Wednesday, 31 July 2013

IVF - the hope comes true for infertile couples

Sperm Collection and Preparation
On the day of egg collection, the husband gives a sperm sample. The semen specimen should be obtained following a 3-4 day abstinence from sexual activity and masturbation is the preferred method of collection. A shorter or longer period of time or the use of a different method of collection may affect semen parameters. After collection the semen sample is delivered to the lab where it is properly prepared for IVF. The purpose of the preparation is to isolate the motile spermatozoa from other elements of the semen and activate them in order to be capable to fertilize the mature oocytes.

It should be noticed that masturbation, especially at the clinic, is sometimes difficult and stressful for men on the day of egg collection. Therefore men could bring the semen sample from home or can freeze a sample several days before the day of oocyte retrieval (fresh samples are always preferred). In cases of men with azoospermia, spermatozoa are retrieved directly from the testis (surgical sperm retrieval).

Egg Retrieval
The ability to collect mature eggs from a woman's ovaries for fertilization outside of the body has revolutionized fertility treatment. Originally developed as a way to help women whose fallopian tubes were irreparably blocked, IVF now allows couples who suffer from a wide range of fertility problems to successfully conceive. In vitro fertilization begins with ovulation induction, a process of stimulating and monitoring the ovaries. Once it is determined that the ovarian follicles are the right size and the eggs ready to be collected, a dose of human chorionic gonadotropin (hCG) is administered to trigger the final maturation process and egg retrieval will take place approximately 36 hours later. Prior to the procedure, anesthesia will be given. In most cases, egg retrieval is performed under moderate sedation (aka MAC), allowing the patient to be asleep for the procedure. The actual technique used to collect eggs for in vitro fertilization is known as an ultrasound-guided transvaginal aspiration.

While an ultrasound probe is used to provide a visual image of the ovary and the surrounding structures, a very fine needle is inserted through the upper wall of the vagina and into the ovary. Through magnification of the ultrasound image, the physician can locate the individual follicles that contain mature eggs and apply gentle suction to remove the contents of each one, which is known as aspiration. The fluid and egg from each follicle are collected into an individual container, which will then be taken to the lab for examination and preparation for fertilization. The procedure is performed on both ovaries, usually taking between 10 and 15 minutes to complete. Once the egg retrieval process is finished, the patient will remain under observation for one or two hours before being sent home. Patients may experience some discomfort after egg retrieval and are encouraged to rest as much as possible. Mild soreness, cramping, and light spotting are normal.

Vigorous exercise and other strenuous activities should be avoided. Specific instructions will be provided prior to the procedure and should be followed carefully. Progesterone, a hormone that would normally be released by the follicle after ovulation, is vital to the support of early pregnancy. Because aspiration of the follicles can interrupt the normal hormonal process and prevent adequate amounts of progesterone from being produced, the patient will generally be given supplemental progesterone from the time of egg retrieval through the end of the cycle.

The whole process is performed under mild sedation with a recovery period of approximately an hour. However, it is important to notice that for safety reasons, women scheduled for egg retrieval must be at the clinic at least 30 minutes before the procedure in order to have a cardiograph and talk to the anesthesiologist about allergies, any medication they are taking and any other health problems they may have. Last but not least, women programmed for this procedure shouldn’t eat or drink anything from the previous night.

Oocyte Fertilization
Several hours after egg retrieval and semen preparation, fertilization occurs. More specifically at a conventional IVF cycle the mature oocytes are placed in 4-well dishes of culture medium containing processed sperm. One of the spermatozoa will penetrate and fertilize the oocyte. In cases of severe male infertility, other laboratory techniques are required following egg retrieval. Fertilization may be assisted by intracytoplasmic sperm injection (ICSI), a micromanipulation technique which involves the injection of a sperm directly into the egg. The eggs are then incubated in the lab overnight.

The next morning, 16-18 hours after the time of fertilization, fertilization check is performed by the embryologists. The first signs of normal fertilization are shown by the presence of two pronuclei (small round structures) within the egg. The fertilization rate is usually between 50 and 100%. The maturity of the oocytes, semen parameters, handling procedures and culture systems are some factors that are responsible for the variance in the fertilization rate.

Embryo culture, selection and transfer
The earliest stages of human development, until day five or six after fertilization, normally occur in the woman’s fallopian tube. However, after in vitro fertilization (IVF), much of this period of early development occurs in the laboratory. The conditions under which the embryos are “cultured” have been carefully formulated to provide an environment that as closely as possible that of the fallopian tube. Recently, commercially prepared culture media have become available. These media support embryo development in the laboratory for up to six days. By allowing the embryo to reach the blastocyst stage, we can make a more stringent selection of those to be transferred during an IVF cycle; as a result, these systems may be preferable for patients who would prefer or benefit from a one- or two-embryo transfer.

Once the embryos have been created in the laboratory, they are placed into the uterus. At this point, in order for pregnancy to occur, an embryo must implant into the uterine lining. For many patients, the two-week wait between the embryo transfer procedure and the initial pregnancy test is the most difficult stage of the process. While the embryos are developing in the laboratory, they are monitored for rate of growth, size, form, and signs of irregularity. Based on this data, the embryos are graded by quality, which helps us to estimate which are most likely to successfully implant and continue to develop. Typically, the embryos of the highest grade are selected for the first IVF transfer. Embryos with significant abnormalities are not suitable for transfer and will be discarded. In most instances, no more than two or three embryos will be transferred during any given IVF cycle. This number allows the best chances for implantation while still keeping the risk of a multiple pregnancy to a minimum. In some cases, depending on age and other factors, our physicians recommend electing a single embryo transfer. Any additional embryos that are created will be cryopreserved for later transfer. The embryo transfer procedure will be scheduled for three to five days after the egg retrieval. In IVF cycles where frozen embryos are to be used, the patient will be closely monitored via ultrasound and the embryos will be placed about two days after ovulation takes place.

This stage of in vitro fertilization treatment involves threading a thin catheter through the opening in the cervix, through which the embryos are gently deposited into the uterus. There is very little discomfort during this part of treatment and anesthesia is not necessary. After the transfer procedure, our IVF patients are advised to take it easy for the next few days. Physical activity should be limited and strenuous exercise should be avoided. Although there is little that can be done at this point that will affect the chances of successful implantation, eating well, getting enough sleep, and minimizing stress will go a long way toward the health and wellbeing of the patient. The process of implantation is complex and unpredictable. First, the embryo must escape, or hatch, from the zona Pellucida. Even if the embryos are transferred on day three, this will not occur until after the embryos have reached the blastocyst stage on day five or six. Once an embryo has hatched, it must attach to the endometrium, or uterine lining, and gradually become imbedded in it. Once an embryo has completed this process, pregnancy is achieved and the in vitro fertilization cycle is a success.

Approximately fourteen days after the embryo transfer procedure, a blood test will be conducted to measure the amount of human chorionic gonadotropin (HCG) in the patient's system. This hormone is released only after implantation and is an accurate indicator of pregnancy. However, because HCG is sometimes used during the ovulation induction process to trigger the final maturation of the oocytes, small amounts may exist even if the patient is not pregnant. For this reason, at-home pregnancy tests that detect the presence of HCG but do not measure the quantity are not considered accurate for women undergoing in vitro fertilization. Elevated levels of HCG indicate that implantation has occurred and the patient is pregnant. If pregnancy is detected, the patient will then undergo an ultrasound examination to confirm the findings, determine how many embryos have implanted, and ensure that everything is progressing normally.

