In Vitro Fertilization (IVF) The Good, The Bad And The Ugly
Assisted Reproductive Technology (ART)
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Even though a women's menstrual cycle will continue to be regular in her 30's and 40's, the quality of the eggs ovulated each month will be poorer than those of her 20's. Though not as abrupt or noticeable as menopause in women, changes in fertility do occur in men as they age. The causes of infertility are multiple:
- Ovulatory dysfunction
- Tubal/uterine/peritoneal factor
- Immunological problems, chromosomal abnormalities, cancerchemotherapy, and serious illnesses
- One should distinguish infertility and fecundity problem (the ability to produce a live offspring after pregnancy occurs)when immunological problems are involved
- Abnormal semen: decreased sperm counts, failure of spermmaturation, increased viscosity of sperm
- Chromosomal abnormalities
- Cryptorchidism (when testicles have not descended into thescrotum after birth)
- Varicocele (abnormal collection of dilated veins in thetesticles resulting in impaired drainage of blood)
- Endocrine disorders
- Drugs (anti-cancer)
- Immunologic reactions
There are numerous forms of Assisted Reproductive Technology (ART) including, ovulation induction, the use of fertility drugs to stimulate the ovarian follicles to produce multiple eggs in one cycle. Ovulation inducing drugs, such as gonadotropins (FSH) or clomiphene also control the time that a women releases eggs (ovulates) so sexual intercourse, intrauterine inseminations or In Vitro Fertilization procedures can be scheduled at the appropriate time to achieve pregnancy.
Clomiphene citrate (CC), the most commonly prescribed ovulation-inducing drug, is an orally administered non-steroidal agent with proven ovulation induction properties. (Brand names are Serophene and Clomid.) CC is used to induce ovulation in women who are not ovulating (anovulation) or not ovulating regularly (oligo-ovulation). It is also used to time ovulation for patients who plan to undergo intrauterine insemination (IUI). CC is the first line treatment for women with PCOS (Polycystic Ovary Syndrome) but is often ineffective when anovulation (no ovulation) results from a hypothalamic or pituitary causes.
Clomiphene citrate (CC) promotes ovulation by signalling the hypothalamus to produce gonadotropin releasing hormone (GnRH), which in turn prompts the pituitary gland to secrete the gonadotropins, FSH and later LH, thus causing the ovarian follicles to produce estrogen, and initiate the process of ovulation. CC administration leads to the maturation of one follicle in about 50% of cycles and 2 or 3 follicles in the other half of cycles. In CC cycles, when the ovarian response is appropriate (growth of one or more follicles), ovulation occurs spontaneously. If the physician wishes to time ovulation, hCG is administered when at least one follicle is 19 mm. Ovulation will occur 36 hours later. CC is used at doses ranging from 50 to 200 mg /day for 5 days, however, the most commonly used dose is 100 mg (50 mg x 2 tablets) from day 3 to 7 of the cycle.
There are limits to the use of clomiphene. Clomiphene has antiestrogenic effects on the cervical mucus and endometrium that can impede conception by altering mucus quality (thickening and drying thereby, preventing sperm passage) and thinning the endometrium, preventing implantation. This partly explains why the ovulation rate with CC is high; nearly 80%, but cumulative pregnancy rates are only 27-40%.
In women who do not respond well to oral clomiphene citrate or who fail to conceive after 3 documented ovulatory clomiphene cycles the gonadotropins, human menopausal gonadotropins (hMG a combination of FSH and LH extracted from the urine of menopausal women), highly purified FSH, and recombinant FSH (rec-FSH) are alternative agents for ovulation induction. These injectable gonadotropins have a direct impact on the ovaries by stimulating multiple follicular development and follicular growth. FSH bypasses the hypothalamus and the pituitary gland to directly stimulate ovarian follicle growth. The goal of gonadotropin use is to achieve one or more mature follicles and appropriate levels of estradiol, so that ovulation can be triggered by a human chorionic gonadotropin (hCG) injection. (hCG is extracted from the urine of pregnant women, or made with biotechnology.) hCG is virtually identical in chemical structure and function to that of pituitary LH but has more persistent effect (longer half-life). hCG is used in ovulation induction cycles as a substitute for the LH surge in a natural cycle.
