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Trazeci razloge za vise neuspesnih VTO, naidjoh na sajt koji mi se cini vrlo korisnim, pa cu iskopirati par tekstova odatle. Ovo je blog koji vodi neki dr, ima dosta i tekstova i pitanaj i odgovora, verujem da i mi mozemo da postavimo pitanja, vidim da redovno odgovara. Blog he: http://www.IVFauthority.com.
Sve je na engleskom, ali, na zalost nemam ni vremena ni snage da prevodim sve. Ko ne razume tu je google translate, moze da posluzi.
Iskopiracu i njegov savet kako da pretrazite blog.
Please go to the Home page of this blog, http://www.IVFauthority.com. When you get there, look for the “search bar” in the upper right hand corner. Type the following subjects into the bar, click on it and it will take you to all the relevant articles posted there.
1. “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)
2. “Ovarian Stimulation in IVF: Why is it important to down-regulate LH?”
3. “Agonist/Antagonist Conversion Protocol”
4. “A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
5. “IVF success: Factors that influence outcome”
6. “Staggered IVF”
7.“Embryo Banking”
8.”Unexplained IVF Failure”.
9.”Immunologic Implantation Dysfunction (IID)”
Consider calling 800-780-7437 or 702-699-7437 to arrange a Skype consultation with me so we can discuss your case in detail
Geoff Sher
Immunologic Implantation Dysfunction (IID): A common Cause of Repeated, “Unexplained” IVF Failure
http://haveababy.com/fertility-information/ivf-authority/unexplained-infertility-and-ivf-failure
The financial and emotional cost associated with unexplained infertility or repeated IVF failures can be devastating. So, to advise couples who have failed one or more attempts that all it would take to ultimately succeed would be to keep on trying over and over again, is both overly simplistic and disingenuous.
About seven to eight days after fertilization, the embryo’s root system begins communicating with the immune cells (lymphocytes) in the uterine lining (endometrium) through an interchange of growth factors known as cytokines. It is upon the integrity of this communicative process (known as the “cytokine network”) that regulated intrusion of the embryo’s root system (that will eventually develop into the placenta) is predicated.
Thus a dysfunctional immunologic interaction between the developing conceptus and the mother can cause all kinds of reproductive problems ranging from failed implantation (presenting as “unexplained” infertility or repeated IVF failure) and miscarriage, to intrauterine growth retardation, stillbirth, fetal loss, and reduced post-birth neurologic and physical development.
It follows that proper implantation is not only a prerequisite for embryonic survival, it is also a major factor in determining intrauterine growth and development of the baby and perhaps most importantly it ultimately can influence the very quality of life after birth.
There are basically two categories of Immunologic Implantation Dysfunction (ID):
Autoimmune ID:
This is by far the most common variety. It is believed to be implicated in >90% of cases of immunologic implantation dysfunction and occurs when an immunologic reaction is produced by the individual, to his/her body’s own cellular components. The most common antibodies that form in such situations are:
a) Anti-phospholipid antibodies (APA)
b) Antithyroid antibodies (ATA)
c) Antiovarian antibodies.
But, it is only when specialized immune cells in the uterine lining known as Natural Killer (NK) Cells, become activated (NKa) and start to release “toxins” that attack the root system of the embryo, that implantation potential is jeopardized. Diagnosis of such NK cell activation (Nka) requires highly specialized blood and/or endometrial tests that can only be performed in a handful of reproductive immunology laboratories in the United States.
Since Autoimmune ID is often genetically transmitted, it is not surprising that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as Lupus Erythematosus (LE), Scleroderma, clinical or subclinical hypothyroidism, Rheumatoid Arthritis etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis.
Autoimmune ID is usually lethal to the implanting embryo. This is because it destroys the embryo’s root system from the get-go. Accordingly, it most commonly presents as “unexplained infertility” or “unexplained (often repeated) IVF failure” rather than as a miscarriage. Autoimmune ID is readily amenable to reversal through timely, appropriately administered, selective immunotherapy (see below).
Alloimmune ID:
This is relatively uncommon, accounting for less than 10% of cases of ID. Alloimmune ID is associated with a reaction to cell components (e.g sperm antigens) derived from another member of the same species (e.g., sperm). Thus, it is the sperm contribution to the embryo (i.e. the paternal antigen) that makes the embryo an allograft. It is quite remarkable therefore, that an embryo which in the vast majority of cases is immunogically “different” to the mother, thrives in her uterus. This paradoxical arrangement came about through magnificent evolutionary adaptations that allowed this to take place. Uterine immune cells (especially NK cells and T-cells) play a pivotal roll in this accommodation. They do so through a balanced release of growth factors (cytokines).
So it is that in less than 10% of IVF cases that are associated with ID the embryo (through the contribution made by the sperm) shares too many genetically similar characteristics with the host (the mother). When this happens, repeated exposures to such an embryo will over time evoke an imbalance in the cytokines released by the uterine immune cells. This is characterized by activation of uterine NK cells (Nka). In such cases the “root system” of the embryo” can be compromised and the the embryo may be destroyed immediately but most often will instead “limp” along only to miscarry when its supply of nutrients and oxygen is outstripped by demand.
Thus alloimmune ID usually does not destroy the embryo immediately. Rather, after sustained erosion of its reserve, the conceptus will miscarry.
We diagnose alloimmune ID by testing the male and female partners for shared of genetic markers known as of as DQa and HLA. A sufficient degree of matching clinches the diagnosis. We also test the embryo recipient for Nka in an attempt to measure the relative severity of the problem. This is because once the NK cells in the uterine lining are activated and the cytokine balance is disrupted, the situation is grave and will remain so (or worsen) unless the NKa cells are medically deactivated (down-regulated) at least 1 week in advance of the embryo(s) reaching the uterus.
It usually takes repeated exposures of uterine NK cells to an alloimmune matching embryo for these cells to become activated (NKa). Until this happens a pregnancy can be established and even proceed to a normal birth inspite of the ID. Subsequently over time, with repeated exposures of matching embryos to the mother’s uterus, NK cells will become activated and the couple will find themselves miscarrying. Eventually the NKa will become permanently established and the couple will fail to conceive. It is thus not unusual to find such couples going from having a baby together through a stage of repeated miscarriages to one of secondary infertility.
Unfortunately, immunotherapy for alloimmune ID is not as likely to be as successful as with the treatment of autoimmune ID. Selective immunotherapy is simply not invariably curative in the case of the former. While selective immunotherapy significantly improves the chances of success, in cases of alloimmune ID, it cannot assure a successful outcome.
Heparin and Aspirin Therapy
There is compelling evidence that the subcutaneous administration of regular heparin twice daily or low molecular heparin (Clexane, Lovenox) once daily, (starting with the onset of ovarian stimulation) significantly improves IVF birth rates in women who test positive for APAs.
Aspirin on the other hand, has little if any value and in my opinion. The reason for this is because it increases the potential to bleed. This effect can last for up to a week and could add bleeding risk to the egg retrieval procedure and resulting in intrauterine bleeding at the time of embryo transfer, potentially compromising IVF success.
IVIG and Intralipid Therapy
The main objective of selective immunotherapy for immunologic ID is to down-regulate (reduce toxicity) of Nka. In the past, the only effective and allowable way to accomplish in the U.S was through the intravenous infusion of a blood product known as immunoglobulin-G (IVIG). However, the administration of a blood product raised understandable concerns about the transmission of viral infections such as HIV and hepatitis.
To make matters worse, competing IVF clinics capitalized on all this bad press by raising red flags and sometimes going as far as to caution infertile couples against seeking IVF services from those who dared to offer access to IVIG. This created “a herd mentality” that severely harmed the practices of those of us who recommended selective IVIG therapy.
Notwithstanding this, we were not willing to be dissuaded by prejudice or malice from doing what we knew was the right thing and the reward for taking this stance which came in the form of thousands of babies (that otherwise would never have been born) now brightens the lives of an equivalent number of couples that otherwise would have remained childless.
In 2006, reports began to surface regarding a product called Intralipid (IL), a synthetic product which, upon being administered intravenously prior to embryo transfer, would elicit a similar regulatory effect on Nka as IVIG had achieved. In 2007 we began administering IL to patients with NKa. At first this treatment was confined to those who needed IVIG but for diverse reasons refused the treatment. Later we expanded the trial to other IVF patients with NKa. Todate we have treated more than 200 women with IL with impressive results (soon to be published). Against this background, SIRM physicians have all but abandoned IVIG, supplanting it with IL.
Compared to IVIG which costs about $4000-$5000 per infusion and can evoke unpleasant and potentially dangerous side effects, IL, when used as recommended by SIRM, is virtually devoid of risk and/or side effects and costs less than $400 per infusion (i.e. 1/10th of the cost of IVIG).
Corticosteroid Therapy (Prednisone, Prednisilone and Dexamethasone)
Steroid therapy is a mainstay in most IVF programs. Some programs prescribe daily oral methyl prednisilone while others prescribe prednisone or dexamethasone, commencing with the initiation of ovarian stimulation with gonadotropins, and continuing until after the ultrasound the diagnosis of pregnancy.
Any seed, if it is to thrive and develop into a healthy plant, requires that it be placed in a fertile soil. So also does a successful pregnancy require that an optimal seed (embryo)/soil (endometrium) relationship be established.
In about 70% of cases, reproductive failure is due to poor embryo “competency” issues, while in 30% of cases, a non-receptive endometrium is the reason for failure. It follows that with IVF, focusing entirely on embryo (seed) quality will not reduce the risk of failure in patients with endometrial receptivity (soil) problems.
The evaluation for immunologic dysfunction as well as for other factors that can affect implantation should form part of the evaluation of patients preparing to undergo IVF, and especially so in women with recurrent pregnancy loss (RPL), women with a personal or family history of autoimmune conditions, and women with “unexplained” infertility or IVF failure(s).
