ivfminar

Doctors and medical staff, in this new digital and social media era, must understand and empathize their patients and spend enough time to clarify issues presented on the internet.

The widespread use of internet research engines and social media have profoundly changed the way patients manage medical issues and interact with medical professionals. Most patients, as avid users of the internet and social media, presenting with a medical problem or question, instantly “google” everything related to what they think of, including doctors and medical facilities. They retrieve an enormous volume of scattered and mostly irrelevant information about terms, diseases, treatments, medical doctors and clinics around the world. These data are costless, but come with a number of automatically appearing digital advertisements with carefully hidden “precious” information, offering unbeatable solutions or perfect treatments for any problem. Patients are not aware or forget that typing terms free of charge on the internet instantly activates algorithms that directs to paid advertisements to your screen, and may also collect information about your current thoughts, problems, sentiments, and choices. Social media follows delivering pictures, information and opinions relevant to your questions. The most likely result, after this data cataclysm, is that our anxious patient will be misinformed and misleaded. Practically speaking, our patient will have very few chances to navigate through the internet to reach a meaningful conclusion.

            However, the internet is a revolutionary progress of mankind that democratizes data, connects people and offers significant help and convenience for medical issues. Professionals can verify the information, but an uneasy patient has no tools and abilities to understand and evaluate it.

Doctors and medical staff, in this new digital and social media era, must understand and empathize their patients and spend enough time to clarify issues presented on the internet.

General rules must be deployed such as knowing who posts the data, whether it comes from institution or an unidentifiable post, whether there are names, addresses, or if there is reliable information about those who post. We ought to doubt and even match the data with similar information, and question if the information is reasonable or “too good to be true”? The biggest challenge today is how to get the best from the digital world and avoid being deceived.

            Patients coming to our office spend most of the time wanting to discuss questions about their digital research, analyzing fancy treatments and procedures that cure everything rather than focus on their presented problems.

Infertility and IVF treatments seem to be a good substrate for misinformation since, normally, few treatments are evidence-based and the IVF success has a significant factor of randomness.

Therefore, medical staff must be updated as to what the “google” searches and social media currently address about relevant medical questions, and be prepared with the proper arguments to persuade patients asserting their professional view. In our times, a new medication or treatment is first released to digital and social media, and then to scientific peer-reviewed journals. Infertility and IVF treatments seem to be a good substrate for misinformation since, normally, few treatments are evidence-based and the IVF success has a significant factor of randomness. Patients easily mistrust scientific information, and tend to adapt strange medical beliefs, showing skepticism for scientific approaches and finally developing a broken patient-doctor relationship and trust.

            Doctors and medical staff, in this new digital and social media era, must understand and empathize their patients and spend enough time to clarify issues presented on the internet. Thus, in addition to providing proper scientific advises and treatments, doctors are also responsible for successfully guiding the patients through digital and social media misinformation, in order to deliver the best treatment for them with lower costs and the fewer side effects. The winner of this “battle” must be science and patients.

Endometrial receptivity is a pivotal “check point” in human reproduction. Even a competent, genetically normal embryo must encounter in proper time a functioning “window” to be implanted

            Embryo implantation is a complex multistep event that involves both the embryo and the endometrium, the internal lining of the uterus. It occurs within a strict time interval at the mid-luteal phase of a woman’s cycle, the so-called “window of implantation”.

 The status and the ability of the endometrium to allow and promote implantation is termed endometrial receptivity

The status and the ability of the endometrium to allow and promote implantation is termed endometrial receptivity. A normally developing embryo must encounter a receptive endometrium to attach and invade. In fact, the endometrium actually blocks embryos from implanting except during the period of the “window of implantation”. It is a barrier to pregnancy, but has an “opening” that a timely developed embryo must find and go through. It is possible that this “opening”, the “window of implantation”, may never occur or might be of very short duration, or occur very early or very late during the luteal phase or as a combination of these situations.  There is also the possibility that endometrial receptivity may be present but the embryo has not yet been appropriately developed, showing slow or fast development or carry some genetic abnormality affecting implantation. All above abnormalities may lead to implantation failure.