These agents are more complex to use and have a greater potential for side effects. Controlled Ovarian Hyperstimulation (COH) requires careful monitoring of multiple follicular growth using repeated ultrasounds and E2 (estrogen) level measurements. The dose of gonadotropins should be adjusted to maximize oocyte retrieval while avoiding the risk of Ovarian Hyperstimulation Syndrome (OHSS), a potentially life threatening condition. In addition, injectable gonadotropins significantly increase the risk of multiple pregnancies.
In Vitro Fertilization (IVF)
The technique that gets the most publicity and engenders the greatest controversy is In Vitro Fertilization (IVF).
Step 1 - Controlled Ovarian Hyperstimulation (COH)
Three types of drugs are used in COH:
1. GnRH-agonist (Gonadotropin Releasing Hormone Agonist) or a GnRH-Antagonist - the purpose of which is to suppress the release of Luteinizing Hormone (LH) from the pituitary gland during the COH protocol. An LH surge would cause premature ovulation and disrupt the timing of the cycle.
2. Gonadotropins, FSH (Follicle Stimulating Hormone) or hMG (Human menopausal gonadotropins) stimulate the development of multiple ovarian follicles. Ovarian response to the gonadotropins is measured using vaginal ultrasounds. Using these ultrasounds physicians can monitor the growth of the follicles.
3. When the largest follicle reaches approximately 18mm in diameter, an injection of hCG (Human Chorionic Gonadotropin) is administered to ensure the final maturation of the follicles. Egg collection occurs approximately 36 hours after the hCG injection.
Step 2. Egg Retrieval
A sterile needle is passed through the top of the vagina under ultrasound guidance to access the ovarian follicles. Once the needle is inside a follicle, suction is created which pulls the egg and the fluid through the needle and into a collection tube. When one follicle is drained, the needle is gently repositioned to collect fluid from each adjacent follicle. The fluid with the eggs is passed to the IVF lab where the eggs are identified, rinsed in culture media, and placed in small culture drops in plastic dishes. The dishes with the eggs are then kept in specialized IVF incubators under carefully controlled environmental conditions.
Exogenous progesterone supplementation for luteal phase support is usually administered 1-2 days after oocyte (egg) retrieval, to help prepare the endometrium for implantation.
Step 3. Egg Fertilization and Embryo Culture
The eggs and several thousand sperm are placed together in a dish, which contains a nutrient liquid. These dishes are kept in an incubator overnight and are examined under the microscope on the morning after the egg retrieval to determine which eggs have been fertilized.
Today because of the often-confounding problem of poor sperm quality a technique called Intracytoplasmic Sperm Injection, or ICSI is used in most IVF cycles. In this procedure an extremely sharp glass needle is used to inject one quality sperm directly into the center (cytoplasm) of the egg under the guidance of a specially fitted microscope.
Step 4. Embryo Culture
One of the most important aspects of a successful IVF cycle is the handling of the eggs and embryos outside of the body. Among the standard protocols is the use of sequential media, which is designed to physiologically resemble the environment in the fallopian tubes and uterus as the embryos matures.
After 16 to 18 hours, the specimen is examined to see if fertilization has taken place. Fertilization is demonstrated by the presence of two pronuclei indicating that the egg has been penetrated by one sperm. A pronucleus (plural: pronuclei) is the nucleus of a sperm or an egg cell during the process of fertilization, after the sperm enters the ovum, but before they fuse. (The egg and sperm each contribute 23 chromosomes to make up the full complement of 46.) The zygote (embryo) forms just after the fusion of the two pronuclei. The zygote remains in the culture medium until the 4 to 8 cell stage is achieved. The 4-8-cell stage embryo is then ready to be transferred in the mother's uterus 3 days after fertilization i.e. prior to normal entry into the uterine cavity and prior to the implantation process. If the embryo(s) are grown until the blastocyst stage, then they will be transferred 5 days after fertilization.
In order for the advanced embryos to implant in the uterine wall and to continue to develop, they must break free of their shell, the zona pellucida. During the initial stages of development, the embryo is contained in a layer of proteins, known as the zona pellucida. The zona pellucida is designed to protect the embryo until it reaches the blastocyst stage of development. In order to successfully implant into the uterine lining, the embryo needs to hatch out of this zona pellucida and attach to the walls of the uterus. Normally, the zona pellucida disintegrates by itself 5 days after fertilization. Sometimes, embryos have a difficult time hatching out of their protective layer. This can occur if the zona pellucida is too thick or if the embryo does not have enough energy to break through the layer. On the third day of laboratory growth and shortly prior to uterine transfer, a small hole is made in the zona pellucida of the embryo with a specially fitted microscope. Through this opening, the cells of the embryo can escape from the she'll and implant at a somewhat earlier time of development, when the uterine lining may be more receptive.
