During In Vitro Fertilization (IVF), medications are often used to help stimulate the development and release of a woman’s eggs. The eggs and sperm are then collected and placed together in a laboratory dish to fertilize. If the eggs are successfully fertilized, the embryos are then transferred into a woman’s uterus or fallopian tubes. Hopefully, one of the fertilized eggs will implant and develop just as in unassisted conception.
An IVF cycle at NCCRM
In this inital phase, our goal is to create a large number of mature follicles so as to increase the chances of fertilization. Since a woman’s body normally releases one mature egg every month, medications are used to stimulate the ovaries to develop more follicles. Follicles are fluid-filled sacs in which eggs mature. During this stage, we may use ultrasound to monitor the number and size of maturing follicles in your ovaries. Blood tests may also be used to monitor hormone levels which will help determine the best time to administer medication and to retrieve the eggs.
In the second stage, a medication is used to stimulate the release of mature eggs. Our staff will identify the mature follicles using ultrasound, and then, with a needle, withdraw as many eggs as possible from both ovaries.
A few hours before the eggs are retrieved, a semen sample is collected. Thousands of sperm are placed with each egg in the laboratory where they will hopefully form an embryo. When only a few or poor quality sperm is available, Intracytoplasmic Sperm Injection (ICSI) is attempted. In this procedure, a single sperm is injected into an egg to facilitate fertilization. The next day, the eggs are examined under a microscope to determine whether fertilization has occurred. If it has, the embryos will be ready to cryopreserve on day 5 or 6. This cycle allows the stimulation medicines to get the ovaries prepared for eggs, although it seems to have an adverse effect on the uterus due to the medicines having an adverse effect on the patient’s uterine lining, as well as having high estrogen levels placing the uterus out of sync with the embryos.** With this, we have changed our protocol so that our second cycle allows the patient to prepare her uterus for implantation with a much lower dose of estrogen to mimic a more natural cycle.
**This type of cycle is called a “freeze all cycle”. Only centers that have a great freezing program can perform this, as the quality of embryos after thaw is critical. Our practice is one of the best at the new technique, known as vitrification. This is the method we use in our egg bank. Eggs are very sensitive to freezing and we have had wonderful success with frozen eggs. Embryos are less sensitive to vitrification, so it has made frozen embryos a much more successful procedure than in the past. Freeze all cycles also allow us to be more aggressive with stimulation since we trigger in a manner that will never cause hyperstimulation and hyperstimulation is the riskiest part of IVF. This cycle allows a patient to stimulate once and transfer embryos as needed in the future. (NCCRM can usually freeze 8-10 embryos after one stimulation cycle.) In addition, freezing all your eggs allows those worried about having too many frozen embryos for the future, to only fertilize a couple of eggs and freeze eggs for future use as needed. Finally, research has also shown that frozen cycles have resulted in healthier babies that have a higher birth weight.
After embryos are frozen, we wait for the female to start her menses to prep her uterus for embryo transfer. The first cycle allows the stimulation medicines to get the ovaries prepared for eggs, but seems to hinder the uterus for preparing for transfer due to the medicines having an adverse effect on the patient’s uterine lining. With this, we have separated the cycles so that our second cycle allows the patient to prepare her uterus for implantation. The patient will begin roughly a 21 day regime of estrogen/progesterone to prepare the lining of the uterus. After this time, the embryo will be ready for transfer into the uterus. The embryos are placed in a tube and transferred back into the uterus. The procedure is usually painless, though some women may experience some cramping. The number of embryos transferred depends on a woman’s age, cause of infertility, pregnancy history, and other factors.
Making an Informed Decision
Societal changes over the past two or three decades have led to an increasing number of women who postpone childbearing to a later age. The purpose of this article is to assist older, infertile couples to make an informed decision about treatment. The important issues to be considered are discussed below:
- Advancing age is associated with a progressive decline in a woman’s fertility. This is true whether considering natural conception or assisted conception.
- All forms of infertility treatment, including in vitro fertilization and embryo transfer (IVF/ET), have reduced pregnancy rates in women over 40 years of age.
- The likelihood that IVF/ET represents the only opportunity of achieving pregnancy is greater for women over 40 years. This is because many diseases such as endometriosis and tubal disease, which lead to infertility, are more common at this age.
The cost of IVF/ET is likely to be greater for older women because reduced success rates and higher miscarriage rates.
National statistics show low pregnancy and birth rates for women over 40 years of age who undergo IVF/ET. However, it is possible to do testing to identify those women whose prognosis is especially poor and suggest other options, such as the use of donor eggs.
