| Month | Monthly Probability | Cumulative Probability |
|---|---|---|
| 1 | 0.2 | 0.20 |
| 2 | 0.2 | 0.36 |
| 3 | 0.2 | 0.49 |
| 4 | 0.2 | 0.59 |
| 5 | 0.2 | 0.67 |
| 6 | 0.2 | 0.74 |
| 7 | 0.2 | 0.79 |
| 8 | 0.2 | 0.83 |
| 9 | 0.2 | 0.86 |
| 10 | 0.2 | 0.89 |
| 11 | 0.2 | 0.91 |
| 12 | 0.2 | 0.93 |
- Clomiphene citrate (50 mg on days 5-9)
- Clomiphene citrate (100 mg on days 2-6) plus FSH (1-2 amps starting on day 8)
- Clomiphene citrate plus human chorionic gonadotropin (hCG) for ovulation induction
- Elevated androgen levels – Dexamethasone (0.25 mg/d) plus clomiphene citrate
- Hyperinsulinemia with elevated androgens - Metformin (500 mg tid) plus clomiphene citrate (Many women spontaneously ovulate on metformin alone; thus, many clinicians allow a trial of 1-3 mo prior to adding clomiphene citrate.)
- Aromatase inhibitors (Letrozole) (2.5 mg PO on cycle days 3-7) has been shown in early studies to work as well as clomiphene citrate to induce mono-ovulation and to have little or no adverse affect on endometrial thickness.
Pregnancy rate following treatment can be dependent upon location of tubal disease.
Laparoscopic lysis of adhesions offers the patient a window of opportunity to conceive either naturally or with minimal types of therapy. If only proximal tubal occlusion is present, these obstructions can be fixed with a balloon tuboplasty under fluoroscopic guidance similar to the common angioplastic procedure in cardiology.
Table 4. Treatment of Tubal Pathology
| Procedure | Pregnancy Rate (3-6 mo) |
|---|---|
| Lysis of adhesions | 50% |
| Mild distal obstructive disease | 80% |
| Moderate distal obstructive disease | 30% |
| Severe distal obstructive disease | 15% |
| Proximal tubal obstruction: | 30% |
Treatment of endocrine abnormalities
Treatment of unexplained infertility
Table 5. Unexplained Infertility and Pregnancy Rates per Cycle According to Treatment
| Protocol | Pregnancy Rate, % |
|---|---|
| No treatment | 1.3-4.1 |
| IUI alone | 3.8 |
| Clomiphene with timed coitus | 5.6 |
| Clomiphene with IUI | 10 |
| Gonadotropins with timed coitus | 7.7 |
| Gonadotropins with IUI | 17.1 |
| IVF | 35-50 |
The first IVF pregnancy was achieved in 1978. Since then, the number of IVF centers and IVF procedures performed has increased dramatically. An intense effort to obtain insurance coverage for these services has also occurred. With the support of organizations such as (ie, the National Fertility Association), 13 US states have the opportunity to provide coverage for these services. Currently, 2 states (Massachusetts and Rhode Island) offer full coverage. Other states exempt health maintenance organization programs, private insurers, or companies with few employees. Other states offer lifetime limits to their coverage (eg, Ohio, $2000; Arkansas, $15,000). Still other states require insurers to offer coverage but do not require employers to purchase plans that actually provide that coverage. The actual cost per paid subscriber is not substantial. A recent study in Massachusetts, which has approximately 5000 IVF cycles per year, calculated that the increase is only$25 per year per subscriber.
As a result of the Fertility Clinic Success Rate and Certification Act, the US Centers for Disease Control and Prevention (CDC) gathers information from 391 of the 428 fertility clinics throughout the United States. Information from 2002 shows that 115,392 ART cycles were performed.
Assisted reproductive techniques
Gamete intrafallopian transfer (GIFT) was developed in 1984 for women with unexplained infertility. At that time, GIFT provided much better pregnancy rates, had a much greater degree of naturalness, and was more acceptable in certain religious and ethnic communities (in which fertilization inside the woman's body is the only type allowed). During this procedure, the patient undergoes a controlled ovarian hyperstimulation. The oocytes are retrieved transvaginally under ultrasonographic guidance, and 3-4 oocytes are placed via laparoscopy into one of the fallopian tubes along with sperm.
