in the uterine lining and mature. IVF is a reasonable treatment choice for couples with various types of infertility. Initially, it was used only when the woman had blocked, damaged, or absent fallopian tubes (tubal factor infertility). IVF is now also used to treat infertility caused by endometriosis, malefactor, immunologic factors, or unexplained infertility. The basic steps in an IVF treatment cycle are ovulation induction, egg retrieval. insemination, fertilization, embryo culture, and embryo transfer.

THE BASIC STEPS OF IVF

Ovulation Induction

During ovulation induction, ovulation drugs, also known as “fertility drugs,” are used to stimulate the ovaries to produce several mature eggs rather than the single egg that normally develops each month. IVF specialists agree that the chances for pregnancy are better if more than one egg is fertilized and transferred to the uterus in a treatment cycle.

Drug type and dosage vary depending on the program and the patient. Most often ovulation drugs are given over a period of seven to 10 days. Ovulation drugs currently in use include clomiphene citrate (Clomid®, Serophene®), human menopausal gonadotropin (hMG) (Humegon™, Pergonal®), follicle stimulating hormone (FSH) (Metrodin®), human chorionic gonadotropin (hCG) (A.PL. ®, Pregnyl””, and Profasi®),
bromocriptine (Parlodel®), and gonadotropin releasing hormone (GnRH) (Factrel® and Lutrepulse®). Sometimes GnRH analogs, such as leuprolide acetate (Lupron®). nafarelin acetate (Synarel®), or goserelin acetate (Zoladex®), are used to suppress normal ovarian function in order to better control ovulation induction.

These drugs may be used alone or in combination with others. Clomiphene citrate is administered orally while most of the other medications are given by injection. The physician can explain how each drug works and its possible side effects.

Timing is crucial in an IVF cycle. The ovaries are scanned frequently with ultrasound to monitor the development of ovarian follicles, the fluid-filled cysts within the ovaries where the oocytes (eggs) grow. Blood samples are drawn to measure the serum levels of estrogen, progesterone, and/or luteneizing hormone (LH). Normally, estrogen production increases as the follicles develop. A surge of LH triggers ovulation, and progesterone levels remain low until after ovulation.

Through the use of ultrasound and blood tests, the physician can determine when the follicles are almost mature. This usually takes place about a day and a half before ovulation would normally occur. The patient is then given an injection of hCG. The hCG replaces the woman’s natural LH surge that would normally trigger ovulation in approximately 36 hours. This allows the IVF team to determine the appropriate time for egg retrieval.

Ovulation occurs spontaneously during some treatment cycles, despite the use of drugs. When a spontaneous ovulation occurs, the eggs may be lost in the pelvic cavity, and the cycle must be canceled. In some cases, however, a spontaneous LH surge will be monitored using blood and urine tests and the physician may decide to retrieve the eggs earlier than originally scheduled.

In the United States in 1993, 14 percent of IVF treatment cycles were canceled before retrieval and 23.5 percent were canceled before transfer. Those women whose cycles were canceled had either responded poorly to ovulation drugs or had premature ovulation. In an attempt to decrease cancellation rates, many programs administer a GnRH analog in addition to the other drugs. GnRH analogs are synthetic and modified forms of natural GnRH. Treatment with GnRH analogs prevents the release of LH and FSH from the pituitary gland, and thereby prevents premature ovulation. Cancellation rates as low as 10 percent have been achieved in some IVF programs using GnRH analogs in combination with other drugs during ovulation induction.

Egg Retrieval

Egg (oocyte) retrieval is accomplished by one or two methods. The first, transvaginal ultrasound aspiration, is a minor surgical procedure that can be performed in the physician’s office or outpatient surgical center with the use of painkilling medications. The ultrasound probe is inserted through the vagina (Figure 1). The probe emits high-frequency sound waves which are translated into images of the pelvic organs shown on a monitor screen. When mature follicles are identified in the ovaries, the specialist guides a needle through the vagina and into the follicles. The eggs are removed (aspirated) from the follicles through the needle by a suction device.