            Endometrial maturation and attainment of the endometrial receptivity depends on the existence of a growing follicle in a natural cycle or on the ovarian stimulation process in IVF, culminating with a luteinization event. They are driven mainly by the sequential actions of estrogen and progesterone. A series of interdependent molecular and cellular properly timed changes occur leading to the development of endometrial receptivity. These events and factors that affect receptivity are not yet well understood.

            IVF research has focused on ovarian stimulation, fertilization, embryo culture and embryo genetic analysis, aiming at optimization of embryo development and selection. In contrast, little research has been directed to the understanding of endometrial receptivity, and even less so on the diagnosis and treatment of its abnormalities. An implantation “bottleneck” has been observed regarding improvement of IVF outcomes. When interpreting a failed IVF cycle with the couple we are unable to clarify if the implantation failure is based on embryonic factors, endometrial receptivity or both.

When interpreting a failed IVF cycle with the couple we are unable to clarify if the implantation failure is based on embryonic factors, endometrial receptivity or both.

            As yet, there are no practical clinically useful markers, or tests to identify endometrial receptivity abnormalities. Furthermore, there is no evidence – based intervention to correct them and to yield more pregnancies. In most cases, only empirical observations may drive to some empirical interventions. Within this context, for several years in our IVF practice we have identified a group of women that systematically showing failed IVF cycles in different IVF clinics, having transferred embryos graded as good and very good. For these cases, a hypothesis was made that abnormal endometrial receptivity could be the cause of failure. There is evidence that in some women the ovarian stimulation in IVF, specifically high responders, may be associated with endometrial receptivity defects, while endometrial receptivity is better in natural cycles or artificial cycles with exogenous estrogens and progesterone. We therefore hypothesize that if we split the IVF cycle by freezing all embryos and then transferring thawed embryos in a subsequent natural or artificial cycle we might increase implantation and pregnancy rates possibly having improved endometrial receptivity. This strategy has showed satisfactory results since implantation rates were restored to that of women of similar age.

if we split the IVF cycle by freezing all embryos and then transferring thawed embryos in a subsequent natural or artificial cycle we might increase implantation and pregnancy rates possibly having improved endometrial receptivity

            Recently, studies have tested this freeze all strategy to unselected IVF cases and has showed no differences in pregnancy rates. It must be pointed out that endometrial receptivity abnormalities are expected to be the cause of IVF failure only in few, selected cases. In these women, specifically with embryos graded as good and very good, the freeze all embryo with transfer in natural or artificial cycle strategy might offer substantial help. The above strategy could offer these women the only chance for successful implantation. Splitting the IVF cycle in certain subgroups of patients might be a useful tool to overcome abnormalities in endometrial receptivity.

            Endometrial receptivity is a pivotal “check point” in human reproduction. Even a competent, genetically normal embryo must encounter in proper time a functioning “window” to be implanted. Practical and clinically useful markers and tests are necessary to be developed for early identification of abnormalities in endometrial receptivity, understanding its importance for successful implantation. Treatments must be also promptly introduced to further improve pregnancy rates.

Facing endometriosis cysts and fertility, a potential concession must be made between an ovarian surgery with a possible negative effect on ovarian reserve or continue suppression with OCs and an “unorthodox” management with an “emergency” IVF

The presence of ovarian endometriosis cysts poses a major dilemma in decision – making analyses regarding subfertility and assisted reproduction. The main reason is that at the time of infertility workup we commonly identify women with a history of ovarian surgery for endometriotic cysts also presenting with premature ovarian insufficiency, in some cases even nearing menopause, if the cysts were bilateral. From a clinical perspective it is bewildering to associate the medical treatment of a common, benign and transient (up to menopause) disease with a decreased ovarian reserve to the point of curbing the probability of pregnancy. Therefore clinicians and patients when deciding towards ovarian surgery for endometriosis cysts should seriously take into consideration if the benefits of surgery override the long-term consequences on the ovarian reserve and the subsequent negative effects on fertility.

            Endometriosis is a common disease in women with very broad and heterogeneous spectrum of manifestation. It either does not interfere or

It is bewildering to associate the medical treatment of a common, benign and transient disease with a decreased ovarian reserve

interferes  partly  with various grades during the reproduction process, and finally recedes at menopause. There is no evidence showing that “treatments” such as surgery, cautery and medical castration positively influences assisted reproduction outcome. The clinical variability and heterogeneity of endometriosis has made most related scientific papers of low quality with very little evidence-based information.

