by Stephen L. Corson, MD
Assisted reproductive technologies (ART) is a blanket term used to cover in vitro fertilization (IVF) and other procedures designed to produce pregnancy if other methods have failed. The decision to employ IVF comes either after years of frustration with other unsuccessful therapies, or after diagnosis of a specific problem, such as advanced tubal disease or major sperm deficits, which requires IVF to achieve pregnancy. Following is a discussion of IVF, but note that treatment is far from standardized, and clinics vary considerably in their individual approach and philosophy of care.
A Brief History of In Vitro Fertilization
IVF was born in 1978 with the arrival in England of Elizabeth Brown, the first "test-tube" baby, whose mother was infertile as a consequence of fallopian tube closure. This landmark event, however, was preceded by decades of success with IVF in various animal species. Successful fertilization of any kind requires a cell commonly known as an egg (or oocyte) from a female and sperm from a male. Initially used to manage solely obstructions of the fallopian tubes (the tubes that carry the female egg from the ovary to the uterus) that were resistant to surgical correction, it soon became obvious that IVF could be used to solve other reproductive problems. Infertility of unknown causes, infertility caused by endometriosis (a condition where the tissue similar to that of the uterine lining appears elsewhere in the body, usually in the abdomen), and even infertility arising from sperm-related problems can all be treated with IVF and lead to delivery of normal offspring.
How Does IVF Work?
IVF can be divided into four phases:
Phase 1: The first phase consists of stimulating the ovary with hormones injected just beneath the skin or into a muscle in order to cause several eggs to mature. Normally, only one egg matures per menstrual cycle, so additional hormones are usually required to prevent the body (specifically the pituitary gland) from reacting negatively to this excess of eggs. During this stimulation phase, which usually lasts for 8-12 days, blood tests for hormonal levels and ultrasound examinations of the ovaries are carried out in order to monitor the development of the eggs. The doses of the hormone injections, which are usually self-administered or given by the husband after training is received, are determined by the results of the blood tests and ultrasound examinations. The last injection given is that of human chorionic gonadotropin (hCG), the hormone normally produced during pregnancy. Under these conditions hCG serves as the final stimulus for egg maturation.
Phase 2: The second phase, that of egg retrieval, occurs about 34-36 hours after the hCG injection. Oocyte collection used to be performed in an operating room but today almost all retrievals are done in an outpatient, office-type setting. A long, thin needle is inserted through the vagina using ultrasound guidance (where images taken by ultrasound are used to target the needle to the ovary) and the eggs are collected with the needle.
The entire procedure usually takes 8-20 minutes depending on the number of eggs that have developed and the ease of accessing the ovaries. In many centers this is performed with local anesthesia and mild sedation, but some patients prefer to be asleep. Generally, the patient may leave after 30-60 minutes of observation. Once the eggs are harvested, they are isolated from the fluid that surrounds them (called follicular fluid) and placed in a special incubator where temperature, humidity and gas content are tightly controlled.
Phase 3: The third phase involves fertilization of the eggs. In most cases this is simply a process of preparing sperm from a specimen produced by the husband and placing sperm in the same dish as the egg(s). For others, a procedure called ICSI (mentioned below) is employed. About 24 hours later, the eggs are observed for changes suggesting that fertilization has taken place, mainly the presence of two early (pronuclear) masses within the egg.
What takes place over the next few days (in between phase 3 and 4) constitutes the weak link in the IVF process. Simply stated, the soup present in the woman’s tubes and uterus contains many substances which we have not identified to date -- let alone duplicated -- but that normally sustain an egg and early embryo in a woman's body. In natural fertilization, the fertilized egg enters the uterus about four days after ovulation and fertilization, and then does not physically implant in the uterine wall for another two days or so. Until recently, our laboratories could not sustain embryo development for this duration, so clinics were forced to place embryos in the uterus two or three days after egg retrieval.
For several reasons, an embryo is less likely to survive when placed in the uterus at this younger age. For example, the embryo's own genes do not take control until four cells have developed; before that, genetic messages come from the egg. Therefore, at three days, 20% to 30% of embryos which appear normal under the microscope are actually genetically imbalanced and will not survive after implantation. Therefore more embryos are generally implanted than are needed in the hope that one will survive. Unfortunately, this results in high multiple pregnancy rates; usually 25%—40% of those who conceive have multiple pregnancies, with triplets not unusual.
As our laboratories become better able to support embryo growth, we can hold an embryo in the lab until day 5-6. This improves results in two ways. First, because genetic abnormalities are much easier to detect by the fifth day, we end up with a population of embryos more likely to be genetically normal and capable of ongoing development. Second, we therefore need fewer embryos per implantation, reducing the multiple pregnancy rate while maintaining high pregnancy rates.
Sometimes the embryo needs additional help in the implantation process. Normally, when the embryo reaches the uterus it must break through its own outer membrane, called the zona pellucida, in order to implant. This is known as "hatching" (imagine a chicken hatching from an egg). When the embryo develops in the laboratory, the outer membrane may become thicker and harder than under normal conditions. This can impede the ability of the embryo to break through its wall and implant in the uterus. Sometimes we aid the embryo by purposefully weakening the membrane, either applying an acidic solution at one point, or making a small hole with a tiny glass needle or special laser (still experimental). This is called "assisted hatching." Authorities in the field do not universally accept assisted hatching as a truly beneficial aid, but some feel that it may be helpful, especially in women over 35.
