In vitro fertilization (IVF) was first successfully performed in Oldham, England, in 1978, resulting in the birth of Louise Brown, who was conceived using Natural Cycle IVF (NC-IVF). Since then, more than 4 million children have been born using IVF. The introduction of this technique completely changed—and greatly improved—our ability to treat even the most difficult cases of infertility, many of which were previously untreatable. Although it is clearly not a “cure-all” for infertility, IVF has revolutionized our approach to, and understanding of, the disease called infertility.
IVF literally means “the fertilization of eggs with sperm in glass,” which translates to fertilization outside of the body in the laboratory. There are two types of IVF: (1) stimulated cycle IVF, and (2) Natural Cycle IVF (NC-IVF). (We will focus on stimulated cycle IVF in this question but for more information on NC-IVF, please refer to Question 59). An IVF cycle consists of several discrete phases, as detailed in the sections that follow.
Phase 1: Ovarian Stimulation
A woman’s ovaries contain thousands of fluid-filled sacs called follicles. Inside each follicle is an egg (or ovum). In a normal reproductive cycle, only a single follicle (and egg) reaches maturity. Louise Brown (the world’s first IVF baby) was produced in a natural cycle from a single follicle. Although a few clinics in the United States (including our own) remain enthusiastic about NC-IVF, most IVF in the United States is performed in a stimulated cycle using injectable fertility medications. The introduction of these medications (called gonadotropins) enabled physicians to increase the efficiency of IVF through the production of multiple mature follicles. Two forms of these medications are used: (1) drugs containing equal parts of the pituitary hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (Menopur), or (2) drugs containing only FSH (Bravelle, Gonal-F, Follistim) or LH (Luveris). Both kinds of medications induce the growth of multiple ovarian follicles, so it is important to monitor the woman’s response to them carefully with ultrasound and blood hormone testing.
Estrogen is produced within each of the developing follicles and induces the growth of the lining of the uterus (endometrium). Unfortunately, the rise in estrogen can also induce the pituitary gland to prematurely trigger ovulation, resulting in the cancellation of an IVF cycle. Two other classes of drugs are used to reduce the chance of this problem occurring during an IVF stimulation: (1) GnRH agonists (such as Lupron and Synarel), and (2) GnRH antagonists (such as Centrotide and Antagon). Lupron (or Synarel) is usually started 1 week prior to the woman’s anticipated next menstrual cycle. Given that a patient may have spontaneously conceived during this cycle, all women beginning Lupron are recommended to use a barrier form of contraception.
Approximately 1 week after starting Lupron, a woman should experience a normal menstrual period. An ultrasound exam is performed at the start of this menstrual cycle to examine the ovaries and measure any existing cysts. In some cases, empty follicles from a previous cycle will persist and may influence the response to FSH. If the baseline ultrasound and blood tests are normal, then the patient receives instructions that afternoon as to when and what dose of medication she should take and when she should report back to the office for repeat ultrasound and blood tests.
Patients remain on Lupron to prevent the premature release of the eggs until the end of the stimulation phase. During a typical treatment cycle, they take daily injections for 9 to 12 days before the follicles reach maturity based on ultrasound results and blood hormone levels. Once the follicles reach a 20- to 24-mm diameter, the woman receives an injection of human chorionic gonadotropin (HCG; Pregnyl, Profasi,Novaryl) at a precise time. This hormone serves as a trigger to incite the final maturation and release of the egg (ovulation). Ovulation typically occurs about 40 hours after this shot, so the egg collection procedure is scheduled for 34–36 hours after the HCG injection. Failure to take the HCG will result in an egg collection with apparently empty follicles as the eggs will not be ready for aspiration or eggs that are retrieved will be immature. Clearly, taking the HCG is absolutely critical which is why we check a blood test for HCG the morning after the shot to ensure that it was given correctly.
Cycles using GnRH antagonists are somewhat different. GnRH antagonists are started several days following the start of ovarian stimulation with gonadotropins. Most clinics add the GnRH antagonist once the largest follicle reaches a diameter of 14 mm. This medication effectively prevents the release of LH from the pituitary within hours of administration. Although many clinics have used GnRH antagonists successfully as part of their IVF stimulation protocols, some studies have demonstrated a trend toward decreased implantation rates in IVF cycles using this class of medications. Some physicians use GnRH agonists (Lupron) instead of HCG to induce follicular maturation. This approach only works in patients who have not already been taking Lupron as part of their stimulation protocol.
