$Unique_ID{PAR00460} $Pretitle{} $Title{Fertility: IVF and its "Cousins"} $Subtitle{} $Author{ Berger, Gary S Goldstein, Marc Fuerst, Mark} $Subject{IVF test-tube in vitro fertilization superovulation hormones eggs sperm chemical clinical pregnancies pregnancy rate dropped cycles freezing egg donor eggs donors Ovulation Induction Pergonal clomiphene citrate pure follicle stimulating hormone FSH Metrodin human chorionic gonadotropin hCG estradiol ovarian follicles luteal phase GnRH agonists leuprolide acetate Lupron Metrodin Egg Retrieval laparoscopic laparoscopy Semen Collection sample Fertilization polyspermy Embryo Transfer Freezing Frozen embryos Post-Embryo Transfer Cancellation Cycle Age Factor Gamete Intra Fallopian Transfer GIFT Zygote ZIFT Intravaginal Culture IVC Ultrasound} $Log{} The Couple's Guide to Fertility CHAPTER 10: IVF AND ITS "COUSINS" When Miriam and Roberto married six years ago, they wanted above all else to have a baby. They were heartbroken when they found out it wasn't going to be easy. Miriam, a thirty-five-year-old policewoman, had conceived while taking Pergonal, but the pregnancy was ectopic. The diagnosis did not come until after the fallopian tube ruptured, causing internal bleeding that required emergency surgery. By that time, the fallopian tube was severely damaged. With more fertility drugs, she conceived again and had another ectopic pregnancy. To avoid yet another ectopic pregnancy, Miriam had her remaining tube sealed off completely. With her ovaries still functioning, but no healthy fallopian tube, Miriam became an ideal candidate for in vitro fertilization. She again took Pergonal to stimulate her ovaries, and had three eggs retrieved and fertilized with Roberto's sperm. When her pregnancy test was positive, Miriam says, "We were ecstatic, overwhelmed." She went back to work as a detective, but took a leave of absence shortly afterward. Nine months later, with Roberto present, she gave birth to their son Omar. "I was happy to hear him cry so loud," says Roberto, a thirty-nine-year-old teacher. "I was happy but at the same time relieved that we had finished the whole thing." Some day, Miriam and Roberto plan to tell their son the miraculous story of how he was conceived. "We plan to show him the pictures taken through the microscope only forty-eight hours after the eggs were retrieved, and the ultrasound pictures taken at twenty-one days and at about fifteen weeks from the transfer into the uterus," says Roberto. "We will tell him exactly what happened, about the whole exciting process of seeing his total development." Somewhere in the world, a "test-tube" baby is born every day. The miracle of babies born through in vitro fertilization (IVF) no longer seems so miraculous. In fact, fertilization outside the human body is now available throughout the Western world. In North America, about two hundred centers perform IVF, and the best report pregnancy rates of 15 to 20 percent per cycle after embryo transfer. That's not too far off the 20 to 25 percent chance of natural pregnancy in any given month under ideal conditions. What Is In Vitro Fertilization? Simply stated, IVF involves removing eggs from a woman, fertilizing them in the laboratory (in a culture dish, actually, not a test tube) and then transferring the fertilized eggs, or "pre-embryos," into the uterus a few days later. More specifically, after superovulation with hormones to produce multiple eggs, the IVF team places the retrieved eggs in sterile culture media along with washed sperm and keeps them at normal body temperature inside an incubator, where fertilization and early cell division take place. Then the team returns the pre-embryos to the uterus. From that point, if the embryos implant successfully, the pregnancy progresses as it would naturally. What to Look For in an IVF Clinic There are about two hundred IVF clinics in the United States and Canada, and finding the right one for you is just as important as your search for the right fertility specialist. Inquire about the program's patient selection process, including any age limitations and the types of infertility patients it accepts. Most programs won't accept a woman over the age of forty. You should know the number of cycles the clinic is performing each week and how soon you can be seen. Waiting can be one year or longer in the busiest centers. Ask straightforwardly about your chances of achieving a pregnancy at that clinic. How does this compare with your chances at other IVF centers? How does it compare with that of other couples with similar diagnoses at that particular clinic? When you ask about the pregnancy rate, you should be aware that various IVF centers report results in different ways. Some include in their pregnancy rates both "chemical" pregnancies and "clinical" pregnancies. Chemical pregnancy refers to a rise in hCG levels about ten to fourteen days after hCG administration, but many chemical pregnancies never make it to the more advanced stage at which the pregnancy can be seen with an ultrasound exam of the uterus. The clinical pregnancy rate is a more important statistic. A clinical pregnancy continues at least until it can be documented with an ultrasound exam showing the presence of a fetus. But even pregnancies that reach this stage can miscarry, and--as after natural conception--up to one-third of all clinical pregnancies established through IVF don't progress to a live birth. By far the most important statistic you want is the clinic's live birth rate. The live birth rate should be calculated by taking into account all of the couples who have had treatment there over a specified length of time. Ask what your chances are of taking home a baby, based on the clinic's past experience. The method of calculating the pregnancy rate varies from one clinic to the next. A program may report its pregnancy rate per patient, per cycle, per embryo transfer, per month, per year, or from its inception. Find out how many cycles were done before the clinic had its first pregnancy and what the success rate has been since then. It may also help you evaluate a program to find out the "dropped cycle" rate. A "dropped cycle" means the woman began ovarian stimulation but never got to the stage of attempting egg retrieval. A high rate of dropped cycles (30 percent or more) may reflect a poor ovulation induction technique, or it may just mean that the clinic has stringent criteria before proceeding to egg retrieval. Cost is obviously important. Does your health insurance policy cover any of the costs incurred during the IVF cycle? Many clinics now offer transvaginal ultrasound-guided egg retrieval instead of laparoscopy, which decreases the cost of the egg retrieval of by as much as 20 to 30 percent. Other Options Another way to assess a clinic's suitability for you is to examine the variety of services and support systems it offers. For example, some IVF clinics provide embryo freezing. The clinic may also provide adjuncts to IVF as well, such as egg freezing and embryo or egg donor programs. Embryo freezing--actually freezing and storing fertilized eggs or pre-embryos--allows preservation for transfer in future spontaneous ovulation cycles. This is an advantage if many eggs are retrieved and fertilized, since most centers prefer to transfer back no more than four embryos per IVF cycle due to the increased risk of multiple pregnancy. If the center offers freezing, ask whether any basic research, using animal models, has been performed to assess the viability of the freezing and thawing technique. There should be a clear-cut policy regarding any remaining frozen embryos that are left after a woman becomes pregnant. What happens to them? How long will they be kept in storage? Would you consent for them to be donated to other couples after you have your child? IVF is an exceedingly difficult technique to perform with good results. Launching and maintaining an IVF program is an expensive, time-consuming process. Strict quality-control standards need to be established and met. A team of committed professionals, each with a specialized expertise, is essential. Besides a reproductive surgeon and reproductive endocrinologist, the team will probably include an embryologist, IVF lab technician(s), nurse-coordinator, and a counselor. Familiarize yourself with the qualifications and previous experience of the staff of the program. Its O.K. to ask about their credentials and experience. Patient Education and Support Before you decide to undergo treatment at any clinic, you should understand the entire IVF process, step-by-step, including when drug therapy begins, how often the woman needs blood tests and ultrasound monitoring, and when egg retrieval will likely take place. If you have traveled from out-of-town, the clinic should help arrange for a place for you to stay during the IVF treatment. Also, a doctor in your area should be contacted to assist in follow-up tests after you have returned home following embryo transfer. Your first set of tests may duplicate the general fertility workup--blood tests for both partners to rule out immunological problems and to confirm that the woman is ovulating; a complete physical exam for the woman, including a measurement of her uterine cavity to determine how far to place the embryos into her uterus; and a semen analysis for the man. You should also receive instructions on how to administer the fertility drugs the wife will take to induce multiple egg production. Ovulation Induction "It was odd giving my wife the injections," says Sam, aged forty, a local councilman. He and his wife Jennifer, also forty, had tried to have a baby for nearly four years before they went to see Dr. Goldstein. He found that Sam had a low sperm count, probably due to a varicocele, which was repaired microsurgically. In the meantime, Jennifer's gynecologist could find nothing wrong with her after a fertility workup. Sam's post-op semen analysis showed that his sperm count was still low. He tried clomiphene for three months, but his sperm count did not rise, so he and Jennifer decided to try IVF. At the start of their first IVF cycle, Sam gave Jennifer an injection of Pergonal in the buttock every night for a week. "I thought, "I can't stick a needle in there.' But she said she hardly felt any pain." The goal of any IVF program is to maximize the couple's chances of having a baby. To achieve pregnancy, there must be successful responses to ovulation medication, egg collection, fertilization, embryo replacement, and subsequent implantation. Failures can occur at any step along the way. For example, of thirty women who start ovulation induction, six may have the cycle dropped because of inadequate stimulation. Of the remaining twenty-four women who undergo egg retrieval, only twenty-one may get to the point of embryo transfer, with three having eggs that didn't fertilize and divide. Of the twenty-one who have embryo transfers, only three might achieve a clinical pregnancy if the clinic's pregnancy rate is 15 percent per embryo transfer. One of those three is likely to miscarry, leaving only two couples that may have a live born infant. This means the live birth rate is 2/30 or 7 percent. To maximize a couple's chances of pregnancy, all successful IVF programs use some combination of ovulation inducing agents to make multiple fertilizable eggs available at the time of scheduled egg retrieval. The first attempts at IVF, a concept developed and made successful by the late British gynecologist Dr. Patrick Steptoe and his co-researcher, embryologist Robert Edwards, had little success because only one egg was recovered during a spontaneous ovulation cycle. These unstimulated cycles required the IVF team to detect the very beginning of the woman's LH surge, and then closely monitor her to find the best time to retrieve her egg. Following her spontaneous LH surge, Steptoe and Edwards would often have to perform egg retrievals very late at night or during early morning hours. The success of IVF improved dramatically with the use of superovulation with Pergonal, first advocated by the Norfolk, Virginia, group headed by Drs. Georgianna and Howard Jones. Larger numbers of eggs could be recovered and, the IVF team could better time egg retrieval. Now, the