In Vitro Fertilization (IVF)   Download "IVF Primer" PDF

IVF was originally developed in the United Kingdom by Dr. Robert Edwards, an embryologist at Cambridge University, Dr. Patrick Steptoe, an obstetrician/gynecologist with expertise in laparoscopy and their nurse, Ms. Jean Purdy, during the late 1970s.

Their goal was to treat inoperable tubal disease. They retrieved a single egg by laparoscopy in a natural cycle. The first human pregnancy achieved was ectopic, i.e. located in the tube. The first live birth after in vitro fertilization (in vitro is Latin for “in glass”) occurred in England in 1978. The first United States birth was in 1981.

The major advances in IVF in the 1980s included: introduction and refinement of ovarian stimulation, embryo freezing, early egg donation and non-surgical ultrasound-guided ovum retrieval. In the 1990s the single major advance was the development of ICSI, MESA and TESE for severe male infertility. Freezing of unfertilized eggs, fertility preservation and extended embryo culture were the notable advances in the first decade of the 21st century. Even more recently, PGS with comprehensive chromosome screening for aneuploidy has been developed at the high-tech end of the spectrum of assisted reproduction while mild stimulation IVF has gained a following at the low-tech end of the ART spectrum.

ICSI

ICSI (intra-cytoplasmic sperm injection) was initially developed for severe male infertility where the number and/or function of sperm is not sufficient for standard insemination. Recently, ICSI has been extended to couples with milder male infertility as well other types of infertility in an attempt to avoid failed fertilization.

Semen analysis does not always predict low or absent fertilization in the laboratory. While uncommon, this can happen even with sperm of men who had previously achieved pregnancy naturally and who have normal semen characteristics. For this reason, we recommend the use of ICSI on some of the eggs in the first IVF cycle even in the absence of male factor with standard insemination of other eggs. If another cycle is required and good fertilization rate was achieved with standard insemination then ICSI would not be performed.

Sharp injection pipette on right, large holding pipette on left of the mature egg

During ICSI, a single sperm cell is injected directly into the egg. The procedure is carried out under a microscope while the eggs are kept on a warm stage. During the injection procedures, we use micromanipulators to reduce hand movements to microscopic movements. A single motile sperm is first immobilized and then inserted inside the egg with a sharp injection pipette while the egg is held in place with a larger holding pipette. After egg retrieval, about 80-100% of the eggs are expected to be mature (MII) and ready for sperm injection. A small percentage of the eggs may be damaged by the ICSI procedure. Most but not all mature eggs will exhibit normal fertilization after ICSI and some fertilized eggs may not divide to form an embryo. Overall, however, the live birth rates with ICSI are comparable to those achieved by conventional IVF. For most couples with severe male factor infertility, ICSI is the only option available to achieve parenthood with their own gametes.

Embryo Freezing

If more eggs are normally fertilized and divide to form healthy-looking embryos than the number that is appropriate to transfer into the uterus during the treatment cycle, then additional embryos can be frozen and stored in liquid nitrogen for future use. Once frozen, the embryos can be maintained in storage for many years, but, whenever possible, we encourage replacement within two years of fertilization.

Embryo cryopreservation is a well-established and highly successful procedure. Therefore, most embryos are expected to survive freezing and thawing even though some embryos may lose one or more cells. However, a few embryos may not survive or be lost in the process of cryopreservation. Freezing is associated with slight reduction in the viability of most surviving embryos. Consequently, the chances of a live birth are somewhat lower with frozen-thawed embryos compared to fresh embryos. Most of this difference in live birth rates is due to the widespread practice of selecting the best embryos for fresh transfer. Therefore, a direct comparison between live birth rates after fresh and frozen transfers may be misleading because of this strong selection bias.

However, the health of babies born from frozen embryos is not affected by cryopreservation. Offspring born from frozen embryo transfer have the same rate of congenital abnormalities as the general population. When damage occurs during the freezing process, the pregnancy usually does not ensue. The likelihood of achieving a live birth following transfer of frozen-thawed embryos in our program has been about 30% per transfer.

The consent form for embryo freezing requests that you indicate how you would like to dispose of the frozen embryo(s) in case of divorce and death. The options include donating the embryos for the benefit of another infertile patient or discarding them. While the embryos remain in storage, you need to pay an annual fee.

Frozen Embryo Transfer (FET)

Frozen embryo transfers contribute an increasing percentage of births from IVF. Currently at Alta Bates, the live birth rates from frozen and fresh embryos are similar. Availability of an excellent embryo and egg-freezing program is key to improving live birth rates per retrieval while minimizing the risks of multiple births. For optimal success, the endometrium (uterine lining) needs to be precisely synchronized with the developmental stage of the thawed embryos. This synchronization can be achieved in one of the two ways. The likelihood of IVF pregnancy is comparable with both strategies but more cancellations occur in natural cycles because ovulation often does not occur as expected.

For optimal success, the endometrium (uterine lining) needs to be precisely synchronized with the developmental stage of the thawed embryos. This synchronization can be achieved in one of the two ways described below. The likelihood of IVF pregnancy is comparable with both strategies but more cancellations occur in natural cycles because ovulation often does not occur as expected.