            A holistic strategy must be developed for the management of endometriosis cysts. It is best to be identified as early as possible and promptly begin administration of  oral contraceptives (OC) as a hold on the cyst expansion and a suppression of endometriosis is anticipated. That seems to be the best management strategy until the consideration for pregnancy. At that time, the option of an “emergency” IVF can be introduced and discussed with the couple, even if it may seem illogical and unfair to proceed with an IVF cycle before any significant exposure to pregnancy.

            The concept is to have a successful IVF cycle relatively immediately after OCs treatment without undergoing ovarian surgery. It is possible that stopping the OCs to attempt pregnancy might once again aggravate endometriosis and restart cyst growth. During ovarian stimulation we observe that the thin ovarian tissue around the endometriosis cysts contain the growing follicles. That tissue can easily damaged if operated at surgery. In the case of a failed IVF cycle, OCs should be restarted immediately. Interestingly, in the case of a full term pregnancy nearly all cysts tend to subside, even disappear. Pregnancy can be considered a strong treatment force for endometriosis.

            To further assist in decision-making regarding the management of ovarian endometriosis cysts, an antimullerian hormone (AMH) test must be done, as a measure to provide an estimation of the ovarian reserve. This is necessary since there is increasing evidence that behind endometriosis lays a coexisting premature ovarian insufficiency. This is not yet confirmed but

A low AMH coexisting with endometriosis cysts and infertility provides a strong rationale for avoiding surgery and deciding towards “emergency” IVF

frequently both endometriosis and low ovarian reserve are in the same clinical picture. It may be possible that endometriosis per se can interfere in some ways with changes in the ovarian reserve. Ovarian surgery therefore will further decrease ovarian reseve. A low AMH coexisting with endometriosis cysts and infertility provides a strong rationale for avoiding surgery and deciding towards “emergency” IVF.

            Facing endometriosis cysts and fertility, a potential concession must be made between an ovarian surgery with a possible negative effect on ovarian reserve or continue suppression with OCs and an “unorthodox” management with an “emergency” IVF. If there is no oncologic reason for surgery we advocate an “emergency” IVF. The benefit can be eggs to become babies and recession of endometriosis cysts after birth. An ovarian surgery will reduce available eggs, even brings menopause, if cysts are bilateral. However, the idea to try IVF without unsuccessful efforts for pregnancy is also difficult to communicate with couples, particularly since this is a strategic management and is not yet supported by properly designed randomized trials.

        Most modern women in their thirties and forties are full of energy, with personal and career ambitions and suddenly might be informed that their reproduction time is limited, and they must rethink all personal, social and working plans.

At birth, a certain number of eggs are embedded in a  women’s ovaries. Thereafter, a few of these are consumed in each menstrual cycle and by menopause that egg pool becomes depleted. Therefore a women’s reproductive life is directly related to the availability of eggs. This, so called ovarian reserve, gradually declines and physiologically zeros at menopause, the median time of which is around 50 years. An indicator of the ovarian reserve is serum AMH, a hormone that is produced by cells from small ovarian antral follicles.

          The ovarian reserve can be low from the beginning at birth, or begin to decrease at faster rate at any time during reproductive life, or may decrease to reach a plateau for a period of time, and then decrease again, or decrease rapidly approaching early menopause. Such impacts can be summarized under the term Premature Ovarian Insufficiency (POI). This might be the most shocking information for women at reproductive age without children yet.

Premature Ovarian Insufficiency might be the most shocking information for women at reproductive age without children yet.

Women usually are not aware about their ovarian condition. A discussion about low AMH and POI initiates anxiety, even anger and sense of helplessness. Today most modern women in their thirties and forties are full of energy, with personal and career ambitions and suddenly might be informed that their reproduction time is limited, and they must rethink all personal, social and working plans.

          The etiology of POI is variable and heterogeneous. It can be due to genetic and hereditary factors, environmental factors, a virus infection, endometriosis, ovarian surgery, radiotherapy, chemotherapy, and even unknown factors, or sometimes a combination of factors. As we know, the major destruction of ovarian eggs happens at fetal life about 20-25 weeks of gestation. Therefore, is unusual to identify precisely the cause of POI.