use of superovulation has become routine with IVF. Recently, gonadotropin releasing hormone (GnRH) s have also been introduced prior to beginning controlled ovulation to prevent the woman from having her own spontaneous LH surge so that egg retrieval timing can be strictly controlled and the chance of a "dropped" cycle minimized. Generally, the woman begins taking ovulation inducing drugs between the first and fifth days of her cycle to stimulate the development of multiple follicles. Several eggs are stimulated to develop at the same time so that a group of eggs will be available for fertilization. This "superovulation" is usually accomplished with combinations of the same hormone medications used to stimulate ovulation in other treatment cycles, such as for IUI: clomiphene citrate, Pergonal, pure follicle stimulating hormone (Metrodin), and human chorionic gonadotropin (hCG). Many couples are already familiar with these medications since they may have used them in previous treatment cycles, before ever considering IVF. Usually, a member of the IVF team teaches the husband how to give his wife the daily injections so that she doesn't have to go to the doctor's office for her medication. Although this may be difficult to do at first, it gives the couple some control over their own treatment. There are almost as many individual stimulation regimens as there are IVF programs. Most IVF clinics start providing high doses of hormones, either alone or in combinations, early in a woman's cycle--when more follicles can be recruited to progress and mature. The woman's response to stimulation is carefully monitored by estradiol levels, ultrasound exams, cervical mucus examination and, possibly, progesterone and LH levels to determine how the follicles containing the eggs are developing. Blood hormone levels may be obtained intermittently during the first week of stimulation, then daily, along with ultrasound exams and cervical mucus monitoring, as ovulation approaches. The doctor adjusts the stimulation schedule to maintain a steady growth in the size of ovarian follicles and a steady rise of estradiol levels. When the follicles reach maturity, usually after seven to ten days of medication, an hCG injection is administered to trigger egg maturation in anticipation of egg retrieval from the follicles. At first, most IVF clinics had one standard way to induce ovulation. If a woman's follicles weren't stimulated sufficiently, she had no egg retrieval, and the cycle was canceled. Today most programs individualize ovulation induction, which has reduced IVF cancellation rates. Since some women do better with larger amounts of hormones, and others with lesser amounts, hormone stimulation should be individualized as much as possible. Doctors often determine individual hormone doses based upon the woman's response to previous cycles of hormone therapy or to previous IVF cycles. IVF researchers have learned that high amounts of gonadotropins can often disrupt and shorten a woman's luteal phase, making it difficult for implantation to occur or for her to carry the pregnancy to term. To help support the luteal phase, most IVF teams now provide progesterone daily from the day of egg retrieval until a pregnancy test is performed two weeks later. Others also provide repeated injections of hCG in the luteal phase of the cycle to keep the ovaries producing progesterone. Unfortunately, between 10 and 20 percent of women attempting IVF have a poor ovarian response to ovulation-inducing drugs and never reach the stage of egg retrieval. Increasing the dose of gonadotropins in the early phase of the menstrual cycle may enhance egg recruitment for such poor responders. Recently, several IVF teams have pretreated these poor responders using GnRH agonists such as leuprolide acetate (Lupron) to wipe the hormone slate clean, and then initiated gonadotropin ovulation induction. GnRH pretreatment, followed by Pergonal, alone or with Metrodin, increases the number of eggs collected, the fertilization rate, the length of the luteal phase, and pregnancy rates. After pretreatment with a GnRH , however, it usually takes larger amounts of Pergonal to produce ovulation than when no GnRH is used. This more controlled stimulation with GnRH and Pergonal has the advantage of fewer cancelled IVF cycles due to a spontaneous LH surge or premature luteinization of the follicles than with Pergonal alone. If a woman has an LH surge, most programs now cancel cycles because it's difficult to predict ovulation accurately, and retrieval of the eggs may be performed either too early or too late. Cycles may also be canceled due to a low number (less than three) of mature follicles, inadequate estradiol production, or poor follicle development. Because of the improved ability to time a woman's egg retrieval to get mature eggs, many IVF teams now use GnRH routinely in IVF cycles. The disadvantages of pretreating the woman with GnRH include a longer duration of treatment, more Pergonal injections, and an increased cost (for extra Pergonal and because Lupron itself is expensive). However, these disadvantages are counterbalanced by fewer canceled cycles. A recent survey of U.S. IVF clinics by Serono, the manufacturer of Pergonal, reveals that 89 percent used GnRH s in at least some cycles in 1988, compared to only 2 percent in 1987. At present, to stimulate ovulation most U.S. IVF clinics only use GnRH in conjunction with Pergonal for those who respond poorly to Pergonal alone. Egg Retrieval Married for two years, Marilyn, aged thirty-six, and Edward, aged forty-six, wanted a baby. Since they had been unsuccessful after trying for a year, they each went to fertility specialists. Even though he had fathered two children in his first marriage, Edward showed a borderline low sperm count. Marilyn had intermittent high prolactin levels and elevated androgen levels. The following years were fraught with frustration as they both tried hormone treatments and numerous artificial inseminations without success. Their next alternative was an IVF procedure. In their first IVF attempt, Marilyn had her eggs retrieved laparoscopically. "I