IVF Failure: The Value of a 2nd Opinion
http://haveababy.com/fertility-information/ivf-authority/ivf-failure-value-of-2nd-opinion
Preface: It frustrates me no end that so many couples who have failed to conceive following IVF are often glibly confronted with platitudes such as “It was just bad luck … so just try again,” and in the process are left “spinning their wheels,” feeling abandoned. While “bad luck” could indeed sometimes be a factor, this is not often the case, especially when, in spite of the transfer to the uterus of microscopically “good quality” embryos, the woman fails (often repeatedly) to conceive. The problem is further magnified when it comes to older women for whom time is running out because of an inevitable age-related decline in egg quality (“competency”), and in cases of diminished ovarian reserve (DOR) where the woman’s supply of eggs is rapidly becoming depleted. Most patients who have failed to conceive with IVF intuitively believe that something might have been overlooked in their cases and that, were the issue(s) to be identified, they could be remedied.
Frankly, given all of the good fortune and opportunity afforded me over a 30 year career in the field of IVF , I feel a strong compulsion to put my extensive experience to work where it can do most good and to offer it unconditionally to infertile patients. This is particularly relevant since several major medical advances that I and my colleagues introduced over the years could be applied to the diagnosis and treatment of many such problems, and make a real difference. These include:
a) In-roads made with regard to defining individualized protocols for ovarian stimulation
b) The Introduction of clinical Comparative Genomic Hybridization (CGH) embryo selection
c) The role of Immunologic Implantation Dysfunction (IID) in failed IVF
It is against this background that I have elected (for the foreseeable future) to offer detailed IVF telephone consultations, free of charge to all US and Canadian patients who are interested in my opinion, regardless of where they subsequently choose to be treated. Accordingly, I have designated specific times (daily) in my schedule for this purpose. Please call 800-780-7437 to schedule or submit the request form HERE.
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IVF treatmentalways exacts a profound emotional and financial toll on patients/couples. Needless to say, the financial burden is often crippling However, ask any woman who has undergone IVF and she will likely tell you that the emotional impact was by far the most devastating….especially when the IVF treatment cycle failed to bring her a baby.
The truth is that even in the simplest of cases (i.e. younger women who have normal ovarian reserve with fertile male partners), and in the most capable of hands, at best 50% will give birth to a baby following the transfer of 1-2 morphologically “normal” embryos. More than 70% will achieve success after two fresh embryo transfers. When this fails to happen, the question will invariably arise as to why the failure occurred.
Currently, in excess of 90% of the IVF patients I treat have at least one prior failed attempt before consulting with me, and more than 80% have failed IVF at least 3 times prior to seeking my services. I could cite many cases where patients have even endured as many as 10 or more prior IVF failures. But there is one case in particular that is permanently embedded in my memory and which highlights the importance of an individualized approach to treating infertility patients, especially when it comes to those with prior IVF failures.
The patient was a 42 year old physician who hailed from Australia. She had endured 23 prior unsuccessful embryo transfers over a period of more than a decade. By the time I got to know her she had developed severely diminished ovarian reserve (her day 3 FSH was 26MIU/ml). After a lengthy telephone consultation with me, I urged her to send a blood sample from Melbourne, Australia to a reputable Reproductive Immunology Reference Laboratory in Southern California for testing, to screen for immunologic implantation dysfunction (IID). It soon became apparent that she had an autoimmune thyroid condition (antithyroid antibodies) plus activation of uterine Natural Killer Cells (NKa+). After putting her on an aggressive agonist/antagonist conversion protocol (A/ACP) with estrogen priming and treating her with selective immunotherapy, I harvested (just) three eggs and subsequently transferred two embryos to her uterus. She conceived on this cycle and gave birth to a very healthy baby boy nine months later.
So then…what are the most common reasons for “unexplained” IVF failure, and what can be done to deal with them?
To adequately address these two all-important questions, we first need to recognize and understand that with the exception of poor technical skill in performing embryo transfer, IVF failure is virtually always due to one of the following two causes, which I will address below:
A. Embryo “Incompetence” (+/- 75% of cases)
B. Dysfunctional/Failed Embryo Implantation (+/- 25% of cases)
A. Embryo Incompetence
What is critical to understand here is that it is the chromosomal integrity (“competence”) of the embryo that is the main determinant of its ability to propagate a normal pregnancy. It is almost always the egg (rather than the sperm) that determines this factor. Only a mature egg (MII) that is numerically chromosomally normal (with 23 chromosomes – also known as a “euploid” egg) at the time of egg retrieval can propagate a “competent” embryo. No manipulation in the IVF laboratory, be it assisted hatching, embryo co-culturing, specialized fancy culture media, or even cytoplasmic transfer from a different (euploid) egg can cause an egg that has an irregular quota of chromosomes (aneuploid) to propagate a competent/euploid embryo (i.e. 46 chromosomes). Patients should be highly skeptical of any suggestion to the contrary. Simply stated, an embryology laboratory can only grow competent embryos from competent eggs.
Thus, egg competency at the time of egg retrieval will ultimately determine the ability to generate competent embryos for embryo transfer. By the time the egg is extracted, the “die has been cast” What this means is that aside from the woman’s age – which influences the percentage of her eggs that will have the potential to develop into euploid mature (MII) eggs following hormonal stimulation – the only manner by which we as IVF physicians can influence egg quality is by applying an individualized approach to ovarian stimulation. Without such an approach, egg development will often be compromised (especially in older women, in those with PCOS, and in women with DOR). Then, the hCG “trigger” would be much more likely to cause disorderly rearrangement of egg chromosomes, leading to a greater likelihood of egg incompetence (aneuploidy) and ultimately to incompetent embryos.
Today, through the use of full embryo chromosomal assessment (i.e. full karyotyping) using CGH, we can identify “competent” embryos for selective transfer. The use of this technique is both diagnostic (in that it allows us to determine whether the cause of IVF failure is embryo incompetence or an implantation issue) and therapeutic (in that we can thereupon selectively transfer only one or two embryos at a time and achieve almost a 70% pregnancy rate while virtually eliminating the chance of high-order multiples (triplets or greater). CGH embryo selection is of special relevance and value in cases of older women or those with DOR for whom “Staggered IVF” with embryo banking is of particular value.
Dysfunctional or Failed Implantation
Endometrial thickness (as measured by ultrasound) is described elsewhere. We previously have published that an ideal endometrium measures at least 9mm in thickness at the time of maximal estrogen stimulation. We have also pointed to the importance of excluding the existence of surface lesions that protrude into the uterine cavity (polyps, fibroid tumors or scarring) as they can, by creating an adverse uterine environment, lead to failed implantation. Only a hysteroscopy or a hysterosonogram (saline ultrasound) can diagnose the latter which needs to be treated surgically before embarking on IVF. A hysterosalpingogram (HSG) is too inaccurate to accomplish this.
Then there is the ever-important and (through either arrogance or ignorance) commonly overlooked issue of immunologic implantation dysfunction (IID) that should always be evaluated and addressed in cases of unexplained or repeated IVF failure. Frankly, since in the absence of Nka+, immunologic problems (regardless of cause) are not likely to cause IID, and given the fact that most of my IVF patients come to see me because of repeated failures in the past, I test almost everyone initially for Nka. If the test result comes back positive, we expand immunologic testing to look for the underlying cause. This having been said, I cannot overemphasize how important it is to always have a high index of suspicion regarding the possibility that failure could be due to IID in any patient who has had an unexplained IVF failure in the past.
My IVF Cycle Failed – What Went Wrong? Question #2 – Was I Adequately Evaluated and Prepared for IVF by My Physician?
http://haveababy.com/fertility-information/ivf-authority/my-ivf-cycle-failed-what-went-wrong_12
his is the second in a series of responses to common questions about Failed IVF Treatment. Question #2 – Was I Adequately Evaluated and Prepared for IVF by My Physician?
Patients often ask “When is it time for me to stop doing IVF?”The answer I consistently give is that it is time to stop “when there is no remediable explanation for failure.”It is against this background that I submit that pre-cycle evaluation of a couple undergoing In Vitro Fertilization (IVF) is probably the most important step in the entire process, and becomes even more critical when it comes to evaluating a couple who has failed to conceive after undergoing 1 or more IVF attempts in the past.
The Seed-Soil Analogy
I have in the past stated that successful human reproduction is akin to the need when gardening, to establish an ideal “seed/soil relationship.” However, when it comes to reproduction, the “seed” is the embryo and the “soil” is the uterine lining.As with horticulture, a successful outcome requires planting a “good seed” in a “good soil.” In the case of IVF, a good seed is analogous to what we refer to as a “competent” embryo. This is an embryo that has the proper number of chromosomes (euploid) and has an optimal chance of developing into a healthy baby.A “good soil” is analogous to a receptive endometrial lining (one that will allow normal and healthy implantation to be established). So, proper (re)evaluation of a woman undergoing IVF requires a critical (re)assessment of those variables that affect embryo competency and endometrial receptivity.
A. Evaluating the Factors That Affect Embryo Competency (The “Seed”)
1. Age
The woman’s age during IVF is the most important factor affecting the chromosomal integrity of her eggs.This in turn, is central to the ability of the egg to develop into a “competent” euploid embryos post-fertilization.The “competence” of an embryo is determined largely by the chromosomal integrity of its egg of origin. Only a euploid eggcan propagate a “competent” embryo and it is the age of the woman that determines the likelihood of any egg being euploid.The percentage of a woman’s eggs that are euploid decreases progressively with advancing age beyond 35.At age 30, slightly less than 1 in 2 of eggs will be euploid; at age 40 about 1 in 6-8, and by her mid 40’s, less than 1 in 10 eggs will be chromosomally normal eggs.Cells that have an abnormal quota of chromosomes are referred to as aneuploid. A “normal” (euploid) mature egg has 23 chromosomes. Anything more or less than that number makes the egg aneuploid and such eggs will invariably propagate “incompetent” aneuploid embryos which will either fail to implant, briefly implant and then be lost as a miscarriage, or (albeit infrequently) propagate a baby with a chromosomal birth defect such as Down’s Syndrome. It follows that the woman’s age must be taken into consideration when discussing the likelihood of a successful IVF outcome.