If pregnancy has occurred, progesterone treatments will be continued for a period of time and then be gradually reduced as the patient's body takes over normal hormone production. The patient will continue to visit our IVF Centre for blood work and ultrasounds during the early weeks of pregnancy to ensure that everything is proceeding as it should. Once we are able to detect the fetal heartbeat, the patient will be referred to an OB-GYN (if she does not have one already), who will handle the remainder of the patient's prenatal care. A high-risk obstetrician is only necessary if certain medical problems are a factor.

If pregnancy has not occurred, progesterone supplements will be ceased and the cycle will come to an end. If the couple has opted to try another in vitro fertilization cycle, we may recommend waiting one or even two complete menstrual cycles before resuming treatment. This allows the body to rest and gives us a chance to examine our treatment strategy and possibly change our approach in future cycles. In subsequent IVF cycles, the ovulation induction phase may not be necessary if frozen embryos are available for transfer.

Complications & Risk Factors after Embryo Transfer
Assisted reproduction technique (ART) is an efficacious treatment in sub fertile couples. So far little attention has been paid to the safety of ART, i.e. to its adverse events and complications; the consensus meeting on Risks and Complications in ART.

Multiple pregnancies
If 25% of all pregnancies after IVF/ICSI are twin pregnancies, 40% of all babies born after ART are born as part of a twin pair. Many physicians and patient couples underestimate the negative consequences of twin pregnancies. Perinatal as well as maternal mortality and morbidity are increased in multiple pregnancies as compared with singleton Pregnancies due to a higher rate of prematurity and low birth weights in the children; and due to pregnancy complications in the mothers. Furthermore, parents of multiple births have more stress, and siblings of multiples are more likely to have behavior problems.

Long-term effects of ART on women
Hormonal and reproductive factors are involved in the etiology of breast cancer and cancers of the female genital tract. Therefore, the effect of fertility drugs on the risk of these
Cancers has been investigated. Many studies have not been able to reach solid conclusions due to low statistical power, lack of control for important confounders (such as cause of sub fertility and parity) and short duration of follow-up.

Effects of ART on offspring
Much concern has been expressed about the health of children born after ART. In particular, the risk of boys born to couples with male factor sub fertility has drawn attention, since in a substantial number of male factor sub fertility cases, a genetic cause can be suspected.

Patient selection and counseling for eSET (elective single-embryo transfer)
It was agreed that the essential aim of IVF/ICSI is the birth of one single healthy child, with a twin pregnancy being regarded as a complication. The chances of having a single healthy child after eSET have increased, and equal the spontaneous pregnancy rate in a normally fertile couple.

Women who can get pregnant without fertility drugs or medical procedures usually have only one baby. Women who need fertility treatment are at higher risk to get pregnant with twins, and rarely with triplets or more. This is called multiple gestations. Multiple gestations can increase the risk of pregnancy for the mother and for all the babies. Multiple gestations are risky for the babies. Because there are too many babies in the womb, you may have a miscarriage. A miscarriage occurs when your pregnancy ends without the birth of any infants that can survive, before the 20th week of pregnancy. Or you could have a premature delivery when the babies may be born too early (but after 20 weeks of pregnancy) and have problems with lungs, stomach, or intestinal tract. They may have bleeding in the brain, which can cause problems with the baby's brain, nervous system, and hamper its development. If the babies are born very early, they will probably be very small and may even die.  Twins, triplets, and other multiples are more likely to have problems with their brain development and nerves if they are born early. One of the more common problems is cerebral palsy, a condition that affects movement. Other problems associated with multiple births may not present for many years after delivery

Embryo transfer and elective single embryo transfer have become popular topics as more couples turn to fertility treatments to conceive. Our Fertility doctor takes your age and in vitro fertilization (IVF) prognosis into account when performing embryo transfer. Pahlajani Test Tube Baby has a clear guidelines offer you the best chances for a healthy pregnancy and delivery. Do you have a good prognosis for IVF? A good, or favorable, IVF prognosis applies to women who:
» Are in their first IVF cycle
» Have healthy embryos or multiple frozen embryos
» Have already had success with IVF

If you are under 35, and have a favorable prognosis for IVF, you are more likely to conceive with a single embryo transfer. If you're over 35 and have a good IVF prognosis, our doctor may prefer to transfer more than one embryo.
» Under 35: 1-2 embryos
» 35 to 37: 2 embryos
» 38 to 40: 2 to 3 embryos
» 41 to 42: 3 to 5 embryos

Becoming pregnant with multiples increases the risk of complications for you and your babies. Single embryo transfer can help you avoid these risks. The most common complications associated with multiples are increased rates of preterm labor and preterm delivery. Preterm delivery can cause a host of problems for the infant, including:
» Respiratory, growth, and digestive problems
» Long-term learning and developmental difficulties
» Low birth weight

Complications for mom are also increased with multiple gestations. Here are some of the increased health risks for moms of multiples:
» C-section
» Emotional stress
» Gestational diabetes
» High blood pressure and preeclampsia
» Increased cost for medical care
» Increased risk of miscarriage

This is why doctors prefer single embryo transfer, or transferring a lower number of embryos during IVF, when possible.

Investigation and Clinical Approach of Recurrent Implantation Failure

Recurrent implantation failure (RIF) derives from the practice of IVF. The ability to identify implantation failure after the transfer of embryos raised the possibility that there exists a patho-physiological state leading to repeated implantation failure. RIF can be defined as the repeated lack of implantation after the transfer of embryos. Prior to IVF, treatment resulted either in a pregnancy or not. IVF added the ability to further compartmentalize the treatment process so that it became possible to know when an embryo was transferred and if an implantation occurred. Hence RIF became a possible clinically identifiable phenomenon. The relevance of defining such a problem lies in the ability to diagnose patho-physiological conditions, which might be amenable to treatment and thus increase the implantation rate thereby increasing a couple’s chance of conception.

Many practical procedural problems exist when trying to define implantation failure. One limitation when defining implantation and implantation failure is that at present, implantation can only be determined by a rising quantitative hCG level which occurs a number of days after implantation has actually occurred or failed. There remains a time-frame which cannot be further compartmentalized and thus limits the ability to precisely define the cause of implantation failure. Thus, for practical purposes, implantation is defined as a rise in the quantitative hGC level determined at some point after embryo transfer. The most accurate way to determine this would be to do daily serum HCG levels starting after embryo transfer. But again practicality dictates that the first level is drawn at some point after embryo transfer and for many programs this is usually 10–14 days after hCG is given.

The timing of when the first hCG determination is performed will affect the implantation rate. The earlier the first hCG determination is done, the lower the failed implantation rate will be since some pregnancy losses will occur prior to the hCG determination for those programs measuring it later in the cycle. Any definition of RIF requires a standardization of the time from embryo transfer to the time used to determine a positive hCG level. The definition also needs to establish what will be considered a pregnancy when using hCG. For example, will any value above the threshold value be considered evidence of implantation or will there need to be rising hCG levels? Finally, the day of embryo transfer needs to be established. For example, suppose there was a preventable cause of failed implantation that occurred at the morula stage. Programs transferring day three embryos would have a higher failed implantation rate than those programs transferring blastocyst embryos.