Another technique used in IVF is "co-culture." Co-culture refers to adding live cells grown in tissue culture from the tube, uterus or sometimes kidney of human, primate, or bovine (cow) sources in order to supply hormones, growth factors and nutrients to the embryo while in the incubator. This approach is far from mainstream, and will probably be used less often as media continue to improve.
Phase 4: Phase four is the actual embryo replacement. This is usually quite straightforward. The embryo(s) are drawn into a soft plastic catheter, which is placed through the cervix into the uterus, sometimes with ultrasound guidance, so that the embryo can be delivered to its natural home in the uterus. No anesthesia is necessary. Hormonal values may be checked over the next week, and frequently progesterone supplements are given as injections, vaginal suppositories, vaginal gels, and less commonly by mouth. A pregnancy test usually is done 12-14 days after retrieval (Phase 2).
Variants of IVF
IVF technology has allowed development of egg donation programs whereby women with poor or absent ovarian function can become pregnant using eggs from a healthy young woman. Women who have ovarian function, but who lack a uterus or who have a uterus that is reproductively incompetent, may supply eggs to be fertilized and placed in a recipient's uterus. Known as "carrier gestation," this type of pregnancy is initiated with husband and wife both having genetic input. This is different from surrogate parenting, in which a surrogate mother is inseminated with the sperm from the husband of the patient so that the surrogate mother supplies the eggs.
Sometimes, dependent on egg quantity, quality, and sperm function, we have more embryos than can reasonably be returned to the uterus. These embryos can be frozen (cryopreserved) in liquid nitrogen, probably for an indefinite period of time. In actual practice, if pregnancy has not occurred from the “fresh” transfer of embryos, the stored embryos can be thawed for replacement in the next cycle without the need for stimulation and all the hormonal monitoring. This is referred to as "frozen-thawed replacement."
Additionally, a couple who wants another child can return for frozen-thawed replacement several years after a successful delivery from previous IVF. Studies have shown that the freeze-thaw process does not introduce any increased risk of malformation in the offspring. Embryos can be frozen and thawed with fair success, and sperm has been stored for years and used later. Storage of eggs, however, is quite another matter. We are still in the early learning phases of how to successfully accomplish this. Banking of eggs would allow women facing chemotherapy that might permanently destroy ovarian function to have a reproductive option at a later date, and would also allow women to initiate pregnancy later in life when career and development goals have been satisfied.
Intracytoplasmic sperm injection (ICSI)
Some men have a low enough sperm quality such that standard IVF is not sufficient to induce pregnancy. Intracytoplasmic sperm injection (ICSI) is an IVF technique that involves drilling a small hole through the outer membranes of the egg (oocyte) and introducing a single sperm into the interior (cytoplasm) of the egg with a hollow glass needle. This technique overcomes most of the sperm abnormalities that prevent normal fertilization.
In some men, no sperm are present in the ejaculate produced during intercourse or masturbation but sperm are, in fact, produced in the testes and are blocked from reaching the outside world. This may be due to the lack of development of a duct which carries sperm from the testes to the penis, previous infection or surgery, or because sperm production is extremely limited. Immature sperm can be extracted from the testes with a needle under local anesthesia and injected into an egg using ICSI to achieve pregnancy. Some cases of poor sperm quality involve a genetic sperm problem that can be passed on to a son, so genetic screening of the parents may be needed.
Gamete intrafallopian transfer (GIFT)
Simply stated, this term means placing sperm and eggs into the fallopian tube(s). This was popular as an alternative to standard IVF when the IVF laboratories were less able to support embryo development. As a result, pregnancy rates for GIFT were substantially higher than for IVF, but this is no longer the case. Patient selection is more stringent with GIFT. Candidates need to have at least one normally functioning tube and the sperm quality has to be reasonably good, since the sperm must enter the egg without assistance from the biologist. Egg and sperm placement into the tubes is done surgically, which increases costs and invasiveness. GIFT is still performed today, but with decreasing frequency.
The American Society for Reproductive Medicine (ASRM) through its Society for Assisted Reproductive Technologies (SART) division promotes standards and guidelines for IVF clinics. A visit to their website may be helpful in identifying member clinics in your area.
Stephen L. Corson is a Clinical Professor of Obstetrics and Gynecology at Thomas Jefferson University School of Medicine, Section Head, Reproductive Endocrinology at Thomas Jefferson University School of Medicine, Director of the In Vitro Fertilization Program, Pennsylvania Reproductive Associates at Thomas Jefferson University Hospital, and Director of the Women’s Institute for Fertility, Endocrinology and Menopause. He is a graduate of Wesleyan University and the University of Pennsylvania Medical School. He served his residency in obstetrics and gynecology at Pennsylvania Hospital and is Board Certified in Obstetrics and Gynecology and Reproductive Endocrinology.
Dr. Corson is a member of the American Society for Reproductive Medicine, American College of Obstetrics and Gynecology and the American Association of Gynecologic Laparoscopists. He is author of Conquering Infertility, author or editor of eight medical textbooks and has published extensively in the medical literature. He is editor-in-chief of the International Journal of Fertility and Women's Medicine.
Copyright © Stephen L. Corson. Permission to republish granted to Pregnancy.org, LLC.