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FAQ Frequently Asked Questions :
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Why would my doctor suggest IVF if all of my tests are normal?
2-What is a blastocyst transfer?
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My clinic allows me to choose between a day-3 and a day-5 embryo transfer. How do I decide?
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My endometrium is only 6 to 7 millimeters thick. Can I do anything to improve its thickness?
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What are PGD and PGS?
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How safe is PGD or PGS?
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Can PGS improve outcomes after IVF?
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What is embryo freezing and how successful is it?
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What is the difference between a natural cycle frozen embryo transfer (FET) and a medicated FET?
10- My last IVF failed. Should I try again?
11-How do I know if I need IVF?
12-How successful is IVF?
13- Are the children born after IVF normal?
Why would my doctor suggest IVF if all of my tests are normal?
Upon complication of the diagnostic evaluation, approximately 10% to 15% of couples will be found to have unexplained infertility, meaning that all of their tests are normal. Such couples are probably best called "subfertile," and most can successfully conceive with IVF. Prior to the introduction of IVF, couples with unexplained infertility had a poor chance of achieving pregnancy with other treatment methods.
We do not know precisely why couples with unexplained infertility are infertile. Some evidence suggests that the source of the problem may be tubal dysfunction or sperm egg interaction. Often, a fertility center uses IVF together with ICSI in such couples to ensure that fertilization of the ova occurs. Thanks to these techniques, today couples with unexplained infertility have a very strong likelihood of ultimately achieving a successful pregnancy with IVF.
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What is a blastocyst transfer?
Embryos on the third day after egg collection are referred to as cleavage stage embryos. At this point, each embryo contains 6 to 10 discreet cells (blastomeres). When assessing these embryos for quality, the embryologist grades them based on the number and appearance of the blastomeres. Embryos that have equal size blastomeres with no fragmentation are usually given a high grade, whereas embryos that have extensive fragmentation with unequal size blastomeres are given a low grade. In general, higher grade embryos have a much better chance of implanting successfully and generating a pregnancy.
If the embryos are maintained in culture beyond day 3, they first form a solid ball containing approximately 30 to 50 cells, called a morula. Over the next day or two, this solid ball of calls becomes a hollow sphere with a clearly defined inner cell mass. This hollow ball of cell is called a blastocyst. Many clinics maintain the embryos in culture until the fifth day to allow for improved selection of embryos to transfer. Patients who undergo an embryo transfer on day 5 or 6 after egg collection are referred to as having a blastocyst transfer.
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My clinic allows me to choose between a day-3 and a day-5 embryo transfer. How do I decide?
The decision to transfer embryos on day 3 or day 5 is one that requires careful thought. In general, embryos that have formed blastocysts have a better chance of implanting successfully. Unfortunately, not all embryos will progress to the blastocyst stage outside of the body. This inconsistency raises the question as to whether the embryos that fail to form a blastocyst would have initiated pregnancy had they been transferred back into the uterus on day 3. Some studies have, indeed, demonstrated acceptable pregnancy rates with day-3 transfers of embryos that were of marginal quality and that, based on historical data, would have been unlikely to form blastocysts in culture. Clearly, the pregnancy rate in the absence of an embryo transfer will be zero, whereas even embryos of borderline quality, if transferred on day 3, may potentially lead to a pregnancy.
So how can you decide between a day-3 and a day-5 embryo transfer? Many clinics make the decision on day 3. If a patient has a certain number of high quality embryos on day 3, then the embryos are maintained in culture for 2 additional days to allow for further embryo selection at the time of transfer. If the embryos fail to progress to the blastocyst stage, however, then there is no transfer---- which often results in profound patient disappointment. If a limited number of embryos are available on day 3 and no embryo selection is needed, then the benefit of a day 5 embryo transfer may be limited.
One additional risk of a day 5 transfer is an increased rate of identical twinning. Carrying identical twins (monozygotic twins) is considered to be a higher risk pregnancy than carrying fraternal twins (dizygotic twins). Identical twins often share a placenta (monochorionic twins) or may even be located within the same pregnancy sac (monochorionic twins); both of these conditions are associated with increased rates of pregnancy complications.