Preliminary Testing Before FET

A follow-up visit to discuss any clinical changes since last treatment, to select the synchronization strategy and to outline the details of the treatment plan is worthwhile. Since the chance of pregnancy depends upon the viability of the embryos, receptivity of the uterus and the ease of the frozen embryo transfer procedure, these three major areas are scrutinized closely.

Uterine receptivity depends upon the uterine anatomy and endometrial thickness which are both evaluated by a saline infusion sono-hysterogram (SIS). SIS is typically performed in the cycle before FET but it can be done in the actual treatment cycle as well. During SIS sterile saline is introduced into the cavity to better outline small polyps or sub-mucous fibroids which might interfere with embryo implantation. If endometrial polyps or fibroids are found, then hysteroscopy can readily remove them.

Normal cavity on SIS test

Embryo transfer procedure is key to successful outcome of all IVF. In patients with a narrow or tortuous cervical canal the passage of the transfer catheter is often difficult. In some cases, laminaria is placed in the cervix to open the canal in advance of the transfer.

“Artificial Ideal Cycle” Protocols

This protocol involves sequential administration of natural estrogen and progesterone. In such cycles ovulation does not occur and the resulting pregnancy needs to be supported until the placenta matures at 10-12 weeks. In addition to its reliability and flexibility, the major advantage of this approach is that the day of frozen embryo transfer is chosen with ample notice to accommodate your and our busy schedules.

Natural estradiol is started on the second day of full menstrual flow. Estradiol can be given by mouth and/or vaginally, by twice-per-week IM injection or as a patch. After 7-8 days on estradiol a vaginal ultrasound is done to measure endometrial thickness and the schedule of medications is modified as needed. In some cases a second ultrasound is required. Blood is drawn to confirm that no ovulation has occurred. Once the endometrium has reached its full development, the FET is scheduled and the final progesterone schedule is provided.

Progesterone is usually given in the form of micronized vaginal capsules and every-other-day IM injections of progesterone-in-oil (50 mg/mL). If you get Prometrium capsules, which have a thick capsule, you should soften them in warm water before insertion. Endometrin tablets and Crinone gel are other forms of vaginal progesterone.

Natural Cycle FET

In select cases, synchronization can be achieved during the woman’s spontaneous cycle provided that her ovarian function is normal. One of the advantages of natural cycles FET is that few if any injections are required but the timing of transfer is often unpredictable. Call our office on the first business day after the onset of full menstrual flow to schedule a baseline ultrasound. About 3-4 days before expected ovulation another ultrasound is done to confirm presence of a pre-ovulatory follicle and normal endometrial thickness. You will test for an LH surge in urine with an ovulation prediction kit available without a prescription. A test is positive when your dot is close to, equal to or darker than the reference dot.

FET Procedure

After the embryo(s) have been thawed, and found to be suitable for transfer, a small tube is gently passed through the cervix into the uterus and the embryos are deposited in the uterine cavity. The frozen embryo transfer requires no anesthesia. If at all possible, we would like your partner to be present. We use an abdominal ultrasound to confirm that the catheter is within the uterine cavity. You need to drink extra fluid 1-2 hours before and stop voiding about 1 hour before the transfer. In the usual position for a pelvic examination, a tiny catheter containing minute amount of fluid with the embryos is gently inserted into the uterus and the fluid is deposited. After the transfer you might notice light spotting for a couple of days.

Following frozen embryo transfer we advise patients to refrain from orgasm and ejaculation of semen into the vagina for 5 days in order to minimize uterine contractions which could expel the embryos through the cervix or up into the fallopian tubes and thus prevent normal implantation within the uterine cavity. Prolonged bed rest is of no benefit after frozen embryo transfer.

Mild Stimulation IVF

The traditional IVF process, with its goal of obtaining the maximum number of eggs, has helped millions of patients but it remains a complex and costly therapy. Mild stimulation IVF represents a different approach in which the woman’s ovaries are stimulated more gently with the aim of developing just a few high quality eggs. Thus mild stimulation IVF is more patient-friendly and potentially more accessible because of reduced overall IVF cost.

With mild stimulation, lower doses of medications, fewer injections and blood draws, less monitoring and fewer office visits are necessary. With a small number of follicles (fluid-filled sacs containing eggs), the retrieval procedure is shorter and requires less anesthesia. With fewer eggs and embryos, the laboratory fees are lower and there is usually no embryo freezing and storage.

To achieve good live birth rates, mild stimulation IVF requires expertise in managing these modified protocols. While less common than traditional IVF in the United States, mild stimulation IVF has been widely adopted in Japan and other countries. Offering a wider choice of treatment options to patients is consistent with our overall practice philosophy.

Infertility provokes anxiety and a loss of control, which may be further exacerbated by the high complexity, invasiveness and traditional IVF cost. A gentler approach approximates natural conception more closely and its simplicity may reduce the stress of treatment.

Independent of financial considerations, some patients desire an IVF option that does not expose their bodies to extremely high doses of hormones, which can result in serious complications. By virtue of lower intensity and expense, mild stimulation IVF can offer satisfactory IVF success rates while reducing the physical and psychological burden of treatment.

Our in vitro fertilization patients come to us from Berkeley, Oakland, Sacramento, San Francisco, the Bay Area and bordering communities.