The accuracy of a clinical definition is to a large extent determined by the simplicity or, conversely the complexity, of the problem. A physiologic process that has a single factor is easy to define in its entirety. A pathological process that alters the physiology of the process in question may be caused by a single factor and, if measurable, the definition of the disease process is simple and accurate. The thesis of this manuscript has two prongs. First, implantation is extremely complex and highly redundant. Continuation of the species is evolutionarily a high priority. Therefore, the evolutionary process has preserved the ability to implant through accruing a number of individual processes, many of which are, in and of themselves, not necessary, but collectively contribute to a maximum chance for implantation. Second, because of the complexity and redundancy of implantation, assigning etiologies for implantation failure and RIF will be difficult.

There are some processes involved in implantation which are simple and absolutely required for implantation to occur. But there are many processes which are not necessary but contribute to implantation. Therefore, the problem with implantation failure as well as RIF is not in defining the problem, which is self-evident, but in assigning causality to the phenomenon. Some causes of IF and RIF will be a single factor. Their identification and their contribution will be easier to discern. However, implantation failure and RIF may be a result of a threshold phenomenon whereby there are a multitude of factors required for maximum implantation efficiency. A failure of any one of these factors might, or might not, reduce the overall implantation rate. But to reach a state whereby implantation failures, or implantation fails repeatedly, might require errors in a number of factors and might not be the same factors for each case of IF or RIF. The identification of this problem becomes complex and very difficult to approach experimentally.

Any deviation from or interruption of the normal structure or function of any part, organ, or system, or combination thereof, of the body that is manifested by a characteristic set of symptoms or signs, and whose etiology, pathology, and prognosis maybe known or unknown. Implantation failure and especially to recurrent implantation failure demonstrates just how difficult it becomes to define a disease. There are two ways of approaching a definition for a normal implantation rate: evaluate spontaneous pregnancy rates in fertile couples, or evaluate implantation rates when using donor oocytes. There are many factors intervening when couples have intercourse which could result in a less than perfect system so that more than 50% of the cycles do not result in a pregnancy. Therefore, using the natural pregnancy rate in maximally fertile women does not provide the best definition of a normal implantation rate.

IVF provides a more definable system since it involves oocyte, sperm and, endometrium. For this more defined system, the relevant statistic is not normal implantation rate but rather, the maximum implantation rate. Any deviation from this maximum implantation rate would represent a compromise that is, by definition, a disease. Identifying the maximum implantation rate requires evaluating implantation rates obtained through the use of normal oocytes, sperm, and endometrium when the IVF procedure is done by the technically most adept IVF units. This condition is frequently met for women using donor oocytes for age-related ovarian failure. The implantation rate for the double embryo transfer patients was equally high at 56%. It would appear that the maximum implantation rate for IVF is between 40% and 60%. For IVF programs with substantially lower implantation rates, the problem may be technical related to either the clinical or laboratory components of the program. Until a program’s implantation rates meet industry standards, evaluating the patient for problems with implantation failure will be premature.

Defining the term “recurrent” is very challenging, analogous to defining infertility or recurrent pregnancy loss. A problem when using pregnancy rates based upon number of transfer cycles relates to the variability of the number of embryos transferred on any given cycle, the quality of the embryos transferred, and the day of embryo transfer. Defining recurrent implantation failure as three unsuccessful IVF attempts actually defines RIF in terms of failed IVF cycles and does not address the issue of implantation rates. Some patients may have a large number of poor quality embryos transferred for a given IVF cycle; whereas, others may have only one or two embryos transferred. Thus, defining RIF in terms of pregnancy rate does not allow an evaluation of the implantation rates. Also, the day of transfer greatly impacts the pregnancy rate since blastocyst embryos have a higher implantation rate than day three embryos.

Therefore, time to pregnancy should be shorter for cycles with blastocyst transfers and especially if many blastocysts are transferred on a given cycle. For example, transferring three blastocyst embryos should result in a pregnancy sooner than transferring only a single blastocyst embryo. The definition of RIF would be fewer transfer cycles for multiple optimal embryos transferred per cycle than for either poorer quality embryos, high quality embryos transferred on day three, or fewer blastocyst embryos per cycle. Age also has an impact on the pregnancy rate and is a known factor for implantation failure. Thus, defining recurrent differs depending upon the age of the population studied. Finally, the choice of the number “three” deserves some attention. For three to be the operational number of IVF cycles, there needs to be some correlation with that number and the incidence of implantation failure. For example, the cycle fecundity needs to decline after three cycles of IVF if RIF is defined by the number of cycles for transfer. Where there is no implantation failure, the cycle fecundity rate remains constant. The cycle fecundity rates of 36.2% for each of the first four cycles of donor oocyte embryo transfers.

However, cumulative pregnancy rates for IVF have demonstrated a decline in cycle fecundity with successive failed IVF cycles. A clinical pregnancy rate of 19.0% for the first IVF cycle, 17.4 for the second, 11.8 for the third, 10.8 for the fourth, and less than 6% for the next three successive cycles of IVF. Defining RIF after three cycles of IVF with this data is problematic given the fact that is seems the number should be either two or four cycles of IVF. Furthermore, notes an even more dramatic decline in pregnancy rates with successive IVF cycles where the embryos transferred were blastocyst embryos. The cycle fecundity rates were 36% for the first transfer, 19% for the second, and 9% for the third. Given this data, RIF may need to be defined as failed two or even one cycle of transfers with blastocyst embryos.

A second method of defining RIF uses the number of embryos transferred. All consecutive pregnancies from a large IVF program were analyzed to determine the total number of embryos that had been transferred to achieve each pregnancy. The number to achieve 80% of the pregnancies was 8 and for 95% of the pregnancies it was 12. Arbitrarily defining normal at the 95 percentile, RIF was defined as having failed to achieve a viable pregnancy if more than 12 embryos had been transferred. The patients participating in this study were all infertility patients and, thus, the pregnancy rates were not maximal as they might have been had donor oocyte recipient patients been used. The pregnancy rates and implantation rates were below what they are today, and these pregnancies were achieved using day three transfers, not blastocyst transfers. Therefore, the number used to define RIF would be lower today and depend upon whether day three or blastocyst transfers were being considered.

Any definition of RIF will be found wanting given the complexity and redundancy of the implantation process. However, a working definition of RIF can be based upon the number of embryos transferred. The definition will depend upon the stage of embryo development. The actual number will vary by center and can best be calculated by using pregnancies delivered in patients using donor oocytes. The definition of RIF used in our program requires the transfer of =8, 8-cell stage embryos or =5 blastocyst embryos. Evidence of implantation is accepted when there is a rise in hCG for hCG measurements made 12 and 14 days after the hCG injection that is given to trigger the time of retrieval.

Implantation Bleeding after Embryo Transfer

Embryo transfer is the most critical step in the IVF procedure. You can have the best quality embryos, but if they are not placed into the uterus correctly, then pregnancy will not occur. That is why transfer technique is so important. Pregnancy rates can vary by Physicians, and this is all because of transfer technique. Once the disparities between transfer techniques were corrected and integrated, the pregnancy rates became consistent. For this reason, you want to seek out a Physician who has a lot of experience with embryos transfers and comparable good pregnancy rates. So, if you were paying much more money for an IVF cycle, would ask for a more experienced doctor to do the transfer.