The older the woman undergoing IVF, the more difficult it becomes to maintain an ideal ovarian hormonal environment that would favor proper egg development and thus, the greater will be the imperative to modify the protocol of ovarian stimulation in order to avoid egg maldevelopment (that is more likely to occur in an abnormal environment) and an increasing likelihood that following the hCG “trigger” (that initiates chromosomal segregation) the “mature” egg will turn out to be aneuploid (see my post on an Individualized Approach for Ovarian Stimulation).
2. Ovarian Reserve
Approximately 6-8 years before the onset of menopause, the number of eggs available declines more rapidly, to the point that a woman progressively develops resistance to fertility drugs.This period of diminishing ovarian reserve (DOR) is known as the climacteric and is characterized by progressively rising basal blood FSH levels as well as by declining AMH and Inhibin B levels.The climacteric usually begins in the late 30’s to the mid 40’s but it can and often does occur sooner.
With DOR goes a change in ovarian response to hormonal stimulation and thus it becomes even more important to individualize the protocol of ovarian stimulation in such cases.
3. Sperm Quality
Male sperm dysfunction accounts for about 50% of infertility.In most cases, it is very difficult to reverse through medical or surgical intervention. When it comes to embryo competence, the egg plays a far greater determining role than does the sperm.However, in cases of male infertility, the contributing role played by the sperm in causing embryo aneuploidy increases significantly. There are circumstances where surgical or medical treatment can improve sperm quality significantly:
Some men who have blocked sperm ducts or a fluid collection around one or both testicles (hydrocele) might benefit from surgical correction, while those with a collection of varicose veins around their testicles (varicocele) might benefit from surgical or radiological occlusion of the spermatic vein(s).
While the egg plays a far greater determining role in embryo competence than does the sperm, in cases of significant male infertility, the role of the sperm increases significantly in this regard.
4. Genetic/Chromosomal Factors
Certain chromosomal and genetic abnormalities involving the man or the woman can thwart successful IVF.In approximately 1 out of 200 cases a balanced translocation (where part of one chromosome is exchanged with that of another) will cause unexplained IVF failure or miscarriage.This is worth looking for in some cases.There are also cases where there is a deletion of part of the chromosomes in the sperm or in the egg that can cause the same problem.Detection of such rare genetic events requires In certain cases where there is a low sperm count and motility, the cause may be related to understimulation of sperm production.In such cases the man might have a low blood FSH level.In such cases, treatment with medications such as low dose clomiphene or letrozole for a period of about 3 months (the sperm cycle) will sometimes result in a marked improvement in sperm function.In other cases, administration of FSH and/or LH medications over a period of 3 months can also be helpful (see my post on Enhancing Sperm Production).
B. Evaluating Factors that Affect Uterine (Endometrial) Receptivity (“The Soil”)
1. Thickness of the Uterine Lining
Measured at the time of the hCG trigger, the thickness of the uterine lining is also a very important factor.A lining of less than 9mm in thickness is suboptimal, while a lining under 8mm is usually totally inadequate.It is very important to recognize this fact because, just as the roots of a plant cannot develop adequately if it is planted in a thin layer of soil, so the embryo’s root system (trophoblast) cannot take proper hold or function adequately if the lining is too thin.Today, through the administration of medications such as Viagra for the uterine lining, estrogen and anti-prostaglandins (e.g., aspirin), it is possible in many such cases to improve the lining.However, when as a result of uterine inflammation or surgical trauma to the a thin inner (basal) germinal layer of the endometrium, such treatment will often be ineffectual, necessitating the use of a gestational carrier (surrogate).
2. Endo-Uterine Pathology
The presence of small surface lesions that protrude into the uterine cavity can interfere with embryo implantation. These can be (and often are) missed, unless proper inspection by a hysterosonogram, hysteroscopy or an MRI is done.The use of a dye X-ray test (hysterosalpingogram) is inadequate to identify small endometrial polyps, or small fibroids (see this article on Uterine Fibroids).
3. Immunologic Implantation Dysfunction (IID)
This is often a cause of “unexplained” IVF failure (in about 30% of cases) and must be looked for.Here, autoimmune rather than alloimmune factors (the latter more commonly results in early miscarriage), are usually the cause.Effective treatment of immunologic infertility is available.I have personal experience with many cases where using selective immunotherapy, I have successfully treated women who previously had failed to achieve viable IVF pregnancies after more than 10 consecutive attempts (and in one case more than 20 prior IVF failures had occurred). It is important to bear in mind that resorting to the use of donor eggs does not offer a solution in cases of immunologic implantation dysfunction.
To their own discredit, many fertility doctors have hitherto denied or even discounted the role played by immunologic factors in implantation failure and have even discredited the use of selective immunotherapy in such cases. In my opinion, in this attitude stemmed from a desire to maintain a competitive edge, since until recently, successful treatment of immunologic implantation dysfunction often required the administration of a blood product known as immunoglobulin-G (IVIg). The administration of this product was very expensive (up to $4,000 per infusion, and more than one administration was often required), and it sometimes caused unpleasant side-effects. In addition patients often expressed fear that because IVIg is a blood product, its administration might lead to the transmission of HIV and hepatitis viruses. The fact is however, that this concern was was unfounded because FDA-approved IVIg products are all screened for viral contamination and thus are safe in this regard. Against this background doctors were fearful that prescribing IVIg treatment (while others denounced it) would put them at a competitive disadvantage.
All this changed with the recent introduction of a product called Intralipid (IL), which has largely replaced IVIg for the treatment of immunologic implantation dysfunction. The reasons for the change of heart are that unlike IVIg, IL is very inexpensive (less than $200 per infusion), is safe, and is free of significant risk or side effects and most importantly, IL is equally effective for the treatment of immunologic implantation dysfunction . Perhaps not surprisingly, the low cost and minimal risk associated with IL therapy, bolstered by an ever increasing demand on the part of IVF patients that they be assessed and selectively treated for immunologic issues, has led to a dramatic increase in the number of RE’s that now test for immunologic implantation dysfunction. In fact, many of the naysayers now strongly advocate the use of selective immunotherapy in such cases. Simply stated, enlightened self-interest has now made it popular and convenient for critics to become advocates. Be that as it may, to ignore the fact that immunologic implantation dysfunction is an important cause of “unexplained IVF failure” is, in my opinion, to deny many women the opportunity to go from “infertility to family”. (See my post on Immunologic Implantation Dysfunction).
A few additional considerations:
As far as the embryo is concerned, a careful evaluation of its appearance microscopically and its rate of development is vital.As an example, an embryo that fails to divide to the 6-9 cell stage of development within 72 hours of fertilization is usually “incompetent.”In the same manner, embryos that develop beyond the 10 cell stage within the same time period are growing too fast and are very often also incompetent.We and others have pointed out that embryos failing to reach the expanded blastocyst stage within 6 days of fertilization are, in more than 95% of cases, aneuploid and would not have resulted in a pregnancy anyway.Also, embryos whose cells (blastomeres) are very discordant in shape and size, or embryos that have numerous small cell fragments disseminated throughout their substance (fragmented embryos) are also far more likely to be “incompetent.” While the age of the woman plays an important role in determining embryo development, so does the protocol of ovarian stimulation.It is in regard to the latter where we as treating physicians can play a very important role.
I have previously pointed out how individualizing the protocol of stimulation for IVF is central to optimizing the environment in which the egg develops, and hence the quality of the embryos it propagates.This is even more critical in woman with DOR, those with polycystic ovarian syndrome (PCOS) and in older women.I cannot emphasize strongly enough how important it is to assess the protocol of stimulation in all cases where there is deemed to be poor embryo quality (see my post on an Individualized Approach for Ovarian Stimulation).
Finally, there is the issue of carefully evaluating embryos for chromosomal integrity (karyotyping).Here the relatively recent introduction of Comparative Genomic Hybridization (CGH) for egg and embryo chromosomal analysis, is a game changer.A “CGH-normal” embryo transferred into a receptive uterine environment has about a 65-70% chance of producing a viable pregnancy regardless of the age of the egg provider.Unfortunately, microscopically “good-looking” embryos – even those that make it to the blastocyst stage – are not necessarily always “competent or euploid, and this fact serves to underscore the need for CGH analysis, especially in cases where there is unexplained IVF failure.(see my post on CGH Egg/Embryo Selection)
It is important to realize that it is often difficult or even impossible for women in their mid-40’s to produce the chromosomally normal eggs necessary to propagate euploid (CGH normal) embryo.This serves to explain why older women are less likely to conceive, even when their embryos appear to look normal under the microscope, and why the selective transfer of CGH-normal embryos should be the goal.(Please refer to the articles on the merits of embryo banking).
My IVF Cycle Failed – What Went Wrong? Question #16: Why did my hCG levels stop rising properly?
http://haveababy.com/fertility-information/ivf-authority/why-did-my-beta-hcg-numbers-stop-rising/comment-page-43#comments
This is the 16th in a series of answers to common questions about failed IVF.
Immediately following implantation, the root system (trophoblast) of the embryo begins to release the pregnancyhormone, human chorionic gonadotropin (hCG) into the surrounding uterine lining (decidua) from where it enters herblood circulation and spills over into the urine. It is only after several days of implantation that the hCG blood level reaches a measurable concentration and only several days later that it becomes detectable in the urine.
Each implanting day-3 (cleaved embryo) should, within 7-9 days of being transferred to the uterus, contribute about 5mIU/ml to the blood hCG concentration and within 5-7 days following the transfer of an implanting day 5-6 blastocyst. Thereupon the blood hCG concentration should double approximately every 48 hours during early normal pregnancy, peaking at about 60,000 mIU/ml at about 10 weeks (but there is a substantial variation with the extremes of normal levels ranging between 10,000 to 250,000 mIU/ml). From the 10th to 20 weeks of gestation, hCG levels decline, reaching an average concentration of about 15,000 mIU/ml. Again, there are considerable variations with hCG concentrations ranging from 3,000 to 115,000 mIU/ml where the blood concentrations remain from 20 to 40 weeks (term).