Factors Influencing Success Following IVF/ET
All the eggs that a woman will ever have are produced by about six months of age while she is still in her mother’s uterus. No new eggs are produced after this time. At six months, there are about 4-5 million eggs. The number has declined to 1-2 million at birth, and by puberty there are less than one million eggs. The number of eggs rapidly declines. At the time of menopause, only a miniscule number of eggs remain. Not only does the number of eggs decrease, but the quality of eggs also are compromised by genetic changes, either chromosomal breaks or more subtle genetic changes. Therefore, in women over 40, the pregnancy rate declines dramatically and the spontaneous abortion rare increases. Some studies show the abortion rate in over 40 women to be over 50 %.
In order to compensate for the decreasing embryo quality, many clinics transfer a larger number of embryos (more than 4) to the uterus in an effort to off-set the quality problems by providing more embryos for implantation. The less healthy embryos will be rejected, favoring implantation of the healthy ones.
Number of Embryos available for Transfer to the Uterus
As the woman ages, the response to fertility drugs decreases, and thus the number of embryos available for transfer to the uterus.
Pelvic disease due to chronic inflammation, previous surgery, or severe pelvic endometriosis may result in a reduction in the amount of functional ovarian tissue available. This could influence ovarian response to hormones that induce ovulation and accordingly the potential to produce an optimal number of eggs for IVF/ET. The presence of uterine fibroids (a benign type of uterine tumor), are more common in older women. If present, may need removal before resorting to one of the assisted reproductive technologies.
Sperm quality is a major factor which influences the likelihood that eggs can be successfully fertilized in vitro. Except in very old age, sperm quality is not age related. The decision use one’s own eggs or resort to donor eggs is sometimes a difficult one. The clomiphene challenge test is useful, in that it can often sort out the women who are predicted to have a poor prognosis.
However, many women decide to try at least one cycle with their own eggs before resorting to a donor. We would be glad to help in any way possible in making this very hard decision.
Intracytoplasmic Sperm Injection (ICSI)
Intracytoplasmic sperm injection (ICSI) is an established technique for insuring that sperm penetration of the egg occurs. Many failures at assisted reproduction can be attributed to failure of the process of fertilization of the egg. Sperm penetration of the egg is the first event that is necessary but not sufficient for completion of the fertilization process. ICSI is highly successful when performed by well trained embryologists and results in pregnancy rates that are similar to those resulting from conventional in vitro insemination of the egg. Indeed, here at the NCCRM, for the calendar year of 1999 pregnancy rates were 59% for ICSI compared to 54% for conventional insemination . The sperm injection technique consists of micro-manipulation of both the egg and a single sperm. Performed at a magnification of from 200 to 400 times normal sight, a single, normally shaped, mobile sperm is aspirated into a glass injection needle. The needle has a barrel size a little bit larger than the size of the sperm head and the sperm is loaded tail first. The egg is held firmly in a certain orientation by using another piece of glass tubing (holding pipette) and the needle is gently pushed through the egg’s shell and into the center of the egg where the sperm is delivered head first and the needle carefully removed. The egg with sperm is then placed in culture medium for completion of fertilization and further embryonic growth. ICSI can only be performed on eggs that have reached the proper stage of maturation . Therefore, not all eggs that are retrieved will undergo the procedure because it is highly unlikely that any ovarian stimulation protocol will produce a harvest of eggs that are all mature.
The decision to include ICSI in the treatment plan of any couple is based on several criteria. Semen analysis results are usually the determining factor in most cases. If the total motile sperm count is less than 40 million and/or the number of abnormally formed sperm in the sample is greater than 96% of the total sperm, then ICSI becomes a part of the treatment plan and is usually performed. Also, if a prior cycle of IVF that used conventional insemination failed to result in fertilization of at least 40% of the mature eggs harvested, then ICSI will be performed. ICSI is the only choice when sperm are obtained by the surgical procedures of epididymal aspiration or testicular biopsy. Further, if five or less eggs are harvested, then ICSI is performed in order to avoid the risk of failure of sperm penetration of such few eggs and total failure of the cycle. Finally, if the male partner has been tested and the results were positive for the presence of anti-sperm antibodies or if his medical history indicates a probability of having anti-sperm antibodies, ICSI will be performed.
There are some potential risks associated with the ICSI procedure. These involve the egg and embryos, not with a risk to the patient or the offspring. Many healthy babies have been born from embryos produced by ICSI at this center and world-wide. There is no clear evidence that ICSI produces a rate of birth defects any greater than those associated with natural conception. The main risk to the egg is disruption of its normal architecture by piercing it with the needle which results in failure of fertilization. However, fertilization rates with ICSI are similar to those of naturally penetrated eggs in vitro (about 75%).
In summary, the ICSI procedure has proven to be an invaluable tool in the embryologist’s arsenal of techniques to jump the first hurdle of sperm penetration of the egg in the overall goal of in vitro production of embryos for transfer into the patient with high expectations of conception, pregnancy and birth.