Step 5 Embryo Transfer
Three to five days after egg collection and fertilization, the embryos are placed inside the woman's uterus. The embryo transfer catheter is loaded with the embryos and the physician passes it through the cervical opening up to the middle of the uterine cavity. Abdominal ultrasound is used simultaneously to watch the catheter tip advance to the proper location.
Step 6. Pregnancy
The most important question is what is the chance of delivering a baby after a day 3 or day 5 (blastocyst) transfer.
IVF centres report their success rates. Several definitions for success are used so it is important to understand the definitions:
- Biochemical pregnancy per cycle rate:the percentage of treatment cycles started that produced a pregnancy, i.e.a positive pregnancy test (serum b-hCG concentration) taken at approximately 2 weeks after fertilization.
- Clinical pregnancy per cycle rate: thepercentage of treatment cycles started that produced a pregnancy confirmedby the presence of a gestational sac observed on ultrasounds 2-4 weeksafter a positive hCG.
- Ongoing pregnancy per cycle rate isdefined by identifying a fetal heartbeat at week 20.
- Overall pregnancy per cycle rate is ofcourse higher than the live birth per cycle rate because some pregnanciesend in miscarriage, therapeutic abortion, or stillbirth.
The recent birth of the octuplets in California has opened a nationwide debate about the ethical use of Assisted Reproductive Technology (ART). First reports from Los Angeles seemed to be touting a miracle. The only miracle would be if these unfortunate eight children avoid severe developmental problems. The objective of Assisted Reproductive Technologies (ART) should always be one pregnancy - one child. I understand that current ART techniques such as IVF will result in twins, which is acceptable but not ideal. It is time we adopted the European standard and forbade the transfer of more than 3 embryos in any IVF procedure. Lack of such a rule clearly leads to unethical abuses that put the health of the mother and children at high risk. It is also a disservice to women in general. How will we ever convince insurance companies that universal coverage for infertility treatment is a woman's right if they can read about it's abuses in their morning paper.
According to SART (Society for Assisted Reproductive Technology) the average number of embryos transferred in women under the age of 37 is approximately 2.5 and for women above 40, it is 3.2. The percentage of live births with twins is 32.3% in women under 35, gradually declining to 15.5% in women above the age of 40. The percentage of triplets or more is 2.0% for women under 35 and 0.6% for women above age 40.
The United States is probably the only country in the developed world that permits practitioners to implant more than three embryos. The recent octuplet fiasco clearly demonstrates the need for ethical restraint in the United States. One obvious solution is for state medical authorities and professional organizations such as The American Society of Reproductive Medicine to ban the transfer of more than three embryos and to encourage the transfer of no more than 2 blastocysts.
To circumvent this problem some ART practitioners ask patients to agree to "pregnancy reduction" when more than 2 or 3 embryos implant. The most common method of pregnancy reduction is the injection of potassium chloride into the fetal cardiac region, usually performed at or after the ninth week of gestation. This is at best an imperfect solution, as many women find it difficult to sanction the selective demise of one or more of the fetuses that have implanted. By limiting the number of embryos transferred this ethical dilemma is avoided.
Multiple births are not the only ethical problem that must be addressed. In some women the age of the eggs precludes success in IVF. In those cases, an egg donor may be chosen so that a younger woman's eggs can be used to enhance the likelihood of conception. The egg donor is matched based on ethnic, social and physical characteristics. Using these technique older women whose ovaries have ceased to produce viable eggs can become pregnant.
Should there be an age limit? Pregnancy, even in a young woman can be physically taxing, and it clearly could be dangerous in a 65-year-old women. Yet, there are practitioners who have assisted women of that age to have a child. There are exceptions, but most 65 year olds would be putting their health at undue risk with a pregnancy.
One solution to this problem would be to limit ovum donation to women 50 to 55 years, unless there we're extraordinary circumstances.
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