An infrequently used method of egg retrieval for IVF is by laparoscopy. Laparoscopy is a surgical procedure usually requiring general anesthesia. In the operating room, a surgeon inserts a laparoscope, a long, thin tube much like a telescope, through an incision in or below the woman’s navel. Looking through the laparoscope, the surgeon guides the needle through the abdominal wall into the ovarian follicles. The eggs and follicular fluid are then aspirated through the laparoscope.

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Figure 1 : Egg retrieval is usually performed through the vagina with an ultrasound guided needle.

Insemination, Fertilization, and Embryo Culture

Once the eggs are retrieved, they are examined in the laboratory and each one is graded for maturity. The maturity of an egg determines when the sperm will be added to it (insemination). Insemination can be performed immediately after the eggs are collected, after several hours, or on the following day. On the day the woman’s eggs are retrieved, the male collects his semen by masturbation. In the laboratory, the sperm are separated from the seminal plasma in a process known as sperm washing. Several different sperm washing procedures can be used in order to separate the most motile sperm in a sample from other non-motile, dead sperm. These motile sperm are placed together with each retrieved egg in a separate laboratory dish containing an IVF culture medium. The dishes are placed in an incubator set at the same temperature as the woman’s body.

In cases where very few sperm are available or a severe male factor is present, the chance of fertilization can be increased in the IVF laboratory using specialized techniques such as micromanipulation. There are several micromanipulation techniques that are used to assist the sperm in passing through the zona pellucida, or outer shell of the egg, to facilitate fertilization. With partial zona dissection (PZD), a slit can be cut in the zona with a small needle so that sperm can more easily reach the egg. With subzonal sperm injection (SUZI), several sperm can be placed underneath the zona to achieve fertilization. With intracytoplasmic sperm injection (ICSI), a single sperm can be injected directly into the egg in an attempt to achieve fertilization. With microinsemination, the sperm are concentrated into a small drop around the eggs to help increase the chance of fertilization. These micromanipulation techniques are new methods that may not be offered in every IVF program. The success of these procedures depends upon semen characteristics and the program’s experience. After micromanipulation, it takes about 16 to 18 hours for fertilization to be completed. About 12 hours after fertilization, the fertilized egg (embryo) divides into two cells. The embryo may divide several times while in the incubator. After 44 to 72 hours, the two to eight-cell embryos are ready to be transferred into the woman’s uterus.

Another new technique, assisted hatching, is sometimes helpful for women who have undergone IVF previously and have not conceived, or for older women undergoing IVF. Assisted hatching is a technique performed after fertilization in which the zona pellucida is thinned or interrupted either chemically or mechanically or with laser beam to facilitate the release of the embryo from the zona. Assisted hatching may, in some cases, improve embryo implantation in the uterus.

Embryo Transfer

The next step in the IVF process is performed on an outpatient basis. No anesthesia is necessary, although some women may wish to have a mild sedative. The woman lies on her back or in the knee-chest position. Using a vaginal speculum, the physician exposes the cervix. One or more embryos suspended in a drop of culture medium are drawn into a transfer catheter, a long, thin sterile tube with a syringe on one end. Gently, the physician guides the tip of the loaded catheter through the cervix and deposits the fluid containing the embryos into the uterine cavity (Figure 2). One or more embryos may be transferred during the procedure. The entire transfer procedure usually takes between 10 and 20 minutes. Some physicians recommend bed rest after the transfer. Extra embryos may be cryopreserved (frozen) with the intent of thawing and transferring them at a later date. The physician and couple make the decision to use cryopreservation in advance of the embryo transfer.

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Figure 2: Embryo transfer is performed through the cervix.

Pregnancy Rates

Among all women undergoing IVF, the rate of pregnancies resulting in a live birth was approximately 20-35% percent per egg retrieval. The pregnancy rate varies from program to program, and occasionally varies even within the same program. At present there is no single accepted national standard for computing pregnancy rates. For guidelines on interpreting the pregnancy and live birth rates cited by a particular clinic.