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My endometrium is only 6 to 7 millimeters thick. Can I do anything to improve its thickness?
The thickness of the endometrium normally changes through out the menstrual cycle. During menstruation, the endometrium is shed. Under the influence of the hormone estradiol, the endometrium then regenerates and usually develops to a normal thickness of 8 or more millimeters (mm). When a woman is undergoing infertility treatment, the thickness of her endometrium is regularly measured using ultrasonography.
When the endometrium fails to develop to at least 8 mm, the embryo may fail to implant because of endometrial immaturity or dyssynchrony.
Although this problem is not very common, when it occurs, it can be difficult to correct. Typical treatments consist of providing additional estrogen early in the menstrual cycle or altering the timing of progesterone administration. Other therapeutic agents include small doses of aspirin (80 to 100 mg per day), and some physicians have prescribed Viagra vaginal suppositories for their female patients with variable success. Some women cannot achieve pregnancy in a fresh IVF embryo transfer cycle but readily become pregnant when the embryos are transferred in a frozen thawed nonstimulated treatment cycle. On rare occasions, a couple may need to use a gestational carrier to successfully overcome abnormalities involving the endometrium and implantation.
Of course, failure of the endometrium to achieve a minimum thickness of 8 mm does not necessarily translate into a problem with endometrium. In our practice, we have seen many patients with maximal endometrial development of only 4 to 7 mm successfully achieve pregnancy, including delivery of twins. A variety of testing methods to assess endometrial maturity have been proposed, including endometrial biopsy testing for surface proteins called integrins, but such testing is currently considered experimental.
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What are PGD and PGS?
Preimplantation genetic diagnosis (PGD) and Preimplantation genetic screening (PGS) are techniques that provide diagnostic information concerning an embryo prior to its transfer to the uterus. The vast majority 1 or 2 cells (or blastomeres) of a 6- to 8- cell embryo on day 3 of embryo culture following IVF. These cells are rapidly analyzed, and on day 5 the unaffected embryos are selected for embryo transfer.
PGD was first performed in 1989 in an effort to avoid the transfer of embryos that carried serious genetic disorders (for example, cystic fibrosis). Thus couples who undergo PGD do not have infertility but rather are at risk for passing a genetic disease to their children. A wide range of single gene and chromosomal disorders can now be diagnosed with PGD, including autosomal recessive diseases (e.g., cystic fibrosis), X-linked recessive diseases (e.g., hemophilia, Duchenne muscular dystrophy), autosomal dominant diseases (e.g., Huntington's disease), and chromosomal rearrangements (e.g., balanced translocations).
PGS is similar to PGD, but refers to screening of embryos produced in the course of fertility treatments. Thus couples who undergo PGS include infertile patients without an underlying genetic problem. PGS is performed in an attempt to identify those embryo selection will ideally result in improved pregnancy rates and lower miscarriage rates.
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How safe is PGD or PGS?
An estimated 5,000 cycles of PGD/PGS are being performed in the United States each year. Although the use of these techniques is clearly increasing, the number of PGD/PGS cycles continues to represent only a small fraction of the 100.000 IVF procedures performed annually in the United States alone. The rate of congenital anomalies and of pregnancy complications following PGD/PGS does not appear to be increased over the baseline measurements.
On occasion, misdiagnosis may occur, so patients undergoing PGD/PGS are usually offered traditional prenatal diagnostic tests (chorionic villus sampling CVS or amniocentesis) to confirm the results.
The rates of misdiagnosis in PGD range from 1% to 9%. Embryos from which no diagnostic information is obtained are usually discarded rather than risk embryo transfer, although this policy varies from clinic. The other risks of PGS/PGD are the same as those associated with any cycle of IVF, including multiple pregnancy and OHSS.
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Can PGS improve outcomes after IVF?
PGS has been promoted as a means to improve the odds of a successful IVF cycle. However, a large scale, randomized, controlled study performed in women older than age 37 failed to demonstrate an improvement in clinical outcome following its use. Although the use of PGS will likely decrease the rate of miscarriage resulting from aneuploidy (an abnormal number of chromosomes in the embryo), the overall delivery rate per IVF cycle initiated may not be increased with this technology.