Pregnancy (weeks)
Days post-ET
Approx. hCG concentration
single conceptus (mIU/ml)
3
5-9
0 to 5
4
14
5 to 450
5
21
180 to 7500
6
28
1,100 to 56,500
7 – 8
35 to 42
7,600 to 230,000
9 – 12
49 to 70
25,300 to 300,000
13 – 16
77 to 100
14,000 to 250,000
17 – 24
4,000 to 170,000
25 -40
3,000 to 115,000
4 – 6 wks after birth
< 5
It is true that some normal pregnancies progress normally in spite of low blood hCG levels The best way to confirm if an early pregnancy is progressing is to repeat with a blood test in 2 days time, and perhaps again 2 days later to determine whether the hCG level is rising adequately. In cases where during the 1st 1-2 weeks of pregnancy the blood hCG concentration fails to double every 2-3 days on a consecutive basis, it often (although not invariably) spells trouble for the pregnancy. It could mean:
a)A failing intrauterine pregnancy that will ultimately miscarry.
b)A tubal / ectopic pregnancy
c)Multiple pregnancy where one or more (but not all) of the concepti are failing (being absorbed).
Ultimately, discrimination between a normally progressing early intrauterine pregnancy and one that is failing or is ectopic gestation requires careful correlation between the trend in blood hCG levels and findings at one or serial ultrasound examinations.
Sve je na engleskom, ali, na zalost nemam ni vremena ni snage da prevodim sve. Ko ne razume tu je google translate, moze da posluzi.
Iskopiracu i njegov savet kako da pretrazite blog.
Please go to the Home page of this blog, http://www.IVFauthority.com. When you get there, look for the “search bar” in the upper right hand corner. Type the following subjects into the bar, click on it and it will take you to all the relevant articles posted there.
1. “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)
2. “Ovarian Stimulation in IVF: Why is it important to down-regulate LH?”
3. “Agonist/Antagonist Conversion Protocol”
4. “A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
5. “IVF success: Factors that influence outcome”
6. “Staggered IVF”
7.“Embryo Banking”
8.”Unexplained IVF Failure”.
9.”Immunologic Implantation Dysfunction (IID)”
Consider calling 800-780-7437 or 702-699-7437 to arrange a Skype consultation with me so we can discuss your case in detail
Geoff Sher
Immunologic Implantation Dysfunction (IID): A common Cause of Repeated, “Unexplained” IVF Failure
http://haveababy.com/fertility-information/ivf-authority/unexplained-infertility-and-ivf-failure
The financial and emotional cost associated with unexplained infertility or repeated IVF failures can be devastating. So, to advise couples who have failed one or more attempts that all it would take to ultimately succeed would be to keep on trying over and over again, is both overly simplistic and disingenuous.
About seven to eight days after fertilization, the embryo’s root system begins communicating with the immune cells (lymphocytes) in the uterine lining (endometrium) through an interchange of growth factors known as cytokines. It is upon the integrity of this communicative process (known as the “cytokine network”) that regulated intrusion of the embryo’s root system (that will eventually develop into the placenta) is predicated.
Thus a dysfunctional immunologic interaction between the developing conceptus and the mother can cause all kinds of reproductive problems ranging from failed implantation (presenting as “unexplained” infertility or repeated IVF failure) and miscarriage, to intrauterine growth retardation, stillbirth, fetal loss, and reduced post-birth neurologic and physical development.
It follows that proper implantation is not only a prerequisite for embryonic survival, it is also a major factor in determining intrauterine growth and development of the baby and perhaps most importantly it ultimately can influence the very quality of life after birth.
There are basically two categories of Immunologic Implantation Dysfunction (ID):
Autoimmune ID:
This is by far the most common variety. It is believed to be implicated in >90% of cases of immunologic implantation dysfunction and occurs when an immunologic reaction is produced by the individual, to his/her body’s own cellular components. The most common antibodies that form in such situations are:
a) Anti-phospholipid antibodies (APA)
b) Antithyroid antibodies (ATA)
c) Antiovarian antibodies.
But, it is only when specialized immune cells in the uterine lining known as Natural Killer (NK) Cells, become activated (NKa) and start to release “toxins” that attack the root system of the embryo, that implantation potential is jeopardized. Diagnosis of such NK cell activation (Nka) requires highly specialized blood and/or endometrial tests that can only be performed in a handful of reproductive immunology laboratories in the United States.
Since Autoimmune ID is often genetically transmitted, it is not surprising that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as Lupus Erythematosus (LE), Scleroderma, clinical or subclinical hypothyroidism, Rheumatoid Arthritis etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis.
Autoimmune ID is usually lethal to the implanting embryo. This is because it destroys the embryo’s root system from the get-go. Accordingly, it most commonly presents as “unexplained infertility” or “unexplained (often repeated) IVF failure” rather than as a miscarriage. Autoimmune ID is readily amenable to reversal through timely, appropriately administered, selective immunotherapy (see below).
Alloimmune ID:
This is relatively uncommon, accounting for less than 10% of cases of ID. Alloimmune ID is associated with a reaction to cell components (e.g sperm antigens) derived from another member of the same species (e.g., sperm). Thus, it is the sperm contribution to the embryo (i.e. the paternal antigen) that makes the embryo an allograft. It is quite remarkable therefore, that an embryo which in the vast majority of cases is immunogically “different” to the mother, thrives in her uterus. This paradoxical arrangement came about through magnificent evolutionary adaptations that allowed this to take place. Uterine immune cells (especially NK cells and T-cells) play a pivotal roll in this accommodation. They do so through a balanced release of growth factors (cytokines).
So it is that in less than 10% of IVF cases that are associated with ID the embryo (through the contribution made by the sperm) shares too many genetically similar characteristics with the host (the mother). When this happens, repeated exposures to such an embryo will over time evoke an imbalance in the cytokines released by the uterine immune cells. This is characterized by activation of uterine NK cells (Nka). In such cases the “root system” of the embryo” can be compromised and the the embryo may be destroyed immediately but most often will instead “limp” along only to miscarry when its supply of nutrients and oxygen is outstripped by demand.
Thus alloimmune ID usually does not destroy the embryo immediately. Rather, after sustained erosion of its reserve, the conceptus will miscarry.
We diagnose alloimmune ID by testing the male and female partners for shared of genetic markers known as of as DQa and HLA. A sufficient degree of matching clinches the diagnosis. We also test the embryo recipient for Nka in an attempt to measure the relative severity of the problem. This is because once the NK cells in the uterine lining are activated and the cytokine balance is disrupted, the situation is grave and will remain so (or worsen) unless the NKa cells are medically deactivated (down-regulated) at least 1 week in advance of the embryo(s) reaching the uterus.
It usually takes repeated exposures of uterine NK cells to an alloimmune matching embryo for these cells to become activated (NKa). Until this happens a pregnancy can be established and even proceed to a normal birth inspite of the ID. Subsequently over time, with repeated exposures of matching embryos to the mother’s uterus, NK cells will become activated and the couple will find themselves miscarrying. Eventually the NKa will become permanently established and the couple will fail to conceive. It is thus not unusual to find such couples going from having a baby together through a stage of repeated miscarriages to one of secondary infertility.
Unfortunately, immunotherapy for alloimmune ID is not as likely to be as successful as with the treatment of autoimmune ID. Selective immunotherapy is simply not invariably curative in the case of the former. While selective immunotherapy significantly improves the chances of success, in cases of alloimmune ID, it cannot assure a successful outcome.
Heparin and Aspirin Therapy
There is compelling evidence that the subcutaneous administration of regular heparin twice daily or low molecular heparin (Clexane, Lovenox) once daily, (starting with the onset of ovarian stimulation) significantly improves IVF birth rates in women who test positive for APAs.
Aspirin on the other hand, has little if any value and in my opinion. The reason for this is because it increases the potential to bleed. This effect can last for up to a week and could add bleeding risk to the egg retrieval procedure and resulting in intrauterine bleeding at the time of embryo transfer, potentially compromising IVF success.
IVIG and Intralipid Therapy
The main objective of selective immunotherapy for immunologic ID is to down-regulate (reduce toxicity) of Nka. In the past, the only effective and allowable way to accomplish in the U.S was through the intravenous infusion of a blood product known as immunoglobulin-G (IVIG). However, the administration of a blood product raised understandable concerns about the transmission of viral infections such as HIV and hepatitis.
To make matters worse, competing IVF clinics capitalized on all this bad press by raising red flags and sometimes going as far as to caution infertile couples against seeking IVF services from those who dared to offer access to IVIG. This created “a herd mentality” that severely harmed the practices of those of us who recommended selective IVIG therapy.
Notwithstanding this, we were not willing to be dissuaded by prejudice or malice from doing what we knew was the right thing and the reward for taking this stance which came in the form of thousands of babies (that otherwise would never have been born) now brightens the lives of an equivalent number of couples that otherwise would have remained childless.
In 2006, reports began to surface regarding a product called Intralipid (IL), a synthetic product which, upon being administered intravenously prior to embryo transfer, would elicit a similar regulatory effect on Nka as IVIG had achieved. In 2007 we began administering IL to patients with NKa. At first this treatment was confined to those who needed IVIG but for diverse reasons refused the treatment. Later we expanded the trial to other IVF patients with NKa. Todate we have treated more than 200 women with IL with impressive results (soon to be published). Against this background, SIRM physicians have all but abandoned IVIG, supplanting it with IL.
Compared to IVIG which costs about $4000-$5000 per infusion and can evoke unpleasant and potentially dangerous side effects, IL, when used as recommended by SIRM, is virtually devoid of risk and/or side effects and costs less than $400 per infusion (i.e. 1/10th of the cost of IVIG).
Corticosteroid Therapy (Prednisone, Prednisilone and Dexamethasone)
Steroid therapy is a mainstay in most IVF programs. Some programs prescribe daily oral methyl prednisilone while others prescribe prednisone or dexamethasone, commencing with the initiation of ovarian stimulation with gonadotropins, and continuing until after the ultrasound the diagnosis of pregnancy.