          A campaign must be initiated for all women to be aware of important issues such as low ovarian reserve and POI, and their role in reproduction. It is critical that these conditions are explored well before the time of diagnosis. Being informed of this complex and unpleasant condition at that late stage can be very emotional, and decision options become limited and harder to make.

          It is wise that women from early on are educated about he importance of subtle menstrual cycle changes associated with POI. These might be a gradual decrease of menstruation volume, a shortening of cycle duration, frequent presence of ovarian functional cysts, and low counts of antral follicles observed by vaginal ultrasound. All women must inform themselves of the time of menopause of their mother, sisters and other maternal females relatives. In case of an ovarian surgery women must extensively discuss the possible consequences on the ovarian reserve, and apply an appropriate cost – benefit analysis regarding reproductive options.

A low AMH is definitely an alarm that forces women to reconsider social, personal and family plans to succefully confront POI

          The encounter with a low AMH is not the end of the world. It does not mean that a woman cannot have a baby. In most cases the cause or the course of POI is not known. Maternal age weighs as the most significant factor. A low AMH is definitely an alarm that forces women to reconsider social, personal and family plans to succefully confront POI. After the initial surprise and anger, an acceptance of the new situation must lead to a solution plan.

          Another subtle issue is that the male partners, most of the time, seem reluctant to understand fundamentals of female reproduction and empathize, particularly in the situation of POI. It is difficult for them to realize that women have a certain time period for reproduction which coincides and interferes with personal, social and professional ambitions, and that in some cases this time period can suddenly be far shorter.

          Taking all these into consideration, a case of POI is a complex and very emotional issue. Ideally, educational tools should be available early on to understand female reproductive dynamics. Discussion and management must embrace all reproductive alternatives and consultation must involve women and their partners.

Factors that are related to IVF outcome can be grouped as laboratory factors, human factors and genetic recombination

IVF clinics are organized, wish and work, to have positive results and healthy live births. This is a pursuit in which most times  result in stress, anxiety and obsession for both the clinics and patients. Everyone involved in the IVF process is constantly thinking of what to do more in order to have the desirable result. In the case of a positive result nobody asks why, but in the case of a negative result, cascade of questions surface: why did that occur? Are more tests necessary? Can we modify the treatment so that might not happen again? Patients desire 100% success, but this is “unnatural” for human reproduction

          To begin with, IVF is a multifactorial, multistep process that involves humans, nature, laboratory and equipment. We try to mimic natural human reproduction in the IVF lab. Yet, how can we control, affect, reproduce and explain every outcome?

In running an IVF clinic, all technical, laboratory factors and procedures must be flawlessly executed

          Paradoxically, IVF is also a chain event. One mistake in a point of the process negatively affects the whole procedure, even if all other steps executed correctly. Lets take an example: all steps have gone well, but a misstep during the embryo transfer compromises the results significantly. In another, all steps are executed correctly, but the embryos are genetically abnormal, and thus destined to negative results. Choosing a protocol for ovarian stimulation might increase the chances for premature luteinization, yet may compromise endometrial receptivity, even though all other steps are optimally executed.

          Factors that are related to IVF outcome can be grouped as laboratory factors, human factors and genetic recombination. Regarding the laboratory factors, quality control procedures have been broadly employed aiming to significantly reduce any missteps and glitches during IVF. Most IVF clinics are operated under extensive and strict ISO certified procedures. The goal is to reach near zero mistakes and minimize variability in these steps, and I believe there is success in that.

          Human factors, as related to clinicians and embryologists, can contribute to a significant variability. Education, training and strict protocols can eliminate much of this variability. But it is very difficult to standardize human performances. Each case of IVF could be monitored and executed by the same IVF specialist and the same embryologist. However, these logistics are difficult to be implemented in busy units.

Each case of IVF could be monitored and executed by the same IVF specialist and the same embryologist.

          Genetic recombination is characterized by variability and randomness, which is entirely out of our ability to be controlled. We know that both these elements increase as a woman’s age increases. Yet, we have no treatments to decrease genetic mistakes at the time of oocyte meiosis, fertilization and early embryo development. The only means we have is to consider maternal age quite seriously and consistently communicate this to society, and planning infertility treatments without time delay.