For couples in whom the use of prenatal diagnosis and possible pregnancy termination are not an option, PGS may be appropriate. According to an October 2006 monograph produced by the European society of human Reproduction and Embryology (ESHRE), "Although widely used, PGS is still considered as an experimental procedure, and its clinical utility is not fully proven."
One limitation of PGS is that many embryo at the 6- to 8- cell stage of development are mosaics, meaning that some of these cells carry a normal complement of chromosomes while other cells are abnormal. During further embryonic development, the abnormal cells presumably end up relegated to the placenta while the normal cells produce a healthy embryo. The high rate of mosaicism in cleavage stage embryos raises a real concern about the accuracy of PGS. One respected geneticist has estimated a rate of misdiagnosis to be 20% with PGS. Approximately 17% of the time a normal embryo is incorrectly labeled as abnormal and discarded. Even more concerning is the 3% chance that an abnormal embryo will be labeled normal and then transferred to the uterus.
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What is embryo freezing and how successful is it?
On the day of embryo transfer, the couple may learn that they have additional embryos of good quality in addition to those embryos that have been selected for embryo transfer. These embryos can be crypreserved by freezing them in liquid nitrogen. Through a series of carefully orchestrated steps, the embryos are ultimately frozen at a temperature of – 196 C, leaving them in a state of suspended animation in which they can remain for many years. Embryos that have been stored for more than 10 years have successfully generated pregnancies (although most patients tend to use their frozen embryos within 3 to 5 years after they are produced). The pregnancy rates associated with replacing frozen embryos depend on the age of the patient and the quality of the embryos at the time of cryopreservation. Top quality embryos from young patients may yield pregnancy rates around 50%, whereas poor-quality embryos may not even survive the thawing process. In some clinics, more than 75% of embryos survive the freeze-thaw cycle.
Many couples are often concerned about their moral obligations concerning their frozen embryos. In such cases, couples may elect to defer embryo freezing, choose to alter their stimulation or pursue natural cycle IVF so as to avoid this problem of excess embryos. Extra embryos that are not used to initiate a pregnancy could represent a source of embryonic stem cells. This potential use of extra embryos lies at the heart of the recent political debate in the United States regarding government funding of stem cell research. Clearly, patients should carefully consider the implications of excess frozen embryos as they embark on an IVF cycle. However, not all patients will have extra embryos of high enough quality to be considered for embryo cryopreservation.
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What is the difference between a natural cycle frozen embryo transfer (FET) and a medicated FET?
There are two possible options for performing a frozen embryo transfer (FET): natural – cycle FET and medicated FET.
Natural – cycle FET is available to women with regular ovulation and monthly menstrual cycles. In patients with predictable menstrual cycles, we can carefully monitor the cycle to determine the precise timing of ovulation. Alternatively, ovulation can be induced with the administration of an HCG injection. Once the precise date of ovulation is set, then the uterine lining should be receptive to embryo transfer 5 days later (for embryos frozen on day 3 in a previous IVF cycle). In this way, the embryos can be replaced at approximately the time when they would normally be arriving in the uterus.
One problem with natural – cycle FET is that the optimal time for implantation may fall at an unpredictable time during the laboratory work schedule. In addition, natural – cycle FET demands frequent patient monitoring around the time of ovulation. If a cycle is suboptimal in terms of the estrogen level and endometrial development, then the embryos should not be thawed and the cycle should be cancelled.
A medicated FET allows the couple to avoid some of the pitfalls associated with a natural – cycle FET. In this type of FET, estragon pills, shots, or patches are used to prepare the endometrium for embryo implantation. Three days prior to embryo transfer, the woman begins talking progesterone to modify the endometrial lining so that it will be receptive when the embryos are placed. Some clinics prescribe GnRH agonists (such as Lupron) to their female patients the month prior to a medicated FET cycle so as to reduce the chances of spontaneous ovulation. The use of Lupron reduces the chances of cycle cancellation owing to unexpected ovulation to near zero.