The use of fertility drugs, especially gonadotropins for ovulation induction, intrauterine insemination and in vitro fertilization have greatly increased the prevalence of multiple gestation. The rate of high order multiples (greater than twins) increased more than 100% between 1972 and 1990, approaching 80 per 100,000 live births by 1990. Because of the increased risk of prematurity and its associated problems, this has placed a large burden on both health care facilities and the couples coping, not only with prematurity, but also with caring for the children after multiple birth
The probability of prematurity (birth weight less than 2500 gms, five and one half pounds) increases with the number of fetuses, rising from about 5% in single births to 50% of twins. The average birth weight of twins is about 2300 gms. In higher order multiple births, 15% weigh 1000 gms or less compared with only 0.4% of single births, and 33% weighed less than 1500gm. The infant will usually reach a weight of 1500 grams at about 29 weeks gestation. This increase in the incidence of prematurity is associated with an increased risk of perinatal death and also a small but real risk for handicap of surviving infants. The risk of neonatal death is directly related to the weight at birth. The perinatal mortality of infants weighing between 600 and 699 grams is 800/ 1000, and 145/ 1000 at 1000 to 1299 gms. Infants who weigh over 2500 gm. have a loss rate of 6/ 1000. One large, recent study of 4004 infants born between 20 and 25 weeks showed that only 1185 (30%) had signs of life at birth, and of these, 843 were admitted to the neonatal intensive care nursery, the remainder having died in the delivery room. At 30 months of age, 49% of surviving infants were normal, 23% had severe disability and another 25% had less severe disability. A large study from Australia showed a prevalence of cerebral palsy in triplet births to be 28/1000 births, while the rates for twins and singletons was 7.3 and 1.6 respectively per thousand births. The evidence for mental impairment is less secure, but most studies show a small increase as the order of multiples increases. Another study from Japan showed that 3% of twins had some handicap, as compared with triplets at 8% and quadruplets at 11%. All the handicaps were not neurologic, and may not have been related to multiple pregnancies.
Maternal complications of pregnancy, while rarely life threatening, are much more common in multiple pregnancies. The risk of pregnancy induced hypertension (pre-eclampsia) is increased, and long term bed rest or hospitalization is frequently necessary. The latter is more common in high order multiples. Because of possible complications of labor and delivery, the incidence of cesarean section is also increased.
Causes of Multiple Gestation
A large portion of infertile women are not ovulating, and ovulation induction is required to achieve pregnancy. All the drugs used to induce ovulation are associated with an increased risk for multiples. Clomiphene citrate (clomid, serrophene) causes a risk of about 6%, but the great majority of these multiples are twins. It is quite unusual to have more than twins, but high order multiples may occur even with clomiphene citrate.
A minority of women do not respond to clomiphene, and more effective drugs are required. The next step in these non-responding women is the use of gonadotropins (GonalF, follistim, humagon etc). These drugs act directly on the ovaries and usually produce multiple ovulations. It is not possible to assure a woman that she will not have a multiple pregnancy when she is taking any of these drugs. The risk for multiples in women taking gonadotropins is about 30%, mostly twins, but these are the women most likely to have high order multiples. Controlled ovarian hyperstimulation with gonadotropins combined with intrauterine insemination is often used in women with open tubes, but also is associated with a high incidence of multiples.
In Vitro Fertilization (IVF)
In patients undergoing IVF, the pregnancy rate is related to the number of embryos placed in the uterus. In a woman less than 35 years of age, placing one embryo in the uterus would yield a pregnancy rate of around 25%, while placing three would result in a rate approaching 70%, but at the cost of a higher rate of multiples. The number of embryos replaced also depends on the patient’s age since there is a lower rate of implantation in older women. The apparent quality of the embryos must also be added to the equation, making the decision about the number of embryos to implant much more difficult than one of simple arithmetic. Ultimately, the patient makes the final decision. But our staff will be involved to try to assure that nothing is done to increase the risk greatly.
What to do if a high order multiple pregnancy occurs?
The choice of care is made, as always, by the patient. Some couples elect to carry quadruplets or triplets and accept the known risks. Others decide to do selective reduction and reduce the number to twins. Please read the section below for information on this procedure.
Selective or Fetal Reduction
Reduction usually is done between nine and ten weeks. The patient is sufficiently sedated that she feels no pain. A needle is inserted through the vagina into the fetal sac under ultrasound guidance, and a small amount of potassium chloride is injected. The reduced fetus is simply resorbed into the woman’s body. There is, of course, a small risk that the entire pregnancy will be lost, and the better centers report this risk at about 5-10%.
The staff at NCCRM understand that the decision to reduce is a very difficult and emotional one, and some women decide to carry a high order multiple pregnancy in spite of the risk. We will make every effort to provide as much support and help in decision making as possible.