didn't feel a thing when I was asleep, and I remember having a pleasant dream. In fact, I was annoyed that they had awakened me when it was over," says Marilyn. "Then my belly hurt where they had made the incision for the laparoscope, my hand hurt where the IV tube had been in place and I felt nauseous." Although three of her eggs were fertilized and transferred into her uterus, the attempt failed. During her next IVF attempt, Marilyn had her eggs retrieved, with ultrasound guidance, through her vagina. "I felt a little uncomfortable when they were rinsing my ovaries, but it wasn't bad," she says. "I hardly felt when they stuck the needle into my follicles. After it was over, I didn't feel any pain." If a woman doesn't take GnRHs, then as she nears the middle of her cycle she usually begins to monitor herself with a home test kit several times a day to check for her LH surge. The IVF team retrieves her eggs based on the prediction of when she will ovulate naturally after the LH surge, or after administering hCG, which is usually more accurate. In most cases, after taking Pergonal, the woman receives an hCG injection and the IVF team retrieves her eggs thirty-four to thirty-five hours later. The team retrieves the woman's eggs either with a laparoscopic procedure or an ultrasound-guided needle placed through the vagina. She receives general anesthesia or local anesthesia with intravenous sedation and possibly takes mild analgesics. With laparoscopy, the surgeon makes a small incision in the woman's abdomen near the belly button for the laparoscope and two smaller incisions in the pubic hair line for egg retrieval instruments. He punctures the follicles with a thin needle inserted through the laparoscope or through a separate second puncture site in the abdomen. Then he withdraws fluid from each follicle and gives the fluid to an embryologist in the operating room or in an adjacent lab, who examines the follicular fluid under a microscope for eggs. The embryologist puts eggs found in the fluid into culture medium and incubates them. Meanwhile the surgeon irrigates the follicles with sterile solution and again collects the fluid to check for any additional eggs. Laparoscopy usually yields an egg from 60 to 80 percent of the follicles. For ultrasound-guided retrieval, the IVF team covers an ultrasound probe, specifically designed for pelvic imaging, with a sterile condom or latex glove and inserts the probe into the woman's vagina. With the aid of a needle guide attached to the probe, the doctor harvests her eggs by puncturing the follicles and removing the follicular fluid. The embryologist immediately identifies and places the eggs in nutritive media in an incubator. Ultrasound-guided egg retrieval has made the most physically demanding part of the IVF procedure less traumatic. In some centers, husbands can be with their wives during the egg retrieval. The procedure is usually easier on the woman than laparoscopy, and is equally effective in retrieving eggs. The quality and number of eggs, and the pregnancy rates, from ultrasound-guided egg retrieval compare favorably to those of laparoscopic retrieval. It is also usually less costly, faster, and leads to a quicker recovery than laparoscopic retrieval. Because of these advantages, at many IVF clinics ultrasound-guided egg retrieval is more common than laparoscopic retrieval. Laparoscopy may be reserved for women who need a simultaneous assessment of pelvic anatomy through a diagnostic laparoscopy, but the best-equipped IVF clinics will have both retrieval methods available to pick the best method for a particular woman. With either method, on average, the IVF team retrieves from six to eight eggs from the woman's follicles. Typically, three or four of the eggs are fully mature. Semen Collection "At first, it was embarrassing providing the sample because of all those people in the waiting room," recalls Sam. "They all knew what I was there for. But then I realized that all the guys were there for the same reason." Before the start of the IVF cycle, the husband makes an appointment to give a semen sample for evaluation. In some cases, the husband's sperm can be frozen as a backup for the day of egg retrieval. As with a semen analysis, he is asked to refrain from ejaculation for two or three days beforehand to increase the number of sperm in the semen. On the day of egg retrieval, he provides a semen sample through masturbation, and the sample undergoes a standard semen analysis along with sperm washing and "swim up" to recover the healthiest sperm. Egg Fertilization For men with normal semen, about 50,000 of the most motile sperm are incubated with each of his wife's eggs. For a man with abnormally shaped sperm or a mild to moderately low sperm count or motility, as many as 500,000 sperm are mixed with each egg. An embryologist inspects the eggs, allows them to incubate in culture media, and then mixes the sperm with mature eggs. From two to twelve hours after egg retrieval, the embryologist places the mixture in an incubator overnight, and the following morning checks the eggs for fertilization. There are four basic steps to fertilization: the egg's metabolism must be turned on, the sperm must be incorporated into the egg, a barrier must be erected to keep other sperm out, and the nuclei and chromosomes from the egg and the sperm must be united inside the egg. Generally, about 80 percent of mature eggs become fertilized at this stage. Eggs penetrated by more than one sperm (polyspermy), which produces an abnormal embryo, are not transferred back to the wife's uterus. In some IVF programs, the team allows immature eggs (about 50 percent of the retrieved eggs) to ripen in culture media for twelve hours or longer and then fertilizes them with the husband's sperm. A few IVF clinics even reinseminate eggs that haven't fertilized believing that the eggs were too immature at first and that incubating them in culture medium matures them enough for a second insemination. Usually, immature eggs don't often become fertilized and lead to a pregnancy. By about thirty hours after fertilization, the sperm and egg