The choice of estrogen supplementation varies somewhat between clinics. Some clinics prescribe oral estrogen, other clinics administer intramuscular estrogen shots twice a week, and still other clinics ask their patients to use transdermal estrogen patches twice a week. The choice of estrogen protocol is clinic-specific and should be discussed with your reproductive endocrinologist.
Most clinics prescribe progesterone in oil injections to prepare the lining for embryo transfer. Women who have a progesterone allergy can use progesterone suppositories or prometrium capsules, instead.
Pregnancy rates have not been shown to differ significantly between natural cycle FET and medicated FET. However, medicated FET's do allow for advance scheduling, which both patients and physicians find attractive.
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My last IVF failed. Should I try again?
To make the best decision about whether to do another IVF, your first step is usually to sit down with your doctor and review your history and the details of the failed cycle. This would include a discussion of the rationale behind attempting IVF in the first place and a careful examination of the results of the IVF cycle. Clearly, if a woman can conceive only through the use of IVF (for example, because she has no fallopian tubes or because her partner's sperm is of such poor quality that no other alternative is available), then the decision becomes one of whether another attempted IVF is warranted.
In reviewing the previous IVF cycle, the woman's response to the stimulation protocol should be carefully examined as well as the findings at the time of egg collection. If the eggs appeared immature at the time of egg collection, then in the future the trigger shot should probably be withheld until the follicles reach a larger diameter. If the stimulation and number of eggs are appropriate but fertilization was unexpectedly poor, then the use of ICSI for a future IVF cycle could be considered. If stimulation, fertilization, and embryo development were good and yet the cycle still failed, then consideration should be given to either an FET cycle (if appropriate) or a repeat cycle of IVF. If the stimulation was poor and the number of eggs was suboptimal, then other stimulation protocols should be discussed. If maximum doses were used and a poor response was still seen, then IVF may not be an appropriate choice; in such a case, other options---ranging from IUI to donor egg or adoption---may warrant discussion.
In cases where patients have frozen embryos remaining from the fresh IVF, we usually encourage them to attempt pregnancy with a frozen embryo transfer. Many patients who fail to conceiver on a fresh IVF will conceive on the FET.The post- IVF consultation is one of the most useful discussions that a couple can have with the physician. It allows the couple to review all aspects of their care and to determine whether IVF represents the best approach to their particular situation. We firmly believe that this feedback is crucial to develop an appropriate plan of treatment for each couple.
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How do I know if I need IVF?
Not all patients need IVF or are good candidates for IFV .Thus the answer to the question can be determined only after you undergo a comprehensive infertility evaluation by your reproductive endocrinologist .Nevertheless, some situations clearly require the use of IVF. Fore example, women with absent or severely damaged fallopian tubes should be treated immediately with IVF. Likewise, should be performed first if the male partner has very poor sperm quality .For other patients, the use of IVF may be less clear-cut, especially given that many different treatment options exist .In such cases,the doctor should discuss with the couple the pros and cons of each option, and then all parties should jointly decide on a treatment plan.
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How successful is IVF?
Overall, the success rates for IVF have improved markedly since 1978(when Louise Brown was conceived), but success rates vary widely depending on the couple's infertility factors and the clinic performing the IVF procedure. Success rates for U.S.IVF clinics are published on the CDC's website (www.cdc.gov/ART/index.htm). The standardization of clinic success rates evolved from 1994 passage of the Fertility Clinic Success Rate and Certification Act (the so-called Wyden Law), which seek to protect U.S. costumers from inflated IVF success rates. Importantly, many subtleties inflated clinic-specific IVF pregnancy rates, including patient selection bias (that is, some clinics tend to treat tougher cases, so their success rates might be lower than those of clinics that take only routine cases).