          It seems that in running an IVF clinic, all technical, laboratory factors and procedures must be executed flawlessly. In addition, any new methods that by evidence–based criteria improve outcomes must be implemented thoroughly. Efforts must be focused on decreasing human induced variability. These include encouraging moderate sized IVF units or segmentation of larger IVF units into separate working areas so that a single physician, a single embryologist and standardized equipment is involved in each case. These ideas however, must be tested thoroughly in a randomized way. Strict monitoring of all possible factors involved in IVF, including human staff performance, digitized in a model of multiple regression analysis, can be helpful in early detection of biases. Patients and clinicians must also properly acknowledge and respect the limitations of genetic recombination. A failure therefore could be expected and an IVF retrial thus will be emotionally manageable.

          Hopefully, in the future we will be able to develop methods and logistics to decrease human induced variability in the IVF procedures. Also, it will be revolutionary if we could device treatments and methods to safely decrease the genetic errors around the period of egg fertilization. These are necessary future steps that will increase significantly IVF success.

There are not yet randomized controlled studies that support the claim that PGS improves IVF outcome, particularly when outcome analysis have as reference point the cycle start.

It is well understood that the gradual decline in human natural and assisted reproduction fecundity, after the age of 35, is based on the relative gradual increase of embryo genetic abnormalities. The “natural” experiment of egg donation from donors younger than 35y characteristically depicts that fecundity rate depends on oocyte age, and can remain steadily stable at any age of embryo recipient.

            These observations have led to an attractively reasonable hypothesis that if we can eliminate aneuploid embryos and transfer only euploid ones, we could improve IVF outcome, particularly in older women. This is the pivotal assumption behind the application of preimplantation genetic screening (PGS) as an add–on in IVF procedures. Although this is a very simple and logical hypothesis, when discussing with couples at an IVF decision making analysis or commenting on a failed IVF cycle, on a clinical level, it is quite complicated to be communicated, as it assumes many scientific uncertainties, still unproven at a randomized clinical trial level.

            PGS following a standard IVF procedure involves many additional steps, including blastocyst culture, embryo biopsy of the outer embryonic cell mass, complicated total chromosomal number analysis in a specialized genetic lab. Meanwhile, all those blastocysts must be vitrified. Then, only those with a normal set of chromosomes, if any, are thawed and must survive in order to be transferred in a natural or artificial cycle. Therefore PGS increases the steps from egg retrieval to embryo transfer, which logically increases the probabilities for missteps and mishandling each procedure and dramatically increases the cost of the IVF. A true cost benefit analysis has not yet been seen.

 Exaggerated claims of better IVF outcomes can easily generate more and persistent negative feelings

As more data about PGS is accumulated, we will address, as simply as possible, some issues regarding clinical utility of modern PGS. These are:

1. Biopsies are done on the external cell mass of the blastocyst which is dedicated for placental development, while the internal cell mass is destined for embryo formation. Nature very frequently has euploid and aneuploid cells mixed together in a term called mosaicism. Finding aneuploid cells in the external cell mass of the blastocyst, particularly at only one biopsy, does not for certain reflect that the embryo will be abnormal. Therefor we might wrongly rejected as abnormal a potentially euploid embryo.

2. Studies of multiple blastocyst biopsies have demonstrated divergence of ploidy results between multiple biopsies of the same embryo at the same laboratories, and even higher divergence between biopsies in different laboratories.

3. Another interesting feature of the embryo is its ability to self-correct as it grows beyond the blastocyst stage, meaning that the euploid cell lines may become prevalent and result in development of a genetically normal embryo.

4. Biopsy of a large number of cells of the blastocyst might impair its ability for implantation.

Risks and benefits must extensively communicate with our patients regardless of the puzzling nature of this intervention

            Advances in biotechnology are very exiting. In our time, PGS is a complicated and quite expensive add-on of the IVF procedure, not showing a clear benefit for our patients, but evidence that it may be harmful in terms of live births rate per cycle initiated. Risks and benefits must extensively be communicated with our patients regardless of the puzzling nature of this intervention. We should not forget that nature eliminates the genetically abnormal embryos by either not implanting or aborting early-on. The emotional load of infertility, specifically for poor prognosis patients, can be better confronted by repeated consultations and counseling, aiming to better serve our patients interests. Exaggerated claims of better IVF outcomes can easily generate more and persistent negative feelings. The likelihood of PGS evolution in terms of precision and accuracy may be clinically useful in the future.