Zygote intrafallopian transfer (ZIFT) is used for couples with a significant male factor. The oocytes are retrieved similar to GIFT, but they are allowed to fertilize in vitro in the laboratory. At the 2-pronuclear stage (usually 24 h later), 3-4 embryos are transferred via laparoscopy into one of the fallopian tubes. If the embryos are allowed to develop to greater than a 2-cell stage, the procedure is termed tubal embryo transfer (TET). The only benefit to a ZIFT or TET versus the more traditional IVF is for women who are thought to have compromised embryo quality due to embryo in vitro culture. Placing these zygotes or embryos back into their own natural incubators is thought to enhance subsequent development, with improved pregnancy rates.
With the development of enhanced culture media, the success rates for IVF are now comparable, if not better, to those of GIFT and ZIFT.
Interpreting IVF success rates
Comparing one program's success rate to another is difficult because of all the variables involved. For instance, perhaps a program is very selective with its patients, allowing only those with a chance for success based on diagnosis, age, or ovarian reserve. Programs in states that are mandated to cover fertility therapy may be more likely to treat patients with a low chance for success simply because the patient has insurance or, perhaps, because the programs may perform more IVF cycles than programs in states without such a mandate. Some have suggested that programs in mandated states, due to the treatment algorithms enforced by the insurance companies, often have to treat patients without a male or tubal factor for many months with insemination cycles before getting approval for IVF coverage. Thus, these patients may actually be the most difficult patients to treat when they eventually get to IVF.
On the other hand, programs in states without a mandate may be dealing with more difficult patients who have had multiple surgeries and other covered or less costly therapy before ultimately deciding on IVF. However, some argue that many of these programs often take patients directly to IVF, or after a few insemination cycles, and, thus, these patients are more likely to be successful.
In general, like any statistical analysis, the more IVF cycles a program has performed, the more valid the numbers. The cancellation rate is a critical number. If the rate is high, the program is possibly very selective for those patients it allows to proceed to egg retrieval. This type of program would rather cancel the patient's procedure than have a low chance for success that may ultimately hurt its overall success rates. The pregnancy rate per retrieval is higher compared with the pregnancy rate per transfer. If this difference is large, it may reflect the quality of the laboratory. The implantation rate refers to thepregnancy rate divided by the number of embryos transferred. If the implantation rate is low and the pregnancy rate is high, this suggests that the program is transferring a large number of embryos per patient to achieve that success. Chances are good that the program's multiple pregnancy rate is high. Optimally, the better programs have a low cancellation rate and good pregnancy and implantation rates.
The ultimate critical number is the birth rate because this represents the final goal of the patient and the physician. This goal is also less vulnerable to misinterpretation than the pregnancy rate (single positive hCG vs serial increases) or the clinical pregnancy rate (gestational sac vs fetal pole vs fetal pole with heartbeat).
IVF outcomes
In 2002, 115,392 IVF cycles were reported started with a 14.6% cancellation rate, and, 45,751 pregnancies were confirmed delivered. One of every 2.5 IVF cycles started ended in a live birth. When observing cycles that ended in a uterine pregnancy (30.5%), most ended in a singleton birth. The miscarriage rate is no higher than that with a spontaneous pregnancy (ie, 16.1%).
Guidelines for embryo transfer
In response to the significant numbers of higher order multiple pregnancies generated from ART, the American Society of Reproductive Medicine (ASRM) released guidelines for the number of embryos transferred in 1999. Shows the risk of having a multiple-fetus pregnancy using fresh, nondonor embryos.
In 2002, the total multiple-fetus pregnancy rate was 36%. A lower number of deliveries of triplets or more compared to pregnancies suggests that these pregnancies were either iatrogenically reduced, spontaneously reduced, or resulted in a miscarriage.
Increasing the number of embryos transferred from 1 to 2 not only increases the chance for a live birth but also increases the likelihood of a multiple-infant pregnancy. However, transferring more than 2 embryos may not increase the overall live birth rate.
Many variables affect the decision of how many embryos to transfer. Factors such as the patient's age, embryo quality, number of prior failed IVF cycles, and use of frozen-thawed embryos are important to consider. New data from Europe suggests that a single embryo transfer in the appropriate patient results in approximately a 35% pregnancy rate with a less than 1% multiple pregnancy rate. These patients typically have embryos that are frozen, ensuring that their cumulative pregnancy rate using either fresh or frozen embryos is similar to transferring 2 or more embryos. Show the relationship between the number of embryos transferred and the risk of having a multiple-infant birth in women of all ages and in women younger than 35 years. Single embryo transfer is appropriate in certain situations where the likelihood of a multiple pregnancy is high. This may include women younger than 35 years, women who conceived with first IVF cycle, women with only tubal factorinfertility, women with concerns about multiple gestation, and donor egg recipients.