GIFT

GIFT stands for gamete intrafallopian transfer. A gamete is a male or female reproductive cell (a sperm or an egg). During GIFT, sperm and eggs are mixed and injected (transferred) into one or both fallopian tubes. Fertilization can then take place in the fallopian tube as it does in natural, unassisted reproduction. Once fertilized, the embryo travels to the uterus by natural processes. As in IVF, a GIFT treatment cycle begins with ovulation induction, but the similarity to IVF ends here. In IVF, eggs are generally retrieved transvaginally, mixed with sperm in a laboratory dish, and the resulting embryos are transferred to the uterus about two to three days later. In GIFT, eggs are retrieved using a laparoscope, and both sperm and eggs are transferred to the fallopian tube(s) during the same laparoscopic procedure.

Women with normal, healthy fallopian tubes are candidates for GIFT, including women who have unexplained infertility or mild endometriosis, and couples whose infertility is caused by male, cervical, or immunological factors. Some physicians recommend that couples with male factor infertility proceed with GIFT only if it has been proven either by IVF or by past pregnancies that the man’s sperm can fertilize the woman’s egg. The extra eggs and sperm not placed in the fallopian tubes during a GIFT cycle may be fertilized in vitro and frozen for transfer at a later date.

The basic steps of GIFT are ovulation induction, egg retrieval, insemination, and gamete transfer. The eggs are usually retrieved during laparoscopy. The retrieved eggs are examined under the microscope and graded for maturity, the selected eggs are then placed in individual dishes and combined with sperm (insemination).

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Figure 3 : In GIFT , eggs are retrieved from the ovaries and mixed with sperm. The sperm –egg mixture is loaded into a catheter and injected directly into the fallopian tube(s).

The sperm are prepared in advance in the same manner as for IVF. Some physicians prefer to allow the eggs and sperm to sit in the dish for about 10 minutes before performing the transfer, since during this period the sperm adhere to the zona pellucida (outer shell) of each egg. For the gamete transfer, the sperm-egg mixture is loaded into a catheter and injected directly into the fallopian tube(s) using the laparoscope (Figure 3).

Usually two eggs are transferred in GIFT. The number of eggs transferred may be increased in women older than 35 years of age without enhancing the chance of multiple pregnancies. Gametes will be transferred only if the fallopian tubes appear healthy. If the physician determines that the tubes are unhealthy, IVF may be recommended instead. For this reason, GIFT should be undertaken only at facilities that have the capability to perform IVF.

Pregnancy Rates with GIFT

Pregnancy rates are five to ten percent higher for GIFT than for IVF. In part, this may be due to the type of patient accepted into GIFT programs, since GIFT is most often recommended for couples with unexplained infertility or minimal endometriosis.

GIFT AND IVF COMPARED

There are several differences between GIFT and IVF. The most important one is that GIFT requires healthy fallopian tubes, whereas IVF is appropriate for women with tubal disease or even absent fallopian tubes. Eggs are retrieved differently in IVF and GIFT In IVF, eggs are usually retrieved using transvaginal ultrasound aspiration. In GIFT, eggs are retrieved laparoscopically, because the gametes will be transferred through the same laparoscopic procedure. Other GIFT techniques, still in experimental stages, are being developed to transfer gametes into the fallopian tubes without laparoscopy. In IVF, the fertilized eggs are transferred through the vagina into the uterus. Laparoscopy is not necessary for embryo transfer during IVF.

With GIFT fertilization is not confirmed. With IVF, fertilization takes place in a laboratory dish and can be visually confirmed. This is important in cases of male factor or unexplained infertility.

VARIATIONS OF IVF/GIFT

When exploring assisted reproductive technologies, you may encounter procedures with names like ZIFT, PROST, and TET. These techniques differ from GIFT in that fertilization takes place in a laboratory dish instead of the fallopian tube. Confirmation of fertilization is especially helpful when infertility may be due to a male factor, such as the inability of sperm to penetrate the egg. These procedures differ from IVF because the fertilized egg is transferred to the fallopian tube rather than to the uterus. Zygote intrafallpian transfer (ZIFT) is also called PROST, which stands for pronuclear stage transfer. A zygote is a fertilized egg before cell division begins. In ZIFT, eggs are retrieved by transvaginal ultrasound aspiration and fertilized in a laboratory dish. The next day, before the fertilized eggs begin cell division, they are transferred to the fallopian tubes during laparoscopy.