Any seed, if it is to thrive and develop into a healthy plant, requires that it be placed in a fertile soil. So also does a successful pregnancy require that an optimal seed (embryo)/soil (endometrium) relationship be established.
In about 70% of cases, reproductive failure is due to poor embryo “competency” issues, while in 30% of cases, a non-receptive endometrium is the reason for failure. It follows that with IVF, focusing entirely on embryo (seed) quality will not reduce the risk of failure in patients with endometrial receptivity (soil) problems.
The evaluation for immunologic dysfunction as well as for other factors that can affect implantation should form part of the evaluation of patients preparing to undergo IVF, and especially so in women with recurrent pregnancy loss (RPL), women with a personal or family history of autoimmune conditions, and women with “unexplained” infertility or IVF failure(s).
IVF Failure: The Value of a 2nd Opinion
http://haveababy.com/fertility-information/ivf-authority/ivf-failure-value-of-2nd-opinion
Preface: It frustrates me no end that so many couples who have failed to conceive following IVF are often glibly confronted with platitudes such as “It was just bad luck … so just try again,” and in the process are left “spinning their wheels,” feeling abandoned. While “bad luck” could indeed sometimes be a factor, this is not often the case, especially when, in spite of the transfer to the uterus of microscopically “good quality” embryos, the woman fails (often repeatedly) to conceive. The problem is further magnified when it comes to older women for whom time is running out because of an inevitable age-related decline in egg quality (“competency”), and in cases of diminished ovarian reserve (DOR) where the woman’s supply of eggs is rapidly becoming depleted. Most patients who have failed to conceive with IVF intuitively believe that something might have been overlooked in their cases and that, were the issue(s) to be identified, they could be remedied.
Frankly, given all of the good fortune and opportunity afforded me over a 30 year career in the field of IVF , I feel a strong compulsion to put my extensive experience to work where it can do most good and to offer it unconditionally to infertile patients. This is particularly relevant since several major medical advances that I and my colleagues introduced over the years could be applied to the diagnosis and treatment of many such problems, and make a real difference. These include:
a) In-roads made with regard to defining individualized protocols for ovarian stimulation
b) The Introduction of clinical Comparative Genomic Hybridization (CGH) embryo selection
c) The role of Immunologic Implantation Dysfunction (IID) in failed IVF
It is against this background that I have elected (for the foreseeable future) to offer detailed IVF telephone consultations, free of charge to all US and Canadian patients who are interested in my opinion, regardless of where they subsequently choose to be treated. Accordingly, I have designated specific times (daily) in my schedule for this purpose. Please call 800-780-7437 to schedule or submit the request form HERE.
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IVF treatmentalways exacts a profound emotional and financial toll on patients/couples. Needless to say, the financial burden is often crippling However, ask any woman who has undergone IVF and she will likely tell you that the emotional impact was by far the most devastating….especially when the IVF treatment cycle failed to bring her a baby.
The truth is that even in the simplest of cases (i.e. younger women who have normal ovarian reserve with fertile male partners), and in the most capable of hands, at best 50% will give birth to a baby following the transfer of 1-2 morphologically “normal” embryos. More than 70% will achieve success after two fresh embryo transfers. When this fails to happen, the question will invariably arise as to why the failure occurred.
Currently, in excess of 90% of the IVF patients I treat have at least one prior failed attempt before consulting with me, and more than 80% have failed IVF at least 3 times prior to seeking my services. I could cite many cases where patients have even endured as many as 10 or more prior IVF failures. But there is one case in particular that is permanently embedded in my memory and which highlights the importance of an individualized approach to treating infertility patients, especially when it comes to those with prior IVF failures.
The patient was a 42 year old physician who hailed from Australia. She had endured 23 prior unsuccessful embryo transfers over a period of more than a decade. By the time I got to know her she had developed severely diminished ovarian reserve (her day 3 FSH was 26MIU/ml). After a lengthy telephone consultation with me, I urged her to send a blood sample from Melbourne, Australia to a reputable Reproductive Immunology Reference Laboratory in Southern California for testing, to screen for immunologic implantation dysfunction (IID). It soon became apparent that she had an autoimmune thyroid condition (antithyroid antibodies) plus activation of uterine Natural Killer Cells (NKa+). After putting her on an aggressive agonist/antagonist conversion protocol (A/ACP) with estrogen priming and treating her with selective immunotherapy, I harvested (just) three eggs and subsequently transferred two embryos to her uterus. She conceived on this cycle and gave birth to a very healthy baby boy nine months later.
So then…what are the most common reasons for “unexplained” IVF failure, and what can be done to deal with them?
To adequately address these two all-important questions, we first need to recognize and understand that with the exception of poor technical skill in performing embryo transfer, IVF failure is virtually always due to one of the following two causes, which I will address below:
A. Embryo “Incompetence” (+/- 75% of cases)
B. Dysfunctional/Failed Embryo Implantation (+/- 25% of cases)
A. Embryo Incompetence
What is critical to understand here is that it is the chromosomal integrity (“competence”) of the embryo that is the main determinant of its ability to propagate a normal pregnancy. It is almost always the egg (rather than the sperm) that determines this factor. Only a mature egg (MII) that is numerically chromosomally normal (with 23 chromosomes – also known as a “euploid” egg) at the time of egg retrieval can propagate a “competent” embryo. No manipulation in the IVF laboratory, be it assisted hatching, embryo co-culturing, specialized fancy culture media, or even cytoplasmic transfer from a different (euploid) egg can cause an egg that has an irregular quota of chromosomes (aneuploid) to propagate a competent/euploid embryo (i.e. 46 chromosomes). Patients should be highly skeptical of any suggestion to the contrary. Simply stated, an embryology laboratory can only grow competent embryos from competent eggs.
Thus, egg competency at the time of egg retrieval will ultimately determine the ability to generate competent embryos for embryo transfer. By the time the egg is extracted, the “die has been cast” What this means is that aside from the woman’s age – which influences the percentage of her eggs that will have the potential to develop into euploid mature (MII) eggs following hormonal stimulation – the only manner by which we as IVF physicians can influence egg quality is by applying an individualized approach to ovarian stimulation. Without such an approach, egg development will often be compromised (especially in older women, in those with PCOS, and in women with DOR). Then, the hCG “trigger” would be much more likely to cause disorderly rearrangement of egg chromosomes, leading to a greater likelihood of egg incompetence (aneuploidy) and ultimately to incompetent embryos.
Today, through the use of full embryo chromosomal assessment (i.e. full karyotyping) using CGH, we can identify “competent” embryos for selective transfer. The use of this technique is both diagnostic (in that it allows us to determine whether the cause of IVF failure is embryo incompetence or an implantation issue) and therapeutic (in that we can thereupon selectively transfer only one or two embryos at a time and achieve almost a 70% pregnancy rate while virtually eliminating the chance of high-order multiples (triplets or greater). CGH embryo selection is of special relevance and value in cases of older women or those with DOR for whom “Staggered IVF” with embryo banking is of particular value.
Dysfunctional or Failed Implantation
Endometrial thickness (as measured by ultrasound) is described elsewhere. We previously have published that an ideal endometrium measures at least 9mm in thickness at the time of maximal estrogen stimulation. We have also pointed to the importance of excluding the existence of surface lesions that protrude into the uterine cavity (polyps, fibroid tumors or scarring) as they can, by creating an adverse uterine environment, lead to failed implantation. Only a hysteroscopy or a hysterosonogram (saline ultrasound) can diagnose the latter which needs to be treated surgically before embarking on IVF. A hysterosalpingogram (HSG) is too inaccurate to accomplish this.
Then there is the ever-important and (through either arrogance or ignorance) commonly overlooked issue of immunologic implantation dysfunction (IID) that should always be evaluated and addressed in cases of unexplained or repeated IVF failure. Frankly, since in the absence of Nka+, immunologic problems (regardless of cause) are not likely to cause IID, and given the fact that most of my IVF patients come to see me because of repeated failures in the past, I test almost everyone initially for Nka. If the test result comes back positive, we expand immunologic testing to look for the underlying cause. This having been said, I cannot overemphasize how important it is to always have a high index of suspicion regarding the possibility that failure could be due to IID in any patient who has had an unexplained IVF failure in the past.
My IVF Cycle Failed – What Went Wrong? Question #2 – Was I Adequately Evaluated and Prepared for IVF by My Physician?
http://haveababy.com/fertility-information/ivf-authority/my-ivf-cycle-failed-what-went-wrong_12
his is the second in a series of responses to common questions about Failed IVF Treatment. Question #2 – Was I Adequately Evaluated and Prepared for IVF by My Physician?
Patients often ask “When is it time for me to stop doing IVF?”The answer I consistently give is that it is time to stop “when there is no remediable explanation for failure.”It is against this background that I submit that pre-cycle evaluation of a couple undergoing In Vitro Fertilization (IVF) is probably the most important step in the entire process, and becomes even more critical when it comes to evaluating a couple who has failed to conceive after undergoing 1 or more IVF attempts in the past.
The Seed-Soil Analogy
I have in the past stated that successful human reproduction is akin to the need when gardening, to establish an ideal “seed/soil relationship.” However, when it comes to reproduction, the “seed” is the embryo and the “soil” is the uterine lining.As with horticulture, a successful outcome requires planting a “good seed” in a “good soil.” In the case of IVF, a good seed is analogous to what we refer to as a “competent” embryo. This is an embryo that has the proper number of chromosomes (euploid) and has an optimal chance of developing into a healthy baby.A “good soil” is analogous to a receptive endometrial lining (one that will allow normal and healthy implantation to be established). So, proper (re)evaluation of a woman undergoing IVF requires a critical (re)assessment of those variables that affect embryo competency and endometrial receptivity.