have become a two-celled embryo. By forty-eight hours after fertilization, the embryo should have four cells, and by sixty hours it should have divided into eight cells. The embryo is usually transferred into the wife's uterus anywhere from the two-cell to the eight-cell stage. If 80 percent of the retrieved eggs become fertilized, why do at best only 15 to 20 percent of women who go to IVF clinics become pregnant? The answer may lie with several factors. The uterus may not be properly prepared for implantation. A woman's hormonal support after embryo transfer may be inadequate. With IVF, embryos are transferred into the uterus much more quickly (after two days) than they would normally appear in the uterus in a natural cycle (five to seven days after ovulation). That is because after the first few days in incubation outside of the body, eggs won't keep dividing normally. Embryo Transfer Of the six eggs retrieved from Jennifer's follicles, three became fertilized by Sam's sperm and were transferred into her uterus. "We were ecstatic about the three fertilizations after spending a tense weekend waiting to hear about the results," Sam says. "We came in early Sunday morning for the embryo transfer. Two other couples were also in the office for the same thing, so we shared bagels and lox together. It was the most unusual Sunday brunch I have ever had." When the fertilized eggs have divided, the woman returns to the IVF clinic for the transfer procedure. The reproductive surgeon threads a thin plastic catheter through the vagina, through the cervical canal, and into the uterus, and transfers the fertilized egg through the catheter. The patient's husband may be allowed to stay with his wife during the transfer process. This ten-minute, outpatient procedure requires no anesthesia. The woman may experience some uterine cramping and discomfort, however, and possibly a small amount of bleeding. After resting for a few hours, she returns home and usually can resume normal activities in a day or two. To enhance the embryo transfer rate, some IVF clinics now have the woman go through a mock embryo transfer using radiopaque dye in a pre-IVF cycle. A fluoroscope reveals where the dye (which is like the fluid that will contain the embryo) ends up. In certain body positions, such as with the woman on her back, the dye may run out of her vagina. She may be better off having her embryos transferred while she is in a knee-chest position (on her stomach, not her back). Others have devised equipment that holds the uterus tilted downward, hoping to use gravity to help the transferred embryos implant in the uterus. The chances of having a child through IVF are also improved by transferring up to four embryos into the uterus. Transferring more than four embryos doesn't seem to improve the overall pregnancy rate, but does increase the likelihood of multiple pregnancy. Most IVF teams like to transfer three or four embryos during each IVF cycle. If more than four eggs are retrieved, all mature eggs are fertilized and the extra embryos may be frozen. If freezing is unavailable, the couple may be asked to donate the eggs to another infertile couple or to allow the IVF team to use them to refine culturing methods and embryo handling techniques. Embryo Freezing If an IVF procedure fails, the couple should wait at least one month while the wife recovers before undergoing superovulation and egg retrieval again. Saving eggs for future use by fertilizing them with sperm and then freezing them as embryos can be helpful. Frozen embryos can be transferred during subsequent spontaneous (natural) ovulation cycles without subjecting the wife to any additional medications and another egg retrieval. At the right time to transfer the embryos during succeeding treatment cycles, the frozen embryos are thawed and transferred into the uterus as with any IVF attempt. The ability to preserve embryos for future use lowers the total cost of repeated IVF treatments since the most costly first few stages (ovulation induction, egg retrieval, fertilization) don't have to be repeated. Another advantage is that the embryos can be transferred during a natural ovulation cycle when the woman's uterus is naturally ready for implantation. About half of frozen embryos survive thawing, and 10 to 20 percent lead to pregnancies. From fifteen to twenty U.S. centers are now freezing embryos, and they have reported dozens of births. Improved freezing and thawing techniques are currently being developed and will almost certainly lead to more centers offering embryo freezing in the future. If a couple has embryos frozen, they have to pay the IVF clinic a storage fee. After a certain length of time, the couple must decide what to do with any unused frozen embryos, such as whether to donate them to another infertile couple. Some IVF clinics, such as the one at Cornell University, have the couple sign an agreement stating that the frozen embryos are the joint property of the couple. Upon the woman's forty-fifth birthday, the frozen embryos become the property of the Cornell IVF team. This ethical dilemma of survivorship gained worldwide attention when a wealthy California couple died in a plane crash without designating what to do with their frozen embryos left in Australia. After a lengthy court battle, the rights to the frozen embryos were transferred to the couple's estate. Post-Embryo Transfer "The first seven days after the embryo transfer were exciting," says Sam. "Jennifer's eggs were implanted in her womb and in a way she was pregnant. Everything was going well." As it got closer to two weeks and the pregnancy test, they spent more time together, nurturing each other. The pregnancy test result came back as borderline, and Sam and Jennifer had to wait another two days. In that time, her hCG levels crashed, and Jennifer got her period. "That was hard for us to take. We started to think again that we would never have a baby," says Sam. "I told Jennifer that this was only our first IVF cycle, that she should keep her spirits up. Although they told us we only have a 20 percent chance, I reminded her that even though we have