Tubul embryo transfer (TET) involves the transfer of a more developed embryo. In TET, a fertilized egg that has reached the four to eight-cell stage is transferred into the fallopian tube. This usually takes place about 24 hours after fertilization. One reason for using ZIFT or TET rather than GIFT is that these procedures allow physicians to determine whether or not the sperm is capable of fertilizing the egg. Another reason to consider using ZIFT or TET over IVF is often based on the experience and results of a particular program. Physicians also recommend ZIFT versus GIFT if the woman’s egg quality is poor (for example, if she has polycystic ovaries) and might, in turn, jeopardize the chance of fertilization. Also. patients who have had a previous GIFT failure may benefit from ZIFT or TET. The cost of ZIFT, PROST, or TET is usually greater than IVF or GIFT because additional procedures are needed.

DONOR SPERM AND EGGS

Couples with no sperm and/or no eggs can undergo IVF and GIFT using donor sperm or eggs. Using a donor is a personal decision based on the couple’s beliefs and the degree of their desire for a child with a biological connection to one parent. Donor sperm have been used for more than two hundred years to achieve pregnancy in couples with few or no sperm. Today, frozen (cryopreserved) sperm are used almost exclusively for donor insemination. Donor sperm is used only after extensive medical and genetic screening of the donor. For IVF, cryopreserved sperm are processed in the same way as fresh sperm. In some cases of male infertility, fertilization may be attempted first with the husband’s sperm, and if this fails, donor sperm may be used in a second attempt. Alternatively, if several eggs are retrieved, some may be inseminated with the partner’s sperm and some with donor sperm.

Donor eggs can be used in GIFT or IVF to impregnate an infertile woman who has no ovaries but does have a healthy uterus. For GIFT, the woman must also have at least one functional fallopian tube. In GIFT, the donor’s eggs are mixed with sperm from the infertile woman’s partner. This mixture is injected into the infertile woman’s fallopian tubes. For IVF, an embryo resulting from the fertilization of a donor egg and the male partner’s sperm is placed inside the infertile woman’s uterus. For both GIFT and IVF with donor eggs, hormone supplements prepare the uterus and aid in the initiation of pregnancy. In both cases the embryo inherits genetic characteristics from the husband and the donor, although the infertile woman carries the fetus.

The egg donor has to undergo ovulation induction and egg retrieval before the 1VF or GIFT procedure. Egg donation carries more risk and inconvenience to the donor than does the sperm donation. Egg donors undergo the same medical and genetic screening as do sperm donors.

A couple may also choose to use donor eggs if the woman has a genetic disease that could be passed on to a child, long standing-infertility when other procedures have failed, or if she is no longer producing healthy eggs. In some cases, when both the man and woman are are infertile, both donor sperm and donor eggs have been used. In some IVF programs, embryos which were cryopreserved by infertile couples who conceived with 1VF and do not desire additional children may be donated to infertile couples.

Considering the use of donor eggs or donor sperm is a complicated issue which has life-long implications. It is important for the couple to grieve the loss of a biological child before they decide to proceed with a donor. Talking with a trained counselor who understands donor issues can be very helpful in the decision making process. Many programs have a mental health professional on staff, or the physician may recommend one” If the couple knows the egg and/or sperm donor, their physician may suggest that both the couple and the donor speak with a counselor and an attorney.

SURROGACY/GESTATIONAL CARRIER

An embryo may be carried by the egg donor (surrogate) or by another woman (gestational carrier}. If the embryo is to be carried by the egg donor, pregnancy may be achieved through insemination alone, or through IVF or GIFT. If the embryo is to be carried by a gestational earner, the eggs are removed from the infertile woman, fertilized with her partner’s sperm using 1VF, and the resulting embryo is placed into the gestational carrier’s uterus. When using a surrogate or gestational carrier, all parties benefit from psychological and legal counseling before persuing this option.

RISKS OF IVF/GIFT

As with all procedures, the medical risks of any form of assisted reproductive technology depend upon each specific step of the procedure. The following are some of the primary risks of 1VF and GIFT.