Phase 2: Oocyte Retrieval
Many physicians perform IVF as an office-based procedure, whereas others utilize a free-standing surgery center. Some programs are located within a hospital. There are advantages and disadvantages to each of these. We prefer to perform egg collections at one of our fertility offices in a special procedure room, as the location and staff are familiar to the patients undergoing the IVF process. We also find that the location of the IVF lab within the office encourages continuous communication between patient, physician, and embryology staff. However, clearly many successful programs utilize a surgery center or a hospital. The use of a hospital setting may allow patients with significant medical conditions (cardiac disease, severe pulmonary disease) to undergo IVF, whereas such patients would be considered an anesthesia risk in the office setting.
Although many patients are nervous about the oocyte retrieval, in fact the vast majority of women find it to be less uncomfortable than some of the screening tests leading up to IVF. The egg collection is performed under intravenous sedation using a vaginal ultrasound probe with a special needle guide adapter. Most patients have no recollection of the actual egg retrieval and sleep through the entire procedure. The needle passes through the side of the vagina into the ovary, and the follicles are easily aspirated. The fluid containing the eggs is then inspected by the embryologist using a microscope. Both the eggs and the sperm are then placed together in small plastic dishes containing media and incubated for the next 3 to 5 days. If there is a significant male factor, then ICSI (see Question 53 to learn What is ICSI?) is performed several hours after the egg collection.
Phase 3: Embryo Culture
On the day following the egg collection, patients learn how many eggs were fertilized. Remember that although your RE measures all of the follicles during stimulation, mature eggs are usually found only in follicles with a diameter of more than 17 mm. In general, about 70% of the mature eggs will fertilize. Unfortunately, some attrition occurs at each point in an IVF cycle so the total number of healthy embryos is often much less than the original number of follicles or eggs.
Three days after the egg collection procedure, the embryos selected for embryo transfer will be identified. Allowing the embryos to grow for an additional 2–3 days in the laboratory may allow for enhanced embryo selection as some excellent appearing day 3 embryos will fail to continue to grow. Thus, implantation rates are usually higher for day 5–6 transfers because of this improved ability to select the best embryos. Additionally, there is some evidence that suggests waiting until day 5–6 may provide for improved synchronization of embryo and endometrium given that, in nature, the embryo usually doesn’t arrive in the uterus until day 5–6 after ovulation. On the day of embryo transfer, your RE should review the quantity and quality of the embryos with the embryologist and then discuss with you his or her recommendations regarding the number of embryos to transfer.
Embryos that are not selected for transfer may still be of excellent quality, so they may be candidates for cryopreservation (freezing) with liquid nitrogen. These frozen embryos can then be replaced into the uterus during a future cycle, eliminating the need for the woman to undergo the entire IVF process of ovarian stimulation and egg collection. There is little benefit to freezing poor-quality embryos, however, because they are unlikely to result in a pregnancy and may not even survive the thawing process.
Phase 4: Embryo Transfer
Embryo transfer is one of the most critical aspects of an IVF cycle. During this phase, the embryos are transferred into the uterus by a procedure similar to an IUI. At our office, we perform our embryo transfers under abdominal ultrasound guidance to ensure the accurate placement of the embryos into the uterus. On the day of embryo transfer, patients are asked to drink 48 ounces of water and keep a full bladder to enable us to visualize the transfer of the embryos. No anesthesia is usually required for an embryo transfer and this step usually takes only 1–2 minutes to complete.
Phase 5: Post-Transfer and Pregnancy
During the 2 weeks after the embryo transfer, patients take supplemental progesterone (shots and/or suppositories). If a patient’s estrogen level drops significantly during the 2 weeks following embryo transfer, her physician may add supplemental estrogen as well.
Two weeks after the transfer, the woman typically undergoes a blood pregnancy test. Once a pregnancy test is positive, the physician may repeat the test every 2 days until the beta HCG level is high enough to visualize the pregnancy sac on transvaginal ultrasound (the beta HCG level should be more than 2000 IU around 3 to 4 weeks following embryo transfer). A follow-up ultrasound is then performed to confirm fetal cardiac activity. At this point, patients are usually referred back to their obstetrician/gynecologist for prenatal care.
Before undergoing IVF, I remember thinking that Phases 1 through 4 would be the hardest part. I was very intimidated by all the drugs and the shots and the egg collection. In reality, it was Phase 5 that was the toughest. I had done everything I could do—mixed the drugs, given the shots, drank the water. Now all that was left was to wait and see if it worked.
One piece of helpful advice I was given was to plan something out of the ordinary during those 2 weeks. Whether it’s a vacation with your husband or visiting a relative, introducing anything that is not part of your normal routine is helpful in keeping your mind off of whether or not you’re pregnant.