a male fertility problem, we had fertilizations. We're looking forward to the next attempt." The two weeks of waiting after embryo transfer often become the most difficult part of the IVF treatment emotionally. After the embryo transfer, the woman may continue to take hCG or progesterone to help support the uterine lining built up in the first half of the cycle. During this period, various blood hormone levels are measured to track the wife's progress. If necessary, she receives more progesterone to help maintain the endometrial lining and prevent premature menstruation. Two weeks following embryo transfer, she returns for a pregnancy test. If her pregnancy test is negative, the IVF team usually encourages the couple to schedule a follow-up visit with the clinic's doctor and a counselor, usually a social worker or psychologist, to ask any questions and to discuss their next step. The couple may decide to try another IVF attempt. A woman who goes through the IVF procedure four times has about a 50 percent chance of taking home a baby. After four attempts, the odds don't get any better. If her pregnancy test is positive, the woman still has a 20 to 40 percent chance of miscarrying (women over forty tend to have a higher miscarriage rate, as high as 60 percent), which is slightly higher than the natural miscarriage rate, and about a 5 percent chance of an ectopic pregnancy, also higher than for the general population. Within two weeks after a positive pregnancy test, she returns for an ultrasound scan to confirm the presence of a fetal heartbeat and to see whether she is carrying more than one baby. Since most IVF clinics now limit the number of transferred embryos to four, the incidence of multiple pregnancies isn't much higher than with superovulation without IVF. In the more than fifteen thousand IVF births worldwide, so far there is no evidence of an increased risk of birth defects or premature births. Most IVF clinics don't consider IVF pregnancies high-risk pregnancies, except for the risk of miscarriage, for which many provide progesterone supplements to help maintain the pregnancy to term. If the woman becomes pregnant, she will be referred back to her obstetrician. If she doesn't have an obstetrician, the clinic usually helps her find one. Genetic counseling and amniocentesis are usually recommended for any woman over thirty-five; a genetic abnormality, however, can occur at any age. Chorionic villus sampling is a newer alternative to diagnose a genetic disorder in the first trimester, but it carries a slightly higher risk of miscarriage than amniocentesis, which is performed in the second trimester. As always, you should discuss the need for and risks of genetic testing with your doctor. Cancellation of a Cycle Occasionally, an IVF team will decide not to attempt to retrieve a woman's eggs, but rather to cancel the treatment cycle. Sometimes the woman doesn't respond optimally to the medications and the blood tests and ultrasound exams don't reveal successful follicle growth. Her eggs may be immature, or too mature, to be fertilized. Or the eggs may fertilize, but not continue to divide, in which case they will not be transferred back into the uterus. You have to realize that your chances for success in any one IVF cycle, even at the best clinics, is no higher than 20 percent once you have gotten to embryo transfer. Of all the couples who start IVF treatment, only 7 to 10 percent take home a baby. These percentages are likely to increase as fertility specialists gain more experience with IVF. Who Are the Candidates for IVF? The woman with the best chances for a successful IVF procedure is younger than thirty-five and has normal menstrual cycles, a good response to controlled ovarian hyperstimulation, and a husband with a good sperm count. IVF can bypass most causes of infertility, including irreversibly blocked fallopian tubes, antisperm antibody problems, endometriosis, a cervical factor problem, very low sperm counts, and even unexplained causes of infertility. IVF is a particularly good alternative for a woman who produces mature eggs but can't conceive naturally because of blocked fallopian tubes, and for a woman with luteinized unruptured follicle syndrome, who develops but doesn't release mature eggs from her follicles. The Age Factor The chances of an IVF birth depend heavily on the wife's age. Younger women have higher pregnancy rates than older women. Women over age forty have only a rare chance of IVF success. Yet, even knowing the odds, many women over forty say they want to go through at least one IVF cycle before giving up their hopes of having a baby. One way to determine whether a woman over forty has a strong chance of success may be to measure her estradiol and FSH levels on day three of the IVF cycle. At the Jones Institute, researchers have seen a trend toward higher pregnancy rates and fewer canceled cycles for women over forty when their FSH level is low on cycle day three. The Male Factor For four years, Diane and John tried to have a baby with no success, even after a dozen attempts at intrauterine insemination. A loan officer in a bank, John, aged forty-eight, had a borderline low sperm count, low sperm motility, and poor sperm morphology. When an IVF clinic opened near their home, their fertility specialist suggested they give it a try. "Our first attempt, with all the injections I had to give her every night, brought us closer together," John says. Four of Diane's healthy eggs were fertilized and transferred, but the attempt failed. They decided to try again. "This time we knew the routine, but we were both feeling bad since we didn't expect to have to go through the procedure twice," he says. That attempt also failed. John and Diane, a thirty-eight-year-old school counselor, took some time off and came back for another attempt three months later. This time, the test showed that Diane was pregnant. "We were scared because we thought it might be a false positive pregnancy test," she says. Then they had an ultrasound exam. "We actually saw a tiny, beating heart. It was a beautiful moment, so exciting to see the fruits of