After we discharge our patients from implantation unit, we send them home with instructions to go about the rest of the day and ensuing two weeks with normal, reduced activity. There is no need to be on bed rest. All our patients have different medication protocols that they go home with. Often referred to as the two week wait so we have now come to the end of the IVF procedure and the maximum that our technology can help a person to achieve a pregnancy. We are at the point where we have to wait and see. If a day-3 transfer was done, it will take approximately 7 days for the remainder of the process to be completed and for the pregnancy test to be positive. For that reason, it is refer to pregnancy tests at 8 or 9 days post transfer. For a blastocyst transfer, you only need three more days to get a positive pregnancy test.

Pregnancy occurs when the egg is released by the ovaries, fertilized by sperm to form a Zygote fertilized eggs. This process occurs in the fallopian tubes, the Zygote travels to the uterus and during this period, it was further divided to form a blastocyst, which can be described as a ball of cells with sheath. Once the blastocyst reaches the uterus, it gets out from the protective outer layer and glued on the inside lining of the uterus (endometrium). Through this entanglement, blastocyst formed a relationship with the mother's blood vessels, to receive the oxygen and nutrients needed for growth.The blastocyst can cause a slight amount of bleeding, such as penetrating the endometrium and will be attached to the uterus. This blood coming out from the uterus through the vagina, and this incident is called implantation bleeding, which is considered as one of the signs of early pregnancy. Although it is a sign of pregnancy, absence does not mean that there is no pregnancy, no. In other words, every pregnant woman is not likely to experience bleeding, because it is not necessary to cause bleeding while the blastocyst implanting itself in the uterine wall. It is said that only a third of women experience this condition. The basic idea about the signs and symptoms of implantation bleeding and the time of the occurrence may be useful in recognizing the condition.

This usually happens right before the estimated date of the menses. The average menstrual date is calculated as the 14 day from the date of ovulation (the cycle can vary between women) and the implantation bleeding occurs between six to twelve days after ovulation. In other words, this bleeding usually occurs on the third or fourth week of the date of the last menstrual period. Eggs that have been fertilized or Zygote takes approximately five to six days to travel from the fallopian tubes toward the uterus. After that, it will be attached to the endometrium. Thus, implantation bleeding is said to occur in nine to twelve days of ovulation. But in some cases, it may occur as early as six days as well. So, the time frame for the occurrence of implantation bleeding is usually given as 6 to 12 days after ovulation. Even the time taken by the blood to come out of the womb may affect the time of implantation bleeding.

As mentioned above, this type of bleeding is caused by small amounts of blood that is released from the blastocyst attachment locations on the endometrium. First of all, you must understand that implantation bleeding is not likely to occur in women. It may happen that the endometrium does not bleed at all, while the blastocyst will be attached. Even the amount of bleeding can vary from one woman to another. So, the first and foremost sign of bleeding implantation bleed itself. The vaginal discharge may be too minimal or spotty in some women, whereas in some others may be a little heavier. However, in this case the type of bleeding, blood will be pink or Brown, like old blood (it takes some time for the blood to come out of the womb). Commonly, implantation bleeding is not associated with any symptoms, but some women may experience minor cramps in uterus and increased basal body temperature (the lowest temperature attained by the body during rest, usually while a sleep).In addition to the implantation bleeding and other symptoms of pregnancy include nausea or vomiting, tender and swollen breasts, frequent urination, fatigue, flatulence and increased sensitivity to odors. If these symptoms develop after implantation bleeding along with the late period; they may indicate pregnancy. However, confirmation of the pregnancy is done with a blood test and urine as well as obstetrical ultrasound. If implantation bleeding is accompanied by pain, you should consult with your obstetrician.

Blood contaminates the endometrial cavity at the time of the transfer, this will kill the embryos and pregnancy will not occur. The catheter must be placed as gently and a traumatically as possible. That is an absolute requirement. The endometrium, which is now in its fullest growth state, thickened from estrogen stimulation, can be easily scraped and these cause bleeding. You should not worry if brown blood or discharge occurs at the time of transfer, it will usually manifest within the first day or so after the transfer, but not into the mid-Luteal phase or later. That type of bleeding would be from a different source. There are situations, however, when bleeding can occur but not be ominous. Sometimes a woman's cervix will bleed easily from being scraped by the speculum or irrigation or wiping. This external bleeding will not affect the endometrial cavity as long as the transfer catheter is not exposed to the blood. For example, I do not let the catheter get exposed until the introducer is well into the cervical canal, near the internal cervical, to begin advancing the catheter. Bleeding that occurs later in the luteal phase, days after the transfer, is very common if vaginal progesterone is used. 

For some patients, because used both vaginal and injectable progesterone by the experts, it is almost 90%, but the bleeding tends to occur near the time of the pregnancy test or soon thereafter. This is probably caused by some erosion occurring on the external cervix. The exact cause, however, is not clearly understood. It is usually light spotting and can be anywhere from red to brown. Red is newer blood and brown is old blood. Patients not to worry about this; the only bleeding that patient would worry about is bleeding that is red and heavy like a period. This is not good, and should not occur if the hormones progesterone and/or estrogen have not been discontinued. Some patients will experience slight spotting 3-5 days after embryo transfer and refer to this as "implantation bleeding." Whether or not this is caused by implantation is not known. Implantation should not cause bleeding. However, again, if it is not bright red blood that is heavy like a period, it should not cause worry.

The body is a fluid and dynamic structure and there will be many sensations that patients report during this period. Some will report many types of “pains”, some will have “cramping” and some will have “bleeding”. Most of these symptoms are not of any consequence but cause patients to needlessly worry. Some doctors have referred to these “pains or cramping” as implantation related. That may be the case but no one knows for sure. Certainly with implantation, the uterus is undergoing changes and cramping tends to be one way that uteri react. So, if the timing is appropriate, namely at the point where implantation would be expected as described above, then these sensations could certainly be related to it. Of course, onset of one’s period can also be signed by cramping but this is usually accompanied by bleeding. If adequate hormone replacement is given in the luteal phase of the process, then the period should not start until the medications are stopped. That is the cause of the onset of the bleeding and cramping associated with a period; it is the withdrawal or abrupt drop in hormone levels. Some will claim that this is the uterus “stretching or growing” but this could not be the case at this point in the pregnancy. 

The embryo is like a mere fleck of dust within the cavity and not big enough for the uterus to begin “growing.”Some patients will experience sharp or stabbing pains, on the other hand, that may not be from implantation but more from the ovaries. About three days after the retrieval, the ovaries will refill with fluid and this stretching of the follicles and ovaries certainly can cause pain in one side or both sides. This is the pain sensation that most patients have during this period of time. Post IVF complications causing severe pain include Ovarian Hyper stimulation Syndrome (OHSS), ovarian torsion (twisting), ovarian flow of blood, Ectopic pregnancy and Pelvic infection. 

If the pain is mild, then intervention is probably not required but if severe, it could be one of these serious medical problems that will require medical treatment because they could be life threatening. You should know, however, that these complications are very rare. On the other hand, if you have had a positive pregnancy test and these symptoms occur impending miscarriage could be another source of cramping or pain.Bleeding within this period of time is also a very common complaint. In most cases this bleeding is inconsequential but it could also indicate problems such as inadequate hormone support for the Luteal phase, thereby causing the endometrial lining to start to slough. 