A. Evaluating the Factors That Affect Embryo Competency (The “Seed”)
1. Age
The woman’s age during IVF is the most important factor affecting the chromosomal integrity of her eggs.This in turn, is central to the ability of the egg to develop into a “competent” euploid embryos post-fertilization.The “competence” of an embryo is determined largely by the chromosomal integrity of its egg of origin. Only a euploid eggcan propagate a “competent” embryo and it is the age of the woman that determines the likelihood of any egg being euploid.The percentage of a woman’s eggs that are euploid decreases progressively with advancing age beyond 35.At age 30, slightly less than 1 in 2 of eggs will be euploid; at age 40 about 1 in 6-8, and by her mid 40’s, less than 1 in 10 eggs will be chromosomally normal eggs.Cells that have an abnormal quota of chromosomes are referred to as aneuploid. A “normal” (euploid) mature egg has 23 chromosomes. Anything more or less than that number makes the egg aneuploid and such eggs will invariably propagate “incompetent” aneuploid embryos which will either fail to implant, briefly implant and then be lost as a miscarriage, or (albeit infrequently) propagate a baby with a chromosomal birth defect such as Down’s Syndrome. It follows that the woman’s age must be taken into consideration when discussing the likelihood of a successful IVF outcome.
The older the woman undergoing IVF, the more difficult it becomes to maintain an ideal ovarian hormonal environment that would favor proper egg development and thus, the greater will be the imperative to modify the protocol of ovarian stimulation in order to avoid egg maldevelopment (that is more likely to occur in an abnormal environment) and an increasing likelihood that following the hCG “trigger” (that initiates chromosomal segregation) the “mature” egg will turn out to be aneuploid (see my post on an Individualized Approach for Ovarian Stimulation).
2. Ovarian Reserve
Approximately 6-8 years before the onset of menopause, the number of eggs available declines more rapidly, to the point that a woman progressively develops resistance to fertility drugs.This period of diminishing ovarian reserve (DOR) is known as the climacteric and is characterized by progressively rising basal blood FSH levels as well as by declining AMH and Inhibin B levels.The climacteric usually begins in the late 30’s to the mid 40’s but it can and often does occur sooner.
With DOR goes a change in ovarian response to hormonal stimulation and thus it becomes even more important to individualize the protocol of ovarian stimulation in such cases.
3. Sperm Quality
Male sperm dysfunction accounts for about 50% of infertility.In most cases, it is very difficult to reverse through medical or surgical intervention. When it comes to embryo competence, the egg plays a far greater determining role than does the sperm.However, in cases of male infertility, the contributing role played by the sperm in causing embryo aneuploidy increases significantly. There are circumstances where surgical or medical treatment can improve sperm quality significantly:
Some men who have blocked sperm ducts or a fluid collection around one or both testicles (hydrocele) might benefit from surgical correction, while those with a collection of varicose veins around their testicles (varicocele) might benefit from surgical or radiological occlusion of the spermatic vein(s).
While the egg plays a far greater determining role in embryo competence than does the sperm, in cases of significant male infertility, the role of the sperm increases significantly in this regard.
4. Genetic/Chromosomal Factors
Certain chromosomal and genetic abnormalities involving the man or the woman can thwart successful IVF.In approximately 1 out of 200 cases a balanced translocation (where part of one chromosome is exchanged with that of another) will cause unexplained IVF failure or miscarriage.This is worth looking for in some cases.There are also cases where there is a deletion of part of the chromosomes in the sperm or in the egg that can cause the same problem.Detection of such rare genetic events requires In certain cases where there is a low sperm count and motility, the cause may be related to understimulation of sperm production.In such cases the man might have a low blood FSH level.In such cases, treatment with medications such as low dose clomiphene or letrozole for a period of about 3 months (the sperm cycle) will sometimes result in a marked improvement in sperm function.In other cases, administration of FSH and/or LH medications over a period of 3 months can also be helpful (see my post on Enhancing Sperm Production).
B. Evaluating Factors that Affect Uterine (Endometrial) Receptivity (“The Soil”)
1. Thickness of the Uterine Lining
Measured at the time of the hCG trigger, the thickness of the uterine lining is also a very important factor.A lining of less than 9mm in thickness is suboptimal, while a lining under 8mm is usually totally inadequate.It is very important to recognize this fact because, just as the roots of a plant cannot develop adequately if it is planted in a thin layer of soil, so the embryo’s root system (trophoblast) cannot take proper hold or function adequately if the lining is too thin.Today, through the administration of medications such as Viagra for the uterine lining, estrogen and anti-prostaglandins (e.g., aspirin), it is possible in many such cases to improve the lining.However, when as a result of uterine inflammation or surgical trauma to the a thin inner (basal) germinal layer of the endometrium, such treatment will often be ineffectual, necessitating the use of a gestational carrier (surrogate).
2. Endo-Uterine Pathology
The presence of small surface lesions that protrude into the uterine cavity can interfere with embryo implantation. These can be (and often are) missed, unless proper inspection by a hysterosonogram, hysteroscopy or an MRI is done.The use of a dye X-ray test (hysterosalpingogram) is inadequate to identify small endometrial polyps, or small fibroids (see this article on Uterine Fibroids).
3. Immunologic Implantation Dysfunction (IID)
This is often a cause of “unexplained” IVF failure (in about 30% of cases) and must be looked for.Here, autoimmune rather than alloimmune factors (the latter more commonly results in early miscarriage), are usually the cause.Effective treatment of immunologic infertility is available.I have personal experience with many cases where using selective immunotherapy, I have successfully treated women who previously had failed to achieve viable IVF pregnancies after more than 10 consecutive attempts (and in one case more than 20 prior IVF failures had occurred). It is important to bear in mind that resorting to the use of donor eggs does not offer a solution in cases of immunologic implantation dysfunction.
To their own discredit, many fertility doctors have hitherto denied or even discounted the role played by immunologic factors in implantation failure and have even discredited the use of selective immunotherapy in such cases. In my opinion, in this attitude stemmed from a desire to maintain a competitive edge, since until recently, successful treatment of immunologic implantation dysfunction often required the administration of a blood product known as immunoglobulin-G (IVIg). The administration of this product was very expensive (up to $4,000 per infusion, and more than one administration was often required), and it sometimes caused unpleasant side-effects. In addition patients often expressed fear that because IVIg is a blood product, its administration might lead to the transmission of HIV and hepatitis viruses. The fact is however, that this concern was was unfounded because FDA-approved IVIg products are all screened for viral contamination and thus are safe in this regard. Against this background doctors were fearful that prescribing IVIg treatment (while others denounced it) would put them at a competitive disadvantage.
All this changed with the recent introduction of a product called Intralipid (IL), which has largely replaced IVIg for the treatment of immunologic implantation dysfunction. The reasons for the change of heart are that unlike IVIg, IL is very inexpensive (less than $200 per infusion), is safe, and is free of significant risk or side effects and most importantly, IL is equally effective for the treatment of immunologic implantation dysfunction . Perhaps not surprisingly, the low cost and minimal risk associated with IL therapy, bolstered by an ever increasing demand on the part of IVF patients that they be assessed and selectively treated for immunologic issues, has led to a dramatic increase in the number of RE’s that now test for immunologic implantation dysfunction. In fact, many of the naysayers now strongly advocate the use of selective immunotherapy in such cases. Simply stated, enlightened self-interest has now made it popular and convenient for critics to become advocates. Be that as it may, to ignore the fact that immunologic implantation dysfunction is an important cause of “unexplained IVF failure” is, in my opinion, to deny many women the opportunity to go from “infertility to family”. (See my post on Immunologic Implantation Dysfunction).
A few additional considerations:
As far as the embryo is concerned, a careful evaluation of its appearance microscopically and its rate of development is vital.As an example, an embryo that fails to divide to the 6-9 cell stage of development within 72 hours of fertilization is usually “incompetent.”In the same manner, embryos that develop beyond the 10 cell stage within the same time period are growing too fast and are very often also incompetent.We and others have pointed out that embryos failing to reach the expanded blastocyst stage within 6 days of fertilization are, in more than 95% of cases, aneuploid and would not have resulted in a pregnancy anyway.Also, embryos whose cells (blastomeres) are very discordant in shape and size, or embryos that have numerous small cell fragments disseminated throughout their substance (fragmented embryos) are also far more likely to be “incompetent.” While the age of the woman plays an important role in determining embryo development, so does the protocol of ovarian stimulation.It is in regard to the latter where we as treating physicians can play a very important role.
I have previously pointed out how individualizing the protocol of stimulation for IVF is central to optimizing the environment in which the egg develops, and hence the quality of the embryos it propagates.This is even more critical in woman with DOR, those with polycystic ovarian syndrome (PCOS) and in older women.I cannot emphasize strongly enough how important it is to assess the protocol of stimulation in all cases where there is deemed to be poor embryo quality (see my post on an Individualized Approach for Ovarian Stimulation).
Finally, there is the issue of carefully evaluating embryos for chromosomal integrity (karyotyping).Here the relatively recent introduction of Comparative Genomic Hybridization (CGH) for egg and embryo chromosomal analysis, is a game changer.A “CGH-normal” embryo transferred into a receptive uterine environment has about a 65-70% chance of producing a viable pregnancy regardless of the age of the egg provider.Unfortunately, microscopically “good-looking” embryos – even those that make it to the blastocyst stage – are not necessarily always “competent or euploid, and this fact serves to underscore the need for CGH analysis, especially in cases where there is unexplained IVF failure.(see my post on CGH Egg/Embryo Selection)
It is important to realize that it is often difficult or even impossible for women in their mid-40’s to produce the chromosomally normal eggs necessary to propagate euploid (CGH normal) embryo.This serves to explain why older women are less likely to conceive, even when their embryos appear to look normal under the microscope, and why the selective transfer of CGH-normal embryos should be the goal.(Please refer to the articles on the merits of embryo banking).
My IVF Cycle Failed – What Went Wrong? Question #16: Why did my hCG levels stop rising properly?
http://haveababy.com/fertility-information/ivf-authority/why-did-my-beta-hcg-numbers-stop-rising/comment-page-43#comments
This is the 16th in a series of answers to common questions about failed IVF.