our labor," John says. Their daughter Doreen is fourteen months old. Although IVF offers new hope to infertile couples, it's not the answer for all causes of infertility. Most IVF programs usually require a man to have a sperm concentration of more than 10 million sperm per ml with more than 20 percent normal sperm motility and at least 5 percent normally shaped sperm. Below these values, a couple rarely achieves a pregnancy without using donor sperm. Male factor patients already have a one-third less chance of fertilizing their wife's eggs in the lab than men with normal sperm counts. Besides a semen analysis, the IVF clinic should also check the man and his wife for sperm antibodies, which reduce the chances of fertilization of both normal and oligospermic men. Many IVF clinics also test a man's sperm function using sperm penetration assays with zona-stripped hamster eggs. Although not totally reliable (some men score poorly and still fertilize their wife's eggs), the hamster test gives an indication of a man's fertilizing ability. The most important determinant of IVF success for a male factor patient is his ability to fertilize his wife's eggs. After two cycles with no fertilization, most men will continue to fail to fertilize in subsequent cycles. If a couple with a male factor problem produces no fertilized eggs after two attempts, they should consider pursuing other alternatives, such as donor sperm or adoption. Sperm from men with male factor infertility can have difficulty both in getting the sperm to the egg, and in penetrating the egg. Once the eggs become fertilized in the IVF lab, however, these couples with a male factor problem have pregnancy rates equal to infertile couples with no male factor problem. In other words, once a sperm fertilizes the egg, its mission has been accomplished and the outcome of pregnancy is just as good as for eggs fertilized by sperm from men with no known male factor problem. To improve the live birth rate of male factor patients, IVF researchers are looking for ways to improve the fertilizing ability of a man's sperm. Competition In their third IVF attempt, Marilyn and Edward had only one two-cell embryo that degenerated, and they never got to the embryo transfer stage. "We had gone to a big place that sent couples through like herds of cattle," Marilyn says. "They tried to tell us what was "best' for us without stopping to understand our needs. They kept saying my eggs would never be fertilized with Edward's sperm, and that donor insemination was for us. But I told them that donor sperm was difficult for me to accept. I'm adopted, I don't know who my father was and I didn't want my baby not to know who his or her father was. They didn't bother to listen. I was so frustrated, that evening I went home and smashed several boxes of light bulbs, one at a time, in our backyard. It was very therapeutic." As IVF has become one of the fastest-growing areas of infertility treatment, it has also become ripe for exploitation. Couples desperate for a baby may be lured by IVF clinics promising results they can't achieve. Entrepreneurs are cashing in on a surging fertility industry, and the most controversial aspect of this commercialization of conception is IVF, which by some estimates is itself a $100 million industry. Of the approximately two hundred U.S. and Canadian IVF clinics, about one-third are at university centers and the rest have private funding or are associated with for-profit hospitals. The most successful centers have long waiting lists, and new IVF clinics are opening all the time. Many programs have never had a live birth. Some programs that shut down after a year or more with no pregnancies are reopening after refining their techniques. Yet, the bulk of IVF births comes from a small number of large programs. Those infertile couples who have gone through IVF treatment have found that IVF can cost them tens of thousands of dollars, with no money-back guarantees and stiff odds against success. Unfortunately, after all the expenses, heartache, poking, and prodding, most couples go home childless. Doctors at the larger centers say that a high volume of patients is necessary to establish a track record, to perfect techniques, to maintain a level of competency, and to support the necessary staff specialists. They claim that a commitment of at least two years and an expenditure of $1 million is necessary for a new program to establish itself, and that physicians who dabble in IVF won't have comparable results if they don't make similar investments. But large programs aren't trouble-free. Some couples at large clinics feel as if they are being put through an assembly line. It's difficult to pinpoint the right balance. If a clinic performs too many cycles, it may be impersonal. Too few cycles, and the clinic staff may not have the experience to give couples the best chances of having a baby. As the number of IVF clinics has grown, so has the professional and public pressure to regulate them. Exaggerated estimates of success have led doctors, insurance companies, members of Congress, and infertile couples to push for stronger regulation. The American Fertility Society has an IVF registry, but in the past has divulged only cumulative data, not information about individual IVF clinics and their success rates. However, clinics that want to have their own data released can now do so through the registry. A couple can check with the American Fertility Society to see whether an IVF clinic is listed in its registry. The more than a hundred official members of the Society for Assisted Reproductive Technology (SART) is restricted to IVF programs that can account for at least forty patients and three live births. Scientists have also been urging the federal government to take a more active role in IVF research to improve a couple's odds. The government, which placed a moratorium in 1980 on federal funding for any research involving human embryos or fetuses, recently took a preliminary step toward allowing federal funding for IVF research. An ethics advisory board that was disbanded in 1980 has been resurrected and will take