It could also indicate that the period is starting or that an abnormal pregnancy exists or is being miscarried. When the bleeding is light, I usually will reassure my patients that no intervention is required. For one, there is no intervention that can be done, other than checking hormone levels and increasing the progesterone if the level is inadequate. Secondly, this could be normal, if in fact it is implantation bleeding. Thirdly, if vaginal progesterone is used, the progesterone may be causing the cervix to be more delicate or friable and therefore cause cervical bleeding. If implantation bleeding is accompanied by pain or heavy bleeding, you should consult with your obstetrician.

Friday, 19 July 2013

Evaluation of Embryo Development and Best Embryo for Transfer

Patients who have been undergoing ovarian stimulation for in vitro fertilization (IVF) must take daily injections of hormones to stimulate the growth of follicles in the ovaries.  Within these follicles are eggs (oocytes) that must then be retrieved so that they can be placed in a laboratory for fertilization by sperm.  The primary reason that IVF is so successful is not only through the development of multiple embryos, but by selecting the best embryos from this group for transfer into the uterus.  In some ways, IVF is like cramming many months of trying to conceive into one cycle, because of the many embryos that result, but it enhances the probability of success by choosing the best embryo(s) from the group to be replaced.  In a natural cycle, typically only one oocyte develops and is ovulated, regardless of the quality.

Advances in embryo culture have made increasing duration of embryo culture possible.  In the early days of IVF, embryo transfer might have been performed after fertilization (day 1) or on day 2 after oocyte retrieval.  Technical expertise and research studies have refined optimal culture conditions so that embryos are now routinely cultured to day 3 or day 5 after oocyte retrieval, and some embryos are even transferred on day 6.  Ultimately, there are limitations to embryo culture in the laboratory, since the development cycle of an embryo requires that it hatch from its shell and implant in a receptive endometrium or fail to develop further.

In order to select the best embryo for transfer, an embryologist observes embryo development in the laboratory over the course of several days.  On the day following oocyte retrieval, the embryos are assessed for normal fertilization.  Problems in development can arise even this early fertilization is a chemical reaction that is initiated after a sperm cell penetrates an oocyte; however, the insertion of a sperm into an egg does not guarantee that fertilization will occur properly.  In addition, sometimes the defense mechanism of the egg, which should prevent more than one sperm from entering, fails, and the resulting embryo will be abnormal.

Factors that determine when to transfer embryos include the age of the patient, the number of embryos that are available to transfer to the uterus, the quality of the embryos in the laboratory, past history of IVF treatment and the outcome of those treatments. Determining the number of embryos to be transferred follows similar considerations, and guidelines for the number of embryos to transfer have been developed.

In order to choose which embryo(s) to transfer, several systems to assess the quality of the embryos have been developed, so that the best embryo can be selected.  In short, the system created to selecting embryos for transfer must be better than picking embryos randomly.  The most common method for choosing embryos is visual morphologic assessment using a microscope, an embryologist observes and takes notes on how the embryo appears using standard criteria.  By assessing embryos daily, the embryologist creates a record by which to compare one embryo against another so that they may rank in order of choice for transfer.  Since embryos are cultured individually in labeled droplets in a culture dish, a record for each embryo can be created over the course of days.  There are numerous standardized grading systems for evaluating embryos, but each laboratory may also set its own criteria for what indicates better quality embryos based on observed outcomes and may follow unique grading systems.

When evaluating embryos under a microscope, morphological items of interest may include the symmetry of the cells, the evenness of cell size, the number of cells, the number of nuclei in each cell, the amount of fragmentation of the cell, the quality of the shell (Zona Pellucida), and the clarity of the cell’s cytoplasm.  For an embryologist, learning to identify and judge these characteristics requires extensive training, and expertise in morphological assessment is gained over time, so it is not surprising when patients don’t even understand some of the terms reproductive endocrinologists sometimes use when talking about embryo quality.

In general, we do our best to convey to patients meaningful information about the quality of their embryos prior to transfer.  Since most people don’t have an education in human embryology, it can be difficult to convey this information in a satisfactory way. The ideal embryo to transfer on day 3 after oocyte retrieval has eight cells.  Sometimes other embryos may have more or fewer cells.  Most people seem to understand that slow development is likely to decrease the probability of success, but not as many understand that faster development (having more than 8 cells on day 3) may not actually be better.  We suspect that 8-cell embryos are generally the best (excluding other considerations) because the resulting pregnancy rates seem to be the highest when 8-cell embryos are transferred.  This observation does not have an easy explanation, but is just something that has been observed.  However, it also does not guarantee success, and it does not always indicate that 8-cell embryos will the best embryos of any group of embryos available for transfer, just that the probability of success may be highest when this specific situation is observed.

When other factors are considered, such as the other morphologic characteristics listed above, other embryos may be found to be superior in implantation potential.  There are theories as to why the 8-cell embryo is likely to be among the best embryos of any group: there are “checkpoints” in cell development, much like a turnstile – the checkpoint that prevents cell division likely does so because proper conditions for cell division have not been met, possibly because the cell is abnormal, and checkpoints that allow too much progress (more rapid cell division) might not be conducting proper quality control and have failed to slow down abnormal cells or premature cell division.

When there more good quality embryos on day 3 than are appropriate for transfer and when the quality of these embryos is so similar that it is difficult to choose which among them are the very best, embryos are generally cultured for two more days.  Typically, embryo transfer is not performed on day 4 because the stage of development on day 4 is difficult to assess using a microscope: on day 4, embryos are typically at the “morula” stage, which is amorphous and lacks clear characteristics by which to judge development.

On day 5, embryos have ideally become “blastocysts.”  Blastocysts have two cell types: an outer ring of cells that are destined to become the placenta and an “inner cell mass” that eventually becomes the developing fetus; because blastocysts typically have more than eighty cells, it becomes impossible to look at each individual cell to assess it, as is done on day 3.  Instead, a quality “staging” system is typically used.  A number score (1-6) to indicate the degree of expansion, like a shoe size, is assigned, and letter grades, A-D, like in school, are given, first for the inner cell mass and then for the outer cells.  So, a high quality blastocyst might be stage: 4AA or 5AB, for example.  A stage 6 blastocyst has “hatched” from the shell surrounding the embryo.  Since two different systems are used, it is impossible to compare day 3 and day 5 embryos.

Day 5 embryos are given letter grades to assess the quality of the two cell types based on morphologic assessment.  For example, numerous cells in a tight cluster are representative of a better quality inner cell mass than sparse cells that are loosely associated.  On day 3, letter grades are not typically given, which is often frustrating for patients.  Although we could assign letter grades to these embryos, it wouldn’t mean the same as on day 5, since different things are being assessed.  Also, assigning letter grades on day 3 might obscure the real quality of the embryo: for example, if two students take a math test and one scores a 96% and the other a 99%, but the teacher gives them both an “A” grade, are they really the same?  By grouping assessments into more encompassing, simplistic categories, important information is lost.  A patient can always ask the doctor to make such a comparison for ease of mind, but that assessment may obscure the true quality of an embryo.

In the absence of more specific information, such as the genetic make-up of a cell, which usually requires invasive procedures such as embryo biopsy, morphologic evaluation is the mainstay of embryo assessment.  Other methods of assessment, such as analyzing the culture medium in which the embryo has been growing to detect markers of embryo health, are being developed, but have not been shown to be more accurate in determining which embryos have the highest implantation potential.  Not all embryos, even when morphologically perfect, may be genetically normal, just as not all poor quality embryos are genetically abnormal, so selecting embryos based on morphology is not a perfect system.  In addition, it is possible that all embryos are abnormal and no pregnancy will result or that other factors unrelated to the embryos will interfere with successful pregnancy despite morphologic assessment.  However, selecting embryos based on morphologic criteria currently remains the best method to choose embryos without using more invasive techniques.