Factors contributing to IVF success
The most important factor that determines a successful cycle is the female patient's age. As mentioned previously, decreases in fecundity rates are observed beginning as early as age 30 years. The dramatic effect that age has on fecundability is also observed in ART (see Image 7). Most egg donors are aged 20-35 years, allowing for an optimal control group to observe these differences.
Ultimately, the success of ARTs mimics the overall fecundity trend observed in the general fertile population. That is, pregnancy and live birth rates start to decrease beginning around age 30 years and continue to decrease until the chance of having a live birth is so low that the benefit of ARTs must be evaluated. In women older than 40 years, the chance of having a liveborn infant with a chromosomal abnormality also increases. The live birth rate with ARTs based on the patient's age and whether she uses her own oocytes or donor eggs, which are typically harvested from women aged 20-35 years.
Oocyte retrieval
Oocyte retrieval is performed approximately 36 hours after 10,000 U of hCG is administered to allow for the resumption of meiosis, cytoplasmic maturation, and loosening of the oocytes within the follicle. This allows for a lower optimal vacuum pressure during aspiration and ultimately less oocyte damage.
The 3 basic methods to retrieve oocytes are laparoscopic, transabdominal, or transvaginal. The laparoscopic approach was used frequently in the 1980s, especially when a GIFT procedure was planned. Often, only the follicles that could be seen on the surface of the ovary were removed, and, if the ovary was very mobile, traction was required to support the ovary as the follicles were aspirated. Associated morbidity occurred with the procedure, which included infection and injury to the pelvic organs. General endotracheal anesthesia was usually used, and the patient's recovery often lasted 2-3 days. As the quality of ultrasonographic images and culture media improved, the need for laparoscopy decreased.
In 1981, ultrasonographic-guided aspiration was first described. Initially, the transabdominal approach was used, usually with the aspirating needle going through the bladder, which, when full, provided a window of visualization for the person operating the abdominal ultrasonographic probe.
Although still used for retrieval of oocytes from ovaries that are adhered high up in the pelvis or to the fundus of the uterus, the transabdominal approach was superseded by the transvaginal approach. The first transvaginal retrieval was performed in 1984 and has now become the procedure of choice because of its ease and low morbidity.
Micromanipulation
Intracytoplasmic sperm injection (ICSI) is the treatment of choice for couples in whom the male partner has azoospermia or severe oligospermia. ICSI is also indicated for men with significant antisperm antibodies, low sperm motility, or significantly abnormal sperm morphology (Kruger strict morphology <4%).>
ICSI is used when poor fertilization occurs with regular insemination techniques in the laboratory. ICSI may be used when a limited amount of sperm is available, such as in couples where the man has stored sperm prior to chemotherapy. ICSI is indicated in certain preimplantation genetic (PGD) procedures—specifically those cases being evaluated for single-gene recessive disorders. This prevents the potential contamination of the specimen with sperm that may be attached to the egg.
Sperm can be obtained from the ejaculate or directly from the epididymis. Recently, success was obtained with spermatids from testicular biopsies.
The potential transmission of a genetic abnormality is a possibility when ICSI is performed. The normal barrier for morphologically abnormal sperm that tend to have genetic abnormalities (ie, zonal pellucida) is bypassed with ICSI. Morphologically normal sperm may also have genetic abnormalities. Approximately 10% of sperm from healthy men have chromosomal abnormalities. Men who are infertile have a 5-7% chance of having a chromosomal abnormality. Chromosomal abnormalities include microdeletions of the long arm of the Y chromosome in areas AZFa, AZFb, and AZFc (DAZ or deleted in azoospermia region). These deletions can be passed on to male offspring, with resulting oligospermia.
Some data suggest a 30% increase in birth defects in children conceived with ICSI. Overall, this implies that the risk of having a child with a birth defect from ART with ICSI goes from a normal baseline of 3% to, at most, 4%.
Approximately 1-2% of men with azoospermia have genetic translocation, Klinefelter syndrome (47XXY), or a congenital bilateral absence of the vas deferens, which is associated with mutations in the cystic fibrosis transmembrane regulator (CFTR) gene or the 5T allele.