Immediately following implantation, the root system (trophoblast) of the embryo begins to release the pregnancyhormone, human chorionic gonadotropin (hCG) into the surrounding uterine lining (decidua) from where it enters herblood circulation and spills over into the urine. It is only after several days of implantation that the hCG blood level reaches a measurable concentration and only several days later that it becomes detectable in the urine.
Each implanting day-3 (cleaved embryo) should, within 7-9 days of being transferred to the uterus, contribute about 5mIU/ml to the blood hCG concentration and within 5-7 days following the transfer of an implanting day 5-6 blastocyst. Thereupon the blood hCG concentration should double approximately every 48 hours during early normal pregnancy, peaking at about 60,000 mIU/ml at about 10 weeks (but there is a substantial variation with the extremes of normal levels ranging between 10,000 to 250,000 mIU/ml). From the 10th to 20 weeks of gestation, hCG levels decline, reaching an average concentration of about 15,000 mIU/ml. Again, there are considerable variations with hCG concentrations ranging from 3,000 to 115,000 mIU/ml where the blood concentrations remain from 20 to 40 weeks (term).
Pregnancy (weeks)
Days post-ET
Approx. hCG concentration
single conceptus (mIU/ml)
3
5-9
0 to 5
4
14
5 to 450
5
21
180 to 7500
6
28
1,100 to 56,500
7 – 8
35 to 42
7,600 to 230,000
9 – 12
49 to 70
25,300 to 300,000
13 – 16
77 to 100
14,000 to 250,000
17 – 24
4,000 to 170,000
25 -40
3,000 to 115,000
4 – 6 wks after birth
< 5
It is true that some normal pregnancies progress normally in spite of low blood hCG levels The best way to confirm if an early pregnancy is progressing is to repeat with a blood test in 2 days time, and perhaps again 2 days later to determine whether the hCG level is rising adequately. In cases where during the 1st 1-2 weeks of pregnancy the blood hCG concentration fails to double every 2-3 days on a consecutive basis, it often (although not invariably) spells trouble for the pregnancy. It could mean:
a)A failing intrauterine pregnancy that will ultimately miscarry.
b)A tubal / ectopic pregnancy
c)Multiple pregnancy where one or more (but not all) of the concepti are failing (being absorbed).
Ultimately, discrimination between a normally progressing early intrauterine pregnancy and one that is failing or is ectopic gestation requires careful correlation between the trend in blood hCG levels and findings at one or serial ultrasound examinations.
KoMetaK- Broj poruka : 7138
Godina : 51
Location : Italija
Datum upisa : 09.01.2010
Re: Neuspeh VTO - razlozi
Ja sam puno citala o neuspesima VTO koje "objasnjava" zvanicna medicina. Danima i nocima...
Pre prve VTO sam odradila sve analize koje se u Srbiji mogu odraditi: imunologiju, trombofilije, OGTT, vitamine, laparoskopiju, histeroskopiju, bakteriolosku analizu endometrijuma itd...
1. put nije uspelo, 2. put se zavrsilo kiretazom. Pre 3. VTO sam otisla kod doktora koji se bavi akupunkturom i koji mi je objasnio pojam hladne materice iliti cold uterus. Krenem da citam i o tome i vidim da je to poznata stvar u kineskoj medicini. Uglavnom, ja sam pre ove uspesne vantelesne 4 meseca sedela na vrucoj soli, pridrzavala se preporucene ishrane i isla na akupunkturu. Ubedjena sam da mi je to pomoglo i da je ta hladna materica jedan od glavnih uzroka neplodnosti i neuspesnih vto postupaka. Upoznala sam iduci na na akupunkturu trudnice koje su uspele nakon godina i godina pokusavanja...
Nedavno je uspela i poznanica koja je resila da pokusa i to pre upustanja u vto pricu. Uspela je i jedna nasa kutanjka koja vise nije aktivna, ali u kontaktu smo. Prosla je isti rezim kao i ja. Niny je takodje sedela na vrucoj soli, iako nije isla na tretmane i koliko znam nije menjala ishranu. Ali ta vruca so i utopljavanje su zakon za nas zene!
Ja svima preporucujem da probaju. To nije poziv za koriscenje nekog leka, nije izlaganje organizma nekim stetnim materijama, niti kupovina skupih proizvoda...To je sedenje na vrucoj soli, uz promene nacina ishrane i nekih zivotnih navika. Nista stetno, nista agresivno - sasvim prirodno i vredi pokusati. Kada smo spremne da se kljukamo hormonima i prolazimo sve ove agresivne vto procese da bismo dosle do bebe, ne bismo trebale da odbijamo jednu ovakvu mogucnost, pokusaj da sebi pomognemo i povecamo sanse. Nije ni to garancija uspeha, ali veliki broj zena koji je uspeo nakon ovog rezima, govori u prilog tome da je prica istinita i da taj pojam "cold uterus" nije za odbaciti.
Pre prve VTO sam odradila sve analize koje se u Srbiji mogu odraditi: imunologiju, trombofilije, OGTT, vitamine, laparoskopiju, histeroskopiju, bakteriolosku analizu endometrijuma itd...
1. put nije uspelo, 2. put se zavrsilo kiretazom. Pre 3. VTO sam otisla kod doktora koji se bavi akupunkturom i koji mi je objasnio pojam hladne materice iliti cold uterus. Krenem da citam i o tome i vidim da je to poznata stvar u kineskoj medicini. Uglavnom, ja sam pre ove uspesne vantelesne 4 meseca sedela na vrucoj soli, pridrzavala se preporucene ishrane i isla na akupunkturu. Ubedjena sam da mi je to pomoglo i da je ta hladna materica jedan od glavnih uzroka neplodnosti i neuspesnih vto postupaka. Upoznala sam iduci na na akupunkturu trudnice koje su uspele nakon godina i godina pokusavanja...
Nedavno je uspela i poznanica koja je resila da pokusa i to pre upustanja u vto pricu. Uspela je i jedna nasa kutanjka koja vise nije aktivna, ali u kontaktu smo. Prosla je isti rezim kao i ja. Niny je takodje sedela na vrucoj soli, iako nije isla na tretmane i koliko znam nije menjala ishranu. Ali ta vruca so i utopljavanje su zakon za nas zene!
Ja svima preporucujem da probaju. To nije poziv za koriscenje nekog leka, nije izlaganje organizma nekim stetnim materijama, niti kupovina skupih proizvoda...To je sedenje na vrucoj soli, uz promene nacina ishrane i nekih zivotnih navika. Nista stetno, nista agresivno - sasvim prirodno i vredi pokusati. Kada smo spremne da se kljukamo hormonima i prolazimo sve ove agresivne vto procese da bismo dosle do bebe, ne bismo trebale da odbijamo jednu ovakvu mogucnost, pokusaj da sebi pomognemo i povecamo sanse. Nije ni to garancija uspeha, ali veliki broj zena koji je uspeo nakon ovog rezima, govori u prilog tome da je prica istinita i da taj pojam "cold uterus" nije za odbaciti.
Erata- Broj poruka : 2458
Datum upisa : 21.06.2012
Re: Neuspeh VTO - razlozi
Ja sam mnogo puta pisala o tome na forumu, a i u privatnom zivotu pricam o tome, jer imam i u svom okruzenju ljude koji imaju problem. I primetila sam da zene vecinom odbijaju ovu pricu kao glupost i da je malo koja spremna da pokusa. Dok govorim, vec u ocima vidim da nece ni probati. I pitam se zasto. Zasto nije problem piti klomifene, glukofaze, antibiotike, sinteticke vitamine, primati menopure, gonale, cetrotide, difereline, suprefakte...anestezije...a problem je pokusati sa jednom tako bezazlenom stvari, a koja moze da pomogne. Ne mozete znati dok ne probate. Moze pomoci, a ne moze odmoci. Samo malo truda. Ne treba odbacivati i reci to je glupost i kako to da je svima hladna materica. Pa nije svima! Nije mojoj sestri, rodici, desetinama zena oko mene koje imaju decu. Njima nije. Meni jeste. Zato sam i stigla do vto i zato i pisem ovo sto pisem. Kad se stigne dovde, onda je problem i hladna materica, problem su i hormoni, problem je i imunologija, trombofilije...Krenes da resavas jedno po jedno, ili bijes istovremeno na svim frontovima.
I jos jedna vazna stvar! Gubitak samopouzdanja, osecaj da necemo uspeti, osecaj nize vrednosti, potistenost, anaksioznost i citav paket koji zovemo PSIHA, a koji se mora resiti. Meni je i tu pomogao ovaj rezim zivota, da steknem samopouzdanje i da znam da cinim SVE i da ce ovog puta uspeti. Na youtube sam gledala klipove o trudnoci, meditacije, vizualizacije...Krenula ponovo u Crkvu, pokusavala da se molim. Zamisljala sam bebu koja se mrda u mom stomaku, zamisljala veliki stomak i sve sto sam radila po kuci, radila sam kao da sam trudnica. Pazila kako se savijam, tj. ne savijam se vec cucnem, ne protezem se, ne dizem tesko...
Ubacila sam se u "trudnicki mod" i to je trajalo mesecima. Ja sam u svojoj glavi i svojim mislima bila trudnica. Vec sam uveliko izasla iz pojma sterilitet i ubacila se u pojmove trudnoca i porodjaj. Citala o vodjenju trudnoce, kod nas i u svetu, o ultrazvuku u trudnoci i stetnosti istog. Pripremala sam se za skoru buducu borbu sa sistemom kod nas i ubacivanjem trudnice u masinu. Informisala se o svemu - porodjaju, dojenju, vakcinisanju dece - da ili ne, MMR vakcini, antibioticima, kako leciti dete i izbeci antibiotike, kako mu ojacati imunitet, kako se pripremiti za porodjaj....itd itd...
Vec uveliko sam bila "sa one strane reke", u svojoj glavi, srcu, dusi i bez straha. Kao ranjeni vojnik koji je stao na noge, naoruzao se kao nikada do tada i krenuo u borbu ljutu resen da pobedi.
Mislim da me je kombinacija zagrevanja materice i resavanja psihickih blokada i vracanja sustinske i duboke VERE u uspeh, dovela do trudnoce.