Assessment of low and high beta HCG: Unveiling the Secrecy

If you visit any forum or infertility group discussion; you are sure to find questions and worried about HCG levels. The posted inquiries run the gamut from “is my beta too low,” to “do you think my number is high enough to indicate twins?” After my initial beta I was one of the many searching out information on HCG and whether or not my number was good or bad. Looking at other people’s beta levels and doubling times really can help ease some of the worry that goes along with just not knowing what it all means. On that site they only put betas in the chart once a heartbeat has been detected so it can be reassuring to read that there was a successful pregnancy that began with a beta level of 3 at fifteen days past ovulation or that some of the successful pregnancies had slower than average doubling times.

The craziness surrounding beta HCG levels is kind of unique to the world of infertility. People who conceive naturally often don’t even think about their HCG levels unless something goes wrong and the doctor orders the quantitative test. Those who have been through treatment spend their two-week wait counting down the days until beta day. If you are lucky enough to get a positive beta, try counting down the days until the second beta so you can get the more important information of your doubling time or even better (and much more difficult) see if you can hold out and not freak out until your ultrasound at 5-6 weeks. The first ultrasound will tell the tale of your pregnancy much more accurately and if you can do it; you will save yourself much worry and concern.

The hormone human chorionic gonadotropin (better known as HCG) is produced during pregnancy. It is made by cells that form the placenta, which nourishes the egg after it has been fertilized and becomes attached to the uterine wall. Levels can first be detected by a blood test about 11 days after conception and about 12 - 14 days after conception by a urine test. In general the HCG levels will double every 72 hours. The level will reach its peak in the first 8 - 11 weeks of pregnancy and then will decline and level off for the remainder of the pregnancy.

“An HCG level of less than 5mIU/ml is considered negative for pregnancy, and anything above 25mIU/ml is considered positive for pregnancy.”

Each and every patient or couple undergoing IVF, makes a huge emotional, physical and financial investment. The fact that receiving the result of the beta HCG (human chorionic gonadotropin) pregnancy test represents the first decisive hurdle that must be confronted, makes this a very big deal!! The few days after the embryo transfer, waiting for this first outcome report from your fertility clinic is usually anxiety ridden and highly stressful. It is thus imperative that the Fertility Specialist and his/her staff deal delicately with the transfer of this critical information. Dropping the ball at this time would be unconscionable. The physician and staff must make themselves accessible to the patient/couple and communicate the results promptly, professionally and with sensitivity.

A single HCG reading is not enough information for most diagnoses. When there is a question regarding the health of the pregnancy, multiple testing of HCG done a couple of days apart give a more accurate assessment of the situation.
The HCG levels should not be used to date a pregnancy since these numbers can vary so widely.

HCG levels in weeks from LMP (gestational age)*:

      1.       3 weeks                               LMP:      5 - 50 mIU/ml
      2.       4 weeks                               LMP:      5 - 426 mIU/ml
      3.       5 weeks                               LMP:      18 - 7,340 mIU/ml
      4.       6 weeks                               LMP:      1,080 - 56,500 mIU/ml
      5.       7 - 8 weeks                         LMP:      7, 650 - 229,000 mIU/ml
      6.       9 - 12 weeks                       LMP:      25,700 - 288,000 mIU/ml
      7.       13 - 16 weeks                     LMP:      13,300 - 254,000 mIU/ml
      8.       17 - 24 weeks                     LMP:      4,060 - 165,400 mIU/ml
      9.       25 - 40 weeks                     LMP:      3,640 - 117,000 mIU/ml

Non-pregnant females: <5.0 mIU/ml and Postmenopausal females: <9.5 mIU/ml

* These numbers are just a Guideline- every woman’s level of HCG can rise differently. It is not necessarily the level that matters but rather the change in the level.

What can a Low HCG level mean?
A low HCG level can mean any number of things and should be rechecked within 48-72 hours to see how the level is changing. A low HCG level could indicate:

  v  Miscalculation of pregnancy dating
  v  Possible miscarriage or blighted ovum
  v  Ectopic pregnancy

What can a high HCG level mean?
A high level of HCG can also mean a number of things and should be rechecked within 48-72 hours to evaluate changes in the level. A high HCG level can indicate:

  v  Miscalculation of pregnancy dating
  v  Molar pregnancy
  v  Multiple pregnancy
  v  Should my HCG level be checked routinely?

While it can be interesting to see what other people’s beta levels are it is important to remember that the number itself is not the most telling or reliable. HCG is the hormone made by pregnancy that is detected to indicate that a woman is pregnant. In general HCG levels will double every 2-3 days in early pregnancy. 85% of normal pregnancies will double every 72 hours and doubling is often more important that the actual HCG number. There is definitely a large variation in “normal” HCG numbers, and it is advisable to resist the urge to compare to others. That being said, I know from personal experience that it is really hard not to seek out information about the levels and even more difficult to just wait patiently for the ultrasound as recommended.

At least two quantitative beta HCG blood tests are done (2-4 days apart). The reporting of “beta” pregnancy test results is best deferred until after the 2nd blood test results are in. This is because a successful IVF outcome will (in younger women) result at best in 50-55% of cycles (with the notable exceptions of IVF using an egg donor and the transfer of genetically [CGH] tested “competent” embryos).  Thus, it is important to counsel patients in advance of them undergoing beta HCG testing to have rational expectations. It is equally important to inform patients exactly how, when, and from whom they will receive the report of their beta HCG results, because they are about as likely to get “bad news” as they are likely to hear “good news”. Thus I usually advise my patients to “prepare for the worst while hoping for the best” and that in the event of a “negative” result they will have prompt access to me (or a designee) for counseling.

As soon as an embryo begins to implant and its root system begins to invade the uterine lining.  it starts to release the “pregnancy hormone” human chorionic gonadotropin (HCG) into the recipient’s blood stream. About 12 days after egg retrieval, 9 days after a day-3 embryo transfer and 7 days after a blastocyst transfer, the woman should have a quantitative beta HCG blood pregnancy test performed. By that time almost all HCG injected to prepare the developing eggs for egg retrieval should have left the woman’s bloodstream. Thus the detection of >5 IU of HCG per ml of blood tested is an indication that the embryo has attempted/begun to implant. Since with third-party IVF (i.e. Ovum donation, gestational surrogacy, embryo adoption) or frozen embryo transfers, no HCG “trigger shot” is administered, the detection of any amount of HCG in the blood is regarded as significant.

Often times, an initial rise in HCG (between the 1st and 2nd test) will be slow (failure to double every 48 hours). When this happens, a 3rd and sometimes even a 4th HCG test should be done at 2-day intervals. A failure to double on the 3rd and/or 4th test is a poor prognostic sign. It usually indicates a failed or “dysfunctional” implantation but in some cases a progressively slow rising HCG level might point to a tubal (ectopic) pregnancy. Diagnosis requires additional serial blood HCG testing, ultrasound examinations and clinical follow-up to detect any symptoms or signs of an ectopic pregnancy.  