For women younger than34 years of age, most will achieve pregnancy within one to three treatment cycles; indeed, many succeed in their first attempt .for women older than 35 years, the success rates tend to decrease simply because the aging process affects the quality of these women's eggs. For a detailed discussion of IVF success rates, couples should visit the website for the clinic where they are considering treatment .They should also discuss their specific likelihood of success with their reproductive endocrinologist. IVF pregnancy rates do vary by clinic, so patients should carefully scrutinize their chances for success at the particular clinic scrutinize their chances for success at the particular clinic rendering treatment.
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Are the children born after IVF normal?
The question of the health of children born after advanced fertility treatments is one that has great importance both to the parents and of fertility physicians .In general ,the data regarding the outcomes for children born after IVF, either with or without the use of ICSI ,have been extremely reassuring.
The problem with these studies remains the identification of an appropriate an appropriate control group with which to compare the rate of problems found in the children conceived with advanced fertility techniques. Overall, most studies suggest a background risk of birth defects in naturally conceived children of approximately 4% to 5%.However, these couples tend to be younger than the couples undergoing IVF and, by definition, do not suffer from infertility. Although the vast majority of studies suggest no increased risk of anomalies in children conceived after IVF, none of these studies have looked at the rates of congenital anomalies in children conceived naturally but born to parents who suffered infertility that spontaneously resolved without treatment. This group of patient would clearly represent a more appropriate control group with which to compare with patients who seek out advanced fertility treatments.
Recently, a systematic review was conducted in Australia of all studies that had previously examined the possible increased risk to children conceived after treatment with IVF and/or ICSI (Hansen, M .et. Human Reproduction .20(2):328-338, 2005).However, many of these studies compare the rate of congenital abnormalities in children conceived spontaneously with the rate in children who were born to older couples undergoing IVF and/or ICSI. In many studies ,the rate of congenital anomalies in the control group have been around 4%,whereas the rate of congenital anomalies in the group of couples undergoing IVF and ICSI have been6% or greater. The difference between 4% and 6%is statistically significant and suggests that there may be an increased risk to children conceived though the use of advanced reproductive techniques .However, the question remains as to whether this is a problem related to IVF itself or to the underlying infertility that leads to the use of IVF. In any case, most patient accept an increased absolute risk of 2% as being reasonable, especially give that their options for spontaneous conception may be significantly limited.
The greatest risk to the children conceived after fertility treatment is that of prematurity related to multiple pregnancy several strategies are used to reduce the rate of multiple gestation (see question 54, which deals with how many embryos to transfer in IVF).The risk of prematurity are significant and should not be discounted quickly, especially given that 50% a month or more before their due date.
In addition, the question has been raised as to whether even IVF singleton pregnancies are at higher risk for low birth weight and prematurity. If true, the cause of this increased risk may be difficult to determine. Patients undergoing IVF suffer from infertility, so any increased rate adverse pregnancy outcome might not be so much a result of IVF process as it is related to the couple's underlying problem of infertility. Several studies have suggested that women who conceive spontaneously, but who have a preceding history of infertility, have a significantly increased of prematurity and pregnancy-related complications such as placenta previa, abruption and low-birth-weight infants.
Another way to look at the question of whether any risk is related the process of IVF itself versus the patient who is undergoing IVF is to examine the pregnancy outcome women who undergo IVF but use a gestational carrier (carriers usually have an excellent reproductive history).A study of these pregnancies found there is no increased risk of prematurity of low birth weight the children conceived and carried in this way. The reassuring outcome would suggest that the problem lies not so much with the IVF process but, unfortunately, with the patients who require IVF to conceive. The impact of new technologies on the rate of congenital anomalies in children bone after fertility treatment remains a subject of ongoing debate. The potential risks inherent in micromanipulation of the embryo prior to embryo transfer-like that require for preimplantation genetic diagnosis (PGD)-remain unknown. Although more than 3 million IVF babies have been delivered worldwide to date, only a relatively small number of children have been delivered after the use of PGD or following unusual situations such as performing rescue ICSI on the day following egg collection because of unanticipated failed fertilization. When considering such novel treatment the physician needs to inform the patient /couple of any known or suspected risks. Currently, several studies are under way in this country and throughout the world to continue to monitor the health of those children delivered following advanced fertility treatments.
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