another look at the funding question. IVF "Cousins" Once considered a last-chance technology, IVF has spawned the development of other procedures that use variations of the same assisted reproductive techniques. These technologies offer couples the advantages of the years of experience that went into making IVF a viable infertility treatment. They carry IVF technology along to the next logical step in an attempt to help more infertile couples have babies. Gamete Intra Fallopian Transfer (GIFT) In addition to IVF as a treatment, most IVF clinics offer a more natural approach to fertilization, called Gamete (for egg and sperm) Intra Fallopian (within the fallopian tube) Transfer (GIFT). This combines eggs with sperm and then places the egg/sperm combination directly into the fallopian tubes, where conception occurs naturally. The GIFT procedure requires a woman to have at least one normal fallopian tube. The ovulation induction and monitoring procedures for GIFT are basically the same as for IVF. After the surgeon retrieves the eggs, the embryologist draws up small amounts of sperm for each egg, and places up to two eggs plus 100,000 sperm into each fallopian tube. If the sperm fertilize the egg, it happens as it would naturally--inside the fallopian tube rather than in an incubator outside the body, as in IVF. Except for women with two damaged fallopian tubes, candidates for IVF are also candidates for GIFT, which in many centers has a higher pregnancy rate (20 to 30 percent) than IVF. It is most suitable for couples with unexplained infertility, cervical or male factor problems, mild endometriosis, or luteinized unruptured follicle syndrome. GIFT also seems to offer women over forty a better chance at live birth than IVF. GIFT has some disadvantages when compared to IVF. At present, GIFT usually requires laparoscopy to transfer the eggs and sperm into the fallopian tubes, making it a more major procedure than an IVF embryo transfer through the vagina and cervix into the uterus. (This difference in the two techniques may change with the use of hysteroscopes or ultrasound guidance to transfer sperm and eggs through the cervical canal into the tubes.) More important, if the GIFT procedure fails, there is no way of knowing whether the woman's eggs were fertilized, which is readily apparent with IVF. IVF + GIFT = "ZIFT" Because of this lack of knowledge about fertilization, some couples with a male factor problem now receive a combination of IVF and GIFT. The wife's eggs, retrieved with ultrasound guidance, are exposed to her husband's sperm in the lab. Within twenty-four hours, the fertilized egg (known as a zygote) is transferred to her fallopian tube, usually by laparoscopy. Since this procedure uses the zygote, not the separate eggs and sperm, it's called Zygote Intra Fallopian Transfer (ZIFT). This has an advantage over a pure GIFT procedure, particularly for male factor couples, because the embryologist will know whether the wife's eggs have been fertilized by her husband's sperm. If his sperm don't fertilize her eggs, then the couple may decide at that point to accept donor insemination rather than pursue further efforts to achieve a pregnancy with the husband's sperm. Intravaginal Culture (IVC) Another technique that takes advantage of the body's own environment is intravaginal culture (IVC). After retrieval the eggs are placed with the husband's sperm in a culture medium inside a sterile, hermetically sealed container carried inside the vagina. A vaginal diaphragm holds the container in place. This maintains the egg and sperm at normal body temperature as well as, if not better than, any incubator in a laboratory. Two or so days later, the doctor opens the container and transfers any fertilized, dividing eggs into the uterus. The simplicity of this procedure is appealing, and may lead to further reductions in costs and more widespread availability of treatment than classical IVF. Ultrasound GIFT To avoid the surgery involved in GIFT, some clinics perform the procedure entirely with ultrasound guidance, both for egg retrieval and tubal transfer of the eggs and sperm. This new technique, first reported from Australia, is gaining popularity in North America. As IVF procedures multiply, researchers are learning more and more about the miracles of conception. By sampling the fluids and protein substances found inside the fallopian tube, they are getting a better understanding of the tube's normal environment. If what's happening inside the fallopian tube and the conditions leading to successful implantation can be better understood, then more couples will have babies through IVF and related treatments. Some researchers believe that it may even be possible eventually to better the 20 to 25 percent natural conception rate per cycle. For the moment, IVF, even at a 10 percent live birth rate, is an acceptable alternative for many couples. But even IVF isn't the last resort. What Couples Should Ask When Looking for an IVF Clinic: - Do you have any limitations on the age or types of infertile couples you accept into your program? - What is your pregnancy rate per embryo transfer? Does this rate include only clinical pregnancies, or does it also include chemical pregnancies? - What is your pregnancy rate for couples our age with our particular problem? - What percentage of your couples initiating an IVF cycle don't make it to transfer? - What percentage of your IVF patients who have egg retrievals go on to embryo transfer? - What percentage of your couples have a male factor problem, and what is your success rate in treating them? - How many cycles does your program induce in a year? - How much does the procedure cost, including hormone treatments? (Costs generally range from about $6,000 to $7,000, including the drugs.) - Do you freeze embryos? - What happens to frozen embryos after we achieve a pregnancy? - Do you offer egg freezing, embryo donation, or egg donation programs? - Do you offer GIFT or other advanced procedures involving assisted reproductive technology? - What is your live birth rate among all couples who have started an IVF cycle in your program?