In some cases the 1st beta HCG level starts high and then drops with the 2nd test, only to re-start doubling every 2 days thereafter. This sometimes suggests that there were initially more than one embryo implanting and that one of these subsequently succumbed and one survived to continue a healthy singleton pregnancy. It is customary for the IVF clinic staff to call the patient/couple (and when applicable, notify the referring physician) with the results of the HCG pregnancy test. Often times, the IVF doctor or nurse-coordinator will work through the office of the referring physician to arrange for the all pregnancy tests to be done. If the patient/ couple prefer to make his/her/their own arrangements, the IVF program should provide them with detailed instructions as to how/when and where these tests should be done.

In the event that serial blood quantitative beta HCG pregnancy tests indicate that one or more embryos are likely to be implanting, some IVF physicians advocate daily injections of progesterone or the use of vaginal hormone suppositories for several weeks to support the implanting embryo(s). Others, including several physicians prefer to prescribe HCG injections three times a week for several weeks until the pregnancy can be defined by ultrasound. Some IVF centers do not prescribe any hormones at all, after the transfer.

Patients who undergoing frozen embryo transfer, egg donor, or surrogate cycles and who have blood HCG levels that show the appropriate 2-day doubling; will receive estradiol and progesterone injections and/or vaginally administered hormone suppositories, for 10 weeks following the diagnosis of implantation by blood pregnancy testing. A “clinical pregnancy” is defined as one where there is clear ultrasound evidence of an intrauterine gestation. Such confirmation is usually sought two to three weeks after the first “positive” beta HCG test.

A chemical pregnancy is one where in spite of the beta HCG test being positive it fails to progress to the point of ultrasound confirmation. Chemical pregnancies occur quite frequently following IVF. While they usually result from a chromosomally abnormal embryo trying to implant, they can also be due to the uterine lining (being insufficiently receptive to allow healthy embryo implantation. Clearly, to the IVF patient, the diagnosis of a “chemical pregnancy” represents a severe disappointment. However its occurrence provides clear evidence that at least one embryo reached the advanced preimplantation phase of development went on to “hatch” and attempted to implant.

The chance of miscarriage progressively decreases from the point of diagnosing a viable clinical pregnancy. From this point on, the risk of miscarriage is usually less than 15% in women under 39 years of age and less than 35% in women in their early forties.

Conveying news of a “positive” beta HCG result is easy. Everyone feels elated and vindicated; It is dealing with the unsuccessful case that offers the real challenge. In this regard, nothing is more important than establishing rational expectations from the get-go. In some cases, the patient/couple will crack under the emotional pressure and will require referral for counseling and in some cases psychiatric therapy.

Thursday, 11 July 2013

An Analysis to Recurrent Embryo Implantation Failure

Several factors may lead to in vitro fertilization (IVF) failure. However, many women who have had a failed cycle will have a subsequent successful cycle (live birth). While not all issues related to IVF failure can be corrected, some issues can be addressed in an effort to reduce the likelihood of another failed cycle. It’s important to understand what factors are involved in each individual situation.

More than 70% of transferred embryos by IVF/ICSI methods fail to be implanted. The causes for repeated implantation failures (RIF) may be reduced endometrial receptivity or other various uterine pathologies, such as thin endometrium, altered expression of adhesive molecules or Immuno-logical factors; whereas genetic abnormalities of male or female individuals, sperm defects, embryonic aneuploidy or zona hardening are other etiologies for implantation failures. Clinically, endometriosis, polycystic ovaries and hydrosalpinx may decrease implantation following embryo transfer due to dual disorders in the quality of embryos or endometrium.

Probable causes and methods of evaluation for RIF patients have been reviewed and the suggested methods for their treatment, including myomectomy, endometrial stimulation, immunotherapy, hysteroscopy, preimplantation genetic screening (PGS), assisted hatching, zygote intra-fallopian transfer (ZIFT), co-culture, blastocyst transfer, cytoplasmic transfer, tailoring stimulation proto-cols, intracytoplasmic sperm injection (ICSI).

Endometrial injury (biopsy or scratch or hysteroscopy) in the cycle preceding ovarian stimulation for IVF has been proposed to improve implantation in women with unexplained recurrent implantation failure (RIF). These analyses compare the effectiveness of endometrial injury versus no intervention in women with RIF undergoing IVF. Endometrial biopsy/scratch or hysteroscopy performed in the cycle preceding ovarian stimulation were included and the primary outcome measure was clinical pregnancy rate. Local endometrial injury induced in the cycle preceding ovarian stimulation is 60% more likely to result in a clinical pregnancy as opposed to no intervention.

The evidence is strongly in favour of inducing local endometrial injury in the preceding cycle of ovarian stimulation to improve pregnancy outcomes in women with unexplained RIF. Some women undergoing IVF treatment fail to conceive despite several attempts with good-quality embryos and no identifiable reason. We call this ‘recurrent implantation failure’ (RIF) where the embryo fails to embed or implant within the lining of the womb. Inducing injury to the lining of the womb in the cycle before starting ovarian stimulation for IVF can help improve the chances of achieving pregnancy.

Injury can be induced by either scratching the lining of the womb using a biopsy tube or by telescopic investigation of the womb using a camera. We performed a collective review of the available good-quality studies that used the above two methods in the cycle prior to starting ovarian stimulation for IVF. Furthermore, scratching of the lining was 2-times more likely to result in a clinical pregnancy compared with telescopic evaluation of the lining of the womb. This study suggests that in women with RIF, inducing local injury to the womb lining in the cycle prior to starting ovarian stimulation for IVF can improve pregnancy outcomes.

Age is a very important factor in the success or failure of IVF. As women age, the number of eggs in the ovaries decrease, and the quality of the remaining eggs lessens. The decline begins in your 30s and increases rapidly after age 37. The chance of a live birth after IVF using fresh, non-donor eggs or embryos is approximately 32 percent for a 35-year-old woman, but only 16 percent for a 40-year-old woman.

Fertility specialists assess the quality of the egg based on the age of the woman, as well as the number of cells in the egg. The fertilized egg (embryo) starts as a single cell and continues to divide until it is multi-celled. Three days after egg retrieval and fertilization, most specialists prefer that some of the embryos have at least 6 or 7 cells. Eggs with fewer cells are less likely to fertilize and the chances of IVF failure increase. In general, the more eggs you produce in a given IVF cycle, the greater your chance that the IVF cycle will be successful.

The ovaries of some women, however, do not develop many follicles because they do not respond to the IVF medication used to encourage the ovaries produce multiple eggs. (One egg develops in each follicle.) You are likely to have poor response to IVF medication if you are older than 37, have elevated FSH levels, or have a reduced number of eggs remaining in your ovaries. IVF is likely to fail if fewer than three mature follicles are produced.

A pregnancy loss or miscarriage after IVF may be due to problems related to the uterus, such as polyps or fibroids. Many fertility specialists, however, believe that most implantation failures are due to the seize of the embryo; in other words, the embryo stops growing. This may be the result of a genetic defect that interferes with the embryo's development.

A pregnancy loss or miscarriage after IVF may be due to problems related to the uterus, such as polyps or fibroids. Many fertility specialists, however, believe that most implantation failures are due to the arrest of the embryo; in other words, the embryo stops growing. This may be the result of a genetic defect that interferes with the embryo's development.