Ja bih uradila sve moguce i nemoguce analize i probala apsolutno sve sto je u mojoj moci, pisala svim klinikama (a i pre prve vto sam kontaktirala 35 klinika da cujem misljenje), probala sve od alternative. Jedino sto nisam i ne bih mogla prihvatiti je stav vecine vto lekara: Samo pokusavajte i bice jednom.
Jer razlog mora da postoji i postoji - samo ga treba otkriti. A odgovor se cesto ne nalazi u okvirima zapadne medicine.
Saborke moje srecno. Od srca vam svima zelim da uspete u onome sto zelite!
I jos jedna vazna stvar! Gubitak samopouzdanja, osecaj da necemo uspeti, osecaj nize vrednosti, potistenost, anaksioznost i citav paket koji zovemo PSIHA, a koji se mora resiti. Meni je i tu pomogao ovaj rezim zivota, da steknem samopouzdanje i da znam da cinim SVE i da ce ovog puta uspeti. Na youtube sam gledala klipove o trudnoci, meditacije, vizualizacije...Krenula ponovo u Crkvu, pokusavala da se molim. Zamisljala sam bebu koja se mrda u mom stomaku, zamisljala veliki stomak i sve sto sam radila po kuci, radila sam kao da sam trudnica. Pazila kako se savijam, tj. ne savijam se vec cucnem, ne protezem se, ne dizem tesko...
Ubacila sam se u "trudnicki mod" i to je trajalo mesecima. Ja sam u svojoj glavi i svojim mislima bila trudnica. Vec sam uveliko izasla iz pojma sterilitet i ubacila se u pojmove trudnoca i porodjaj. Citala o vodjenju trudnoce, kod nas i u svetu, o ultrazvuku u trudnoci i stetnosti istog. Pripremala sam se za skoru buducu borbu sa sistemom kod nas i ubacivanjem trudnice u masinu. Informisala se o svemu - porodjaju, dojenju, vakcinisanju dece - da ili ne, MMR vakcini, antibioticima, kako leciti dete i izbeci antibiotike, kako mu ojacati imunitet, kako se pripremiti za porodjaj....itd itd...
Vec uveliko sam bila "sa one strane reke", u svojoj glavi, srcu, dusi i bez straha. Kao ranjeni vojnik koji je stao na noge, naoruzao se kao nikada do tada i krenuo u borbu ljutu resen da pobedi.
Mislim da me je kombinacija zagrevanja materice i resavanja psihickih blokada i vracanja sustinske i duboke VERE u uspeh, dovela do trudnoce.
Ja bih uradila sve moguce i nemoguce analize i probala apsolutno sve sto je u mojoj moci, pisala svim klinikama (a i pre prve vto sam kontaktirala 35 klinika da cujem misljenje), probala sve od alternative. Jedino sto nisam i ne bih mogla prihvatiti je stav vecine vto lekara: Samo pokusavajte i bice jednom.
Jer razlog mora da postoji i postoji - samo ga treba otkriti. A odgovor se cesto ne nalazi u okvirima zapadne medicine.
Saborke moje srecno. Od srca vam svima zelim da uspete u onome sto zelite!
Erata- Broj poruka : 2458
Datum upisa : 21.06.2012
Re: Neuspeh VTO - razlozi
Erata bas sad slucajno sam nasla tvoj post ovde i citala sam i odusevljena sam. Zanima me kako si zagrevala matericu i gde si kupila tu so na koju si sedela? Treba da odradim jos neke d.analize al bi ovo svakako probala. I gde ai na internetu gledala te vezbe? Joj bas me zanima ovo.... ja imam drugarucu kojoj stitna ne radi i njen tsh je uzasno visok i ima visoka antitela i veoma je krupna al ona se svako vece molila i verovala da ce biti trudna i sada ima troje dece i ja mislim da je problem steriliteta ima malo sa psihom i stresom.
srculence 84- Broj poruka : 1175
Godina : 40
Datum upisa : 09.05.2014
Re: Neuspeh VTO - razlozi
Srculence napisi mi mail na pp, pa ti saljem.
Erata- Broj poruka : 2458
Datum upisa : 21.06.2012
Re: Neuspeh VTO - razlozi
Erata da li ti je stigla moja pp
srculence 84- Broj poruka : 1175
Godina : 40
Datum upisa : 09.05.2014
Re: Neuspeh VTO - razlozi
Jeste draga, samo moram da se dokoam racunara i odgovaram ti. Cim mi bubica zaspi :)
Erata- Broj poruka : 2458
Datum upisa : 21.06.2012
Re: Neuspeh VTO - razlozi
Hvala ti puno erata i ljubac za bubicu
srculence 84- Broj poruka : 1175
Godina : 40
Datum upisa : 09.05.2014
erata
Hej Erata, mozes li mi poslati kontakt osobe kod koje si radila akopunkturu? Jesi li iz BG
Padobranka- Broj poruka : 168
Datum upisa : 25.11.2014
erata
Hej Erata, mozes li mi poslati kontakt osobe kod koje si radila akopunkturu? Jesi li iz BG
Padobranka- Broj poruka : 168
Datum upisa : 25.11.2014
Re: Neuspeh VTO - razlozi
Erata mozes li mi molim te reci nesto vise o tom sedenju na vrucoj soli.ja zaista verujem da je kljuc usleha bas u tome.logicno-to poboljsava cirkulaciju i prokrvljenost materice a to naravno povecava mogucnost ugradnje embriona.ali na zalost o tome ne mogu NISTA naci na netu.pa sam na svoju ruku pocela da sedim na soli 30min pre spavanja.da li je to malo?mnogo??heeelp!!
Svaka informacija mi znaci...
Svaka informacija mi znaci...
branka86- Broj poruka : 328
Datum upisa : 25.07.2014
Re: Neuspeh VTO - razlozi
I mene interesuje ako bi mogla da mi objasnis kako si tačno zagrevala matericu, koje su proporcije soli, da li je neka posebna so u pitanju i na koji način se so zagreva? Cula sam i za dr. Zorana Mancica u Beogradu, ali mi njegov ceo fazon deluje malo možda isuvise invanzivne i radikalno... Da me malo uputiš, jer mi je tvoje iskustvo i razmisljanje veoma bliskoi apsolutno se slažem sa svim sto si napisala. Pitanje se odnosi na Eratu. Hvala unapred i pozdrav svim devojkama! :)
Ja sam ovde potpuno nova i ovo mi je prvi post, pa bi mi znacilo
Ja sam ovde potpuno nova i ovo mi je prvi post, pa bi mi znacilo
Principessa- Broj poruka : 1104
Godina : 51
Datum upisa : 23.10.2015
Re: Neuspeh VTO - razlozi
Draga Erata, i mene interesuje ako bi mogla da mi objasnis kako si tačno zagrevala matericu, koje su proporcije soli, da li je neka posebna so u pitanju i na koji način se so zagreva? Cula sam i za dr. Zorana Mancica u Beogradu, ali mi njegov ceo fazon deluje malo možda isuvise invanzivne i radikalno...ja sam na forumu kutak potpuno nova, ovo mi je zapravo prvi post i znacilo bi mi da me malo uputiš, jer mi je tvoje iskustvo i razmisljanje veoma blisko i apsolutno se slažem sa svim sto si napisala. Inače sam iz Beograda...
Hvala unapred i pozdrav svim devojkama! :)
Hvala unapred i pozdrav svim devojkama! :)
Principessa- Broj poruka : 1104
Godina : 51
Datum upisa : 23.10.2015
Re: Neuspeh VTO - razlozi
Principessa molim te posalji mi svoj mail ovde preko poruke i ka cu ti proslediti moj fajl. Ne mogu da kopiram ovde, jer se uglavnom ulogujem preko telefona. Za kompjuter nemam vise vremena, sto i tebi zelim :)))
Erata- Broj poruka : 2458
Datum upisa : 21.06.2012
Re: Neuspeh VTO - razlozi
Draga Erata, hvala ti puno unapred na pomoći 😊
I uzivaj u svom nemanju vremena!
I uzivaj u svom nemanju vremena!
Poslednji izmenio Principessa dana 7/11/2015, 00:24, izmenjeno ukupno 1 puta
Principessa- Broj poruka : 1104
Godina : 51
Datum upisa : 23.10.2015
Re: Neuspeh VTO - razlozi
Izvinjavam se na greskama u prethodnom postu, još ucim da se snalazim po ovom forumu...i na kasnom odgovoru takođe, ceo dan sam radila...hvatala još jednom!
Principessa- Broj poruka : 1104
Godina : 51
Datum upisa : 23.10.2015
Re: Neuspeh VTO - razlozi
Erato prekopiraj sto si pisala u mail Princezi . Nije na odmet jos jedan post o soli i hladnoj materici ...
noja- Broj poruka : 6242
Godina : 46
Location : tamo gde Dunav teče
Datum upisa : 24.02.2011
Re: Neuspeh VTO - razlozi
Erata, ne znam da li sam uspela da ti pošaljem u privatnu poruku podatke, posto mi skladisti tu poruku međju poruke za slanje, a ne među poslate poruke...javi samo da li si dobila 😩
Hvaaaala ❤
Hvaaaala ❤
Principessa- Broj poruka : 1104
Godina : 51
Datum upisa : 23.10.2015
Re: Neuspeh VTO - razlozi
Noja hocu, ali nikako da sednem za komp. Ovako sam sa telefona prosledjivala mail curama. Cim ugrabim vremena prekopiracu sve i ovde.
Erata- Broj poruka : 2458
Datum upisa : 21.06.2012
Re: Neuspeh VTO - razlozi
Draga,Erata ::Noja hocu, ali nikako da sednem za komp. Ovako sam sa telefona prosledjivala mail curama. Cim ugrabim vremena prekopiracu sve i ovde.
Pusti i meni mail na daki_mm@yahoo.com
Pa ti si sjajna
daki_mm- Broj poruka : 123
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Location : Lapovo
Datum upisa : 26.12.2013
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