Ovulation induction carries with it a risk of hyperstimulation syndrome, where the ovaries become swollen and painful. Fluid may accumulate in the abdominal cavity and chest, and the patient may feel bloated, nauseated, and experience vomiting or lack of appetite. About 10 percent of patients undergoing ovulation induction will have a mild case of hyperstimulation syndrome. Of these, less than two percent have a case severe enough to require hospitalization. The condition tends to resolve itself without intervention unless pregnancy occurs, in which case recovery may be delayed. In 1VF and GIFT, hyperstimulation syndrome occurs less frequently probably because the follicles are emptied of fluid during the egg retrieval procedure.

A recent study suggested that women who use ovulation drugs such as clomiphene citrate and hMG may be at increased risk for ovarian cancer. It is not currently known if a risk exists, but this study shows that more research is needed to determine if there is a causal relationship between the use of ovulation drugs and ovarian cancer. If a risk does exist, it is not known whether the risk is due to being infertile and anovulatory or to not conceiving, or if the risk is limited to a certain class of drugs, to a certain duration of use, or to the amount of use. This ill-defined suggested risk must be weighed against the risk of not being treated and not conceiving. Pregnancy and childbirth have always been associated with clear-cut medical risks, but most women willingly assume these risks because of their desire to have a child. Patients should discuss this topic with their physician in order to get an up-to-date perspective.

Other possible risks are related to the egg retrieval procedure. Laparoscopy carries with it the risks of any surgery requiring anesthesia. Removing eggs through an aspirating needle entails a slight risk of bleeding, infection, and damage to the bowel, bladder, or a blood vessel. This is true whether the physician uses laparoscopy or ultrasound to guide the needle. Approximately one patient in 1,000 will require major surgery to repair damage from complications of the egg retrieval procedure. In rare cases, the uterus may be perforated during embryo transfer or an infection may occur after the embryo has been transferred.

In all assisted reproductive technologies, the chance of multiple pregnancy is increased when more than one egg or embryo is transferred. Although some couples would consider twins a happy result, there are many problems associated with multiple births, and problems become progressively more severe and common with triplets and each additional fetus thereafter. Women carrying a multiple pregnancy may need to spend weeks or even months in bed or in the hospital. There is also a greater risk of late miscarriages or premature delivery in multiple pregnancies. Premature babies require prolonged and intensive care. In addition, there is approximately a 5 percent chance of ectopic pregnancy with IVF and GIFT. Another commonly seen problem with all pregnancies is miscarriage, which occurs about 20 to 25 percent of the time.

Another risk is first trimester bleeding which may signal a possible miscarriage or ectopic pregnancy. If bleeding occurs, an appropriate medical evaluation will be needed to determine the cause. Some evidence suggests that early bleeding is more common in women who undergo IVF and GIFT and is not associated with the same poor prognosis as it is in women who conceive spontaneously.

Assisted reproductive technologies also entail psychological risks. Couples undergoing IVF and GIFT have described the experience as an emotional roller coaster. The treatments are lengthy, involved, and costly. These procedures often create high expectations but are more likely to fail than to succeed in a given cycle.

The unsuccessful couples will feel frustrated in their quest for pregnancy. It is common to feel angry, isolated, and resentful toward both the spouse and the medical team. At times, this feeling of frustration leads to depression and feelings of low self-esteem, especially in the immediate period following a failed IVF or GIFT attempt. The support of friends and family members is very important at this time. Some couples may want to consider psychological counseling as an additional means of support. Many programs have a mental health professional on staff to help couples deal with the grief, tension, or anxieties associated with infertility and its treatment.

WHEN TO END TREATMENT

Studies indicate that the chance for pregnancy in consecutive IVF cycles remains similar in up to four cycles. Many other factors, however, should be considered when determining the appropriate endpoint in therapy, including financial and psychological reserves. Members of the IVF team can help couples decide when to terminate treatment and discuss other options, such as adoption, if appropriate. The physician, support groups, and other couples undergoing infertility treatment can provide valuable support and guidance.

CONCLUSION

The decision to seek treatment for infertility is a viable one thanks to the assisted reproductive technologies available today. With patience, a positive attitude, and the appropriate treatment, many infertile couples can eventually experience the joys of parenthood