Tuesday, 2 July 2013

Low AMH Level, Need not to panic; find out the Solution

Anti-Mullerian Hormone (AMH) is a hormone produced by cells in small developing egg sacs (follicles) that contain an egg in a woman's ovaries. Therefore, AMH gives an indication of the number of eggs being produced during a woman's monthly cycle. The level of AMH in a woman's blood is a good indicator of her ovarian reserve and is helpful in assessing her fertility status. A low level of AMH suggests that there is a significant reduction in the remaining supply of eggs. a substance produced by granulosa cells at the earliest (primordial) stage of ovarian follicle development. Since the number of these primordial cells is linked to the number of follicles that ultimately grow into viable, fertilizable eggs, AMH levels are used to assess a woman’s remaining egg supply.

Several factors lead fertility specialists to believe that AMH is a good way of measuring ovarian reserve. Some studies in women being treated by IVF have found lower AMH levels in those who responded poorly to fertility drugs. Other tests of ovarian reserve such as FSH must be measured at particular time(s) in the menstrual cycle. One potential advantage of using an AMH test to assess ovarian reserve is that it does not seem to change over the course of the menstrual cycle, and so AMH can be tested by obtaining a blood sample at any time of the month.

For women undergoing IVF treatment, AMH results can be used to help choose the best dose of fertility medicine(s) used to stimulate the ovaries. AMH levels may help to identify women who are more likely to over-respond or hyper-stimulate during IVF treatment, and the dose of fertility medicine can be adjusted to minimize that risk. AMH may help to identify woman who have polycystic ovarian syndrome (PCOS). AMH can also help to identify women who have a lower pregnancy rate from fertility treatment.

Most common measurement of AMH levels is as follows:

High AMH                           over 3.0ng/ml
Normal AMH                     over 1.0ng/ml
Low Normal AMH            0.7-0.9ng/ml
Low AMH                            0.3-0.6ng/ml
Very low AMH                  less than 0.3ng/ml

The above values are then used to predict chances of conception with higher numbers indicating a larger ovarian reserve and as such a more promising odd of pregnancy and lower levels mirroring poor reserve and poor chances of conception.

The low AMH and Vitamin D deficiency link, mostly ignored in clinical practice and during the infertility diagnosis is nonetheless becoming a much discussed subject on infertility forums and blogs. If your vitamin D levels are low, you might get a “false” low AMH level reading and as a result receive a “false” prognosis that might send you into a self-fulfilling spiral of defeat. So if you received a low AMH diagnosis, it makes sense to start your investigation by testing your vitamin D levels. All you need is a simple blood test to determine your Vitamin D levels.  Although as recently as few years ago, levels of   20-100 ng/ml were considered normal, currently the optimal levels have been raised to 32-100 ng/ml. 

Anti-Mullerian Hormone test results are mostly useful in assessing a woman’s response to ovarian stimulation for IVF, where retrieving more eggs is thought to increase chances of pregnancy. Some study reports the case of two women with very low AMH levels who became pregnant spontaneously, the other one compared AMH levels of two groups of healthy women: obese and non-obese. The obese women, whose overall level of health and organ function may have been compromised, had lower AMH levels. And the last explores the link between Vitamin D levels and low AMH. AMH levels though they may reflect a diminishing size of the remaining ovarian pool, are also a reflection of ovarian function related to a woman’s overall level of health; Since AMH levels do not reflect egg quality, when the overall level of the woman’s health increases, chances of pregnancy increase.

Here you all of need to know about the ovarian reserve also that a woman's ovarian reserve is the amount of good quality eggs remaining in her ovaries. Although men continually produce new sperm, women are born with their lifetime supply of eggs. In other words, women do not produce new eggs and as they age their supply of eggs in their ovaries decreases. As the rate of loss of eggs varies between women, it can be difficult to predict the amount of eggs and level of fertility a woman has as she ages. Therefore, measuring ovarian reserve can be an important part of fertility evaluation and potential advantages of having your ovarian reserve measured include;

-       -  If you have decided to delay starting a family you may wish to check your ovarian reserve to confirm that   your supply of eggs is not already significantly reduced.
-         - A low ovarian reserve is one factor in identifying women who may have a low chance of success from fertility treatment.
-          - If a woman has an unusually high ovarian reserve she may have polycystic ovarian syndrome (PCOS).
-      - Measurement of ovarian reserve is helpful in deciding the best dose of medicine(s) to use during fertility treatments such as in-vitro fertilization (IVF).

A number of different blood hormone levels and ultrasound measurements have previously been used to assess ovarian reserve. However, there are potential drawbacks and inaccuracies associated with each of those tests.
These include;

-          - Follicle Stimulating Hormone (FSH) measured on day 3 of the cycle
-          - Inhibin B
-          - Antral follicle count
-          - Ovarian volume assessment
-          - Clomiphene challenge test

A common question was regarding the clinical significance of a low AMH level. “I am young and my AMH level is low”.  What does this mean?  Does a low AMH level mean I will never get pregnant? Today, because the test is so easily available, many doctors do AMH level testing in order to counsel infertile women. While a normal AMH level is reassuring, many doctors do not seem to understand what to advise their patients when their AMH level is low. While low AMH levels do suggest poor ovarian reserve, this does not mean that these patients cannot get pregnant with their own eggs. However, there are some IVF specialists who reflexively advise their patients with low AMH levels to use donor eggs as their first treatment choice!

Both doctors and patients need to remember that doctors do not treat lab results – we treat patients. Sadly, it’s so much easier to order lab tests and “fix” these rather than talk to the patient that we tend to over treat abnormal lab results such as low AMH levels.

Please remember that women with low AMH levels do get pregnant in natural way as well! This is especially true for young women with low AMH levels – in these women; a low AMH level does not correlate as well with poor fertility as compared to low AMH levels in older women!

The trouble is that when infertile women find out they have a low AMH level, this is what they start obsessing about – much like the man with a low sperm count that is exclusively focused about his sperm counts!

Please remember that an AMH level is just one piece in a complex mystery! If you do have a low AMH level, please do not panic. Remember that every problem has a solution - we just need to find the right one for you!

Here are some ground rules, which may help to what should do next.

1.    Please don’t jump to conclusions based on just one report.  Please retest from another lab – remember that not all labs are reliable!

2.    You need to collect additional evidence to confirm the diagnosis of poor ovarian reserve. One of the best ways of doing this is by checking your antral follicle count, using a vaginal ultrasound scan.

3.    it’s worth trying alternative medicines to try to improve your ovarian reserve. While these are untested and unproven, they are unlikely to cause any harm – and will give you peace of mind you did your best. You can use yourself as a personal guinea pig and run a clinical trial on yourself – this is a great way of becoming an expert patient!

Low AMH levels in young healthy women do not seem to be a predictor of reduced productive ability.  This is consistent with high egg quality in these young women, despite a reduced ovarian reserve.  Conversely, women with high AMH levels had a 40% reduction in the FR, and this persisted even after exclusion of women with irregular cycles.

So what does all this mean?  At present, routine measurement of AMH level as a “fertility check up” in young women is not useful.  It clearly shows that young women with low AMH levels did not have a decreased chance of conception compared to women with normal AMH levels.

It’s important to remember that we do have solutions to this common and frustrating problem, and that a low AMH level does not mean that your dreams of having a baby will never be fulfilled!

It’s a good idea to try IVF to see how your ovaries respond. Using donor eggs should always be second option!