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1. Patient Selectionto "Why does IVF fail?" main page The selection of patients for IVF may have the greatest impact on pregnancy rates. The patients that undergo IVF are a very heterogeneous group. It is unlikely that prior to their IVF they have had the same treatments. This makes it difficult to directly compare the results of treatment. In fact, different clinics have different patient populations and selection criteria, so one cannot compare clinic pregnancy rates directly according to SART. Factors involved with patient selection include age, ovarian reserve, diagnosis, smoking, and pre-op evaluation. a. AgeJust as fertility rates decline with age normally, we see the same with IVF patients. The most important factor affecting the outcome of assisted reproductive technologies is the age of the woman. When couples undergo IVF, the national statistics, as presented by the Centers for Disease Control (CDC) shows that not all IVF cycles result in conception. Table 1 below represents patients of all ages doing IVF in the US for the year 2004. Overall, 33.7 % were pregnant, 65.6 % were not pregnant and 0.7% had an ectopic pregnancy. Of the patients that got pregnant (82.1 %) 55.4 % had singletons and 26.7 % had multiple gestations? 17% had adverse outcomes which were miscarriages (15.5 %), stillborns (0.7%) and induced abortions (0.8%). Age plays a huge role in pregnancy rates. Table 1. Effect of age on IVF pregnancy rate nationally in 2004.
Individual programs have different pregnancy rates for these age groups and it is difficult to compare programs because programs may have different selection criteria and different patient populations. During a patient’s mid to late thirties a decline is seen in pregnancy rates. This is due factors present within the egg that affect fertilization, embryo growth, and eventual pregnancy. Tests of ovarian reserve, i.e. clomid challenge test, basal follicle count, or day #3 FSH, may identify patients with a significantly reduced chance to conceive (see below). We are beginning to understand factors that may be involved with ovarian ageing. Studies have noted age dependent declines in ovarian enzymes that are responsible for decreasing reactive oxygen molecules (i.e. superoxide dismutase, catalase, and glutathione transferase) and a reconfiguration of the total antioxidant profile with ageing. One study found that reactive oxygen molecule determination in follicular fluid may be a marker for egg quality in IVF. Other factors play a role with ageing. For instance, aneuploidy (abnormal numbers of chromosomes) increases with age. This is most commonly seen with the increased incidence of Down’s Syndrome (Trisomy 21) with age (Figure 2). The incidence is about 1/375 at 35 years of age, 1/100 at 40 years of age, and 1/10 at 45 years of age. The mechanism of this may be non-disjunction of the chromosomes in meiosis or anaphase lag. Given the fact the chromosomes begin their development when the patient is in utero, literally before birth and does not complete the process of meiosis until ovulation often decades later it is easy to see how factors over time affect the number of the chromosomes in the egg and ultimately the outcome of the pregnancy. Figure 2. Generation of aneuploid embryo
A woman’s age not only affects the chances to conceive from ART, but also affects the risk of miscarriage. Most miscarriages (60 %) are due to numerical fetal chromosome abnormalities. The eggs a woman is born with have only partially completed the division of the chromosomes prior to ovulation. They may be in this suspended state for decades. If the chromosomes fail to completely separate, the resulting egg may have an extra chromosome. When fertilized by a normal sperm, the resultant offspring will have an abnormal chromosome number and likely miscarry. This is consistent with the increased risk of Down’s Syndrome (Trisomy 21, an extra chromosome 21). The miscarriage rate for patients having ART is shown below. It is very similar to that seen in the fertile population. Figure 3. Miscarriage rate versus age in IVF
From the above, it is clear that patients should consider the effects of age on the outcome of assisted reproductive technologies. All programs in the country see a decline with the pregnancy rate with age. b. Diagnosis; Male and FemaleOne might expect that, for instance, if a patient has severe endometriosis she may do less well than a patient with mild endometriosis. This appears not to be the case. The stage of the disease has not been shown to influence the outcome. Thus, factors other than the stage of endometriosis play a role in the final outcome. The following are the pregnancy rates as reported by the CDC for all IVF cases in 2004 based on diagnosis. Figure 4. Pregnancy rates for different diagnoses
The delivery rates are very similar for all diagnoses with the exception of decreased ovarian reserve as would be expected. Many physicians approach patients differently. For instance, if a patient has pelvic adhesions (tubal factor) one physician may consider laparoscopic repair of distal adhesions (mild- 80 % pregnancy rate, moderate- 31 % pregnancy rate, and severe-16 % pregnancy rate) while another considers IVF. Ultimately, there may be no ‘correct’ answer, as so many individual variables play a role in our treatment decisions. Some patients will undergo ovulation induction with intra-uterine insemination before considering IVF-ICSI. c. Ovarian ReserveOvarian reserve is as important as age in determining the outcome of IVF. While we have no crystal ball to predict pregnancy, certain tests have been developed which are associated with an increased or decreased likelihood to conceive. Thus, a poor result indicates a poor prognosis to conceive by any method. Of course, pregnancies do spontaneously occur in this group although they are rare. One of the most important issues we deal with in reproductive medicine is the concept of ovarian reserve. Women are born with a finite number of eggs, which peak at about 7 million total when she is five months along in her mother’s womb. She has one to two million at birth and about 400,000 at puberty. She will ovulate approximately 400 times in her life reaching menopause at about 51 years. Thus, there is a tremendous attrition rate for eggs. This plays a very important part in her reproductive potential, that is, her ability to conceive. Diseases such as endometriosis, Turner’s Syndrome, and autoimmune ovarian failure may substantially decrease the reproductive potential and clearly compromise reproductive potential. Considering the fact that many couples now delay childbearing into their mid to late 30s, we feel that it is important to have some assessment of ovarian reserve. While a 20-year-old woman and a 40-year-old woman ovulate the approximate same number of times each year, their monthly pregnancy rate, or fecundity, is much different. This is related to the above. When patients undergo In-Vitro Fertilization, there is an age-related decline in pregnancy rates as shown above. When women undergo egg donation, the dramatic decline in pregnancy rates associated with age is not seen, indicating the effects that age has pregnancy rates and egg quality. As patients age they often stimulate less well in IVF, producing fewer total eggs. The may have lower estrogen levels, higher miscarriage rates, and lowers implantation rates. Women in their mid-thirties have been found to have elevated FSH levels, which may be the first sign of declining ovarian reserve. The onset of the decline in reproductive potential is extremely variable. Therefore, ovarian reserve testing can be seen as a qualitative test to estimate where a person is in the process of depleting her ovarian reserve. Tests of ovarian reserveThe basic concept of the menstrual cycle helps us to understand the various tests that have been developed to assess ovarian reserve. The pituitary gland secretes follicle stimulating hormone (FSH) which travels through the blood stream to the ovaries to stimulate the growth of follicles that contain eggs. The developing follicle secretes hormones which travel in the bloodstream back to the pituitary gland to decrease the FSH production. This is called negative feedback. Estradiol and inhibin are two hormones involved with this process. In a normal menstrual cycle, the FSH level is lower in the first few days of the cycle and then begins to rise as it stimulates the ovaries. A high FSH level on day 3 of the cycle indicates that the pituitary is attempting to stimulate an ovary that has diminished capacity to respond. This is a problem and a bad prognostic sign. Tests of ovarian reserve:Cycle day 3 FSH. Many studies have shown that an increasing FSH level is associated with a decreased pregnancy rate. Women in their early 40s were found to have elevated FSH levels associated with accelerated follicular phases of the menstrual cycle compared to younger patients. Patients with high FSH levels that underwent IVF had granulosa cells in their ovarian follicles that produced less estrogen, were less viable in culture, had reduced mitotic index, and made less growth factors and inhibin than those from follicles than those of younger patients. In effect, they were less robust. There is an increased inter-cycle variability in patient’s FSH levels when elevated compared to normal levels. Some studies have added a basal estradiol level to the FSH. There is some controversy in the literature with some showing a significant effect of an elevated estradiol level on outcome and others showing no effect. In a study of over 800 IVF patients, the group at St. Barnabas Hospital were not able to show that the estradiol contributed any more information than the FSH levels. Figure 5. Clomiphene Citrate Challenge Test
FSH, mIU/ml (scale on left) Clomiphene Citrate Challenge Test. This simple test (Figure 5, above) involves a day 3 FSH level, 100 mg clomid from day 5-9, and a day 10 FSH level. An abnormal test is an elevated day 10 FSH level. An elevated day 3 FSH is a positive test. This is a ‘provocative test’, which will unmask patients which might be missed with a day 3 FSH level. It is 2-3 times more sensitive than a day 3 FSH level. This may be the best screening test to date. A positive or abnormal test is associated with a poor chance to conceive (<5%). Serum Inhibin levels. Inhibin in a protein that is secreted by the follicles of the ovary to inhibit FSH secretion by the pituitary. An ovary with decreased ‘reserve’ will secrete less inhibin and thus will have a higher day FSH level and worse prognosis. This blood test is done in research labs, at present. Ovarian volume/follicles. Several studies have shown that patients with decreased ovarian volume and baseline follicles have decreased reserve. d. SmokingIt should come as no surprise that tobacco use is associated with decreased pregnancy rates in IVF. Large meta-analyses have shown that smokers have increased infertility and lower pregnancy rates in ART (as much as 50% lower). Women who smoke have been found to have higher basal FSH levels at younger ages, need much more medicine to have an adequate ovarian response, decreased numbers of oocytes, increased cycle cancellations and increased fertilization failures in IVF. Additionally, their zona pellucida’s are thicker (i.e. reduced implantation), and uterine receptivity lower. It has been suggested that there is increase oxidative stress in the follicles causing damage. In the male, smoke by product and toxin benzopyrene has been shown to bind sperm DNA raising the possibility of sperm damage and embryo damage. The maturation of the sperm in the epididymis may be affected. It is possible that even passive smokers may have the same problems. It is obviously in our patient’s best interest to stop smoking. e. Other Pre-IVF evaluations; HSG, SIS, ASAThe evaluation of the uterus proper is generally done with the hysterosalpingogram (HSG) or saline infusion sonogram (SIS). It is important to evaluate the uterus for the presence of structural defects that may affect implantation, such as uterine polyps, fibroids, or septae. A HSG involves an X-Ray where dye is passed into the cavity and pictures are taken. Other pages on our site show these (see "Basic Infertility Evaluation"). A polyp is a benign growth of the endometrium that may interfere with implantation. Fibroids are benign smooth muscle tumors arising from the uterine wall that may be seen in as many as 1/3 of women. Generally they cause problems based upon their location. The may be protruding inside the cavity (i.e. submucosal) or be on a pedicle inside the cavity (i.e. pedunculated submucosal), inside the wall (i.e. intramural), or on the outside of the surface of the uterus (i.e. subserosal). By injecting dye into the uterine cavity, we can see defects that correlate with these. A uterine septum is a fibrous band that is in the center of the uterine cavity. It may be associated with recurrent pregnancy loss. It has been suggested that a septum be excised prior to IVF treatment. The Saline Infusion Sonogram (sometimes called a hydrosonogram) is similar to an HSG but we do it in the office. A thin catheter is places inside the uterine cavity, much like an intra uterine insemination, and a transvaginal ultrasound is performed while injecting saline. The saline distends the cavity and the sonogram then shows the defects and well as the uterine wall at the same time. Thus, the positions of myomas in the wall can be better determined. There have been a number of studies concerning the effects of the myomas on the outcome of IVF. All agree that submucosal fibroids that invade the cavity should be removed, as well as intramural fibroids that indent the cavity or distort it. The issue of the intramural fibroid that does not impinge upon the cavity seems more controversial. Some studies show no effect of these regardless of size, some show decreased pregnancy rates if the fibroids are over 4, 6, or 7 centimeters depending on the study. A through discussion with your RE and examination of the patients unique reproductive history will help patients make an informed decision. The HSG also provides information about the fallopian tubes. The presence of distal tubal dilation and occlusion (i.e. hydrosalpinx), often cause by a pelvic infection has implications of IVF. Studies have shown that these tubes lower the pregnancy rate, possibly by allowing fluid form the tubes to flow back into the cavity where the embryo is placed. This fluid may be toxic to the embryo or somehow disrupt its implantation. The options include performing a neosalpingostomy (i.e. open end of tube) or salpingectomy (i.e. excise tube). The excision may be better for IVF patients. Of course, salpingectomy means that the patient will always need IVF to get pregnant. There is a place for salpingostomy for patients that may wish to have more conservative therapy. Another finding of the HSG is salpingitis isthmica nodosa (SIN) which is a stippled pattern of contrast material outside of the small line showing the tube lumen where there are outpockets or diverticuli of the tube lumen. SIN is evidence of tubal disease and indicates that IVF may be needed for tubal dysfunction. Anti-sperm antibodies (ASA) are discussed on other pages of our web site (http://www.ivf-indiana.com/education/antisperm_antibodies.html). There are concerns about the validity of this testing as well as concerns of low sensitivity and predictive value. If a test is not very reproducible it may not be useful as a diagnostic tool. A high clinical suspicion, such clumping of sperm on semen analysis, a history of testicular trauma, mumps orchitis or a vasectomy reversal, or failed fertilization may all lead the patient and her doctor to consider IVF-ICSI which should overcome the negative effects of potential antisperm antibodies on IVF fertilization and pregnancy. Another test of sperm function is the Acrosome Reaction Test.
The acrosome is part of the sperm head that contains enzymes that help the
sperm penetrate the granulosa cells as they try to approach the egg. Many
of the tests for sperm function, like the acrosome reaction test or even
the sperm penetration assay were developed in the 1980’s to 1990’s. They
may not be relevant today with the advent of ICSI (Intracytoplasmic sperm
injection). In general, if there is a problem with sperm count,
morphology, or motility ICSI is recommended. If there is unexplained
infertility ICSI is recommended. Given the fact that many of these tests
suffered from poor predictive value and performance, it is